EA043393B1 - REPLACEMENT OF CYTOTOXIC PRECONDITIONING BEFORE CELLULAR IMMUNOTHERAPY - Google Patents

Description

Cross references to related applications

This patent application claims priority to US Provisional Application No. 62/480414, filed April 1, 2017, US Provisional Application No. 62/613697, filed January 4, 2018, and US Provisional Application No. 62/624454, filed January 31, 2018. g., each of which is incorporated herein by reference in its entirety.

Field of technology to which the invention relates

The technical field of the invention relates to compositions and methods, including novel dosage regimens, that enhance short-term and long-term killing of tumors and pathogens through cellular immunotherapy by maintaining the cellular immunotherapy in the bloodstream or injection site for extended periods of time without the need for cytotoxic preconditioning. The field of technology to which the invention relates further enhances the long-term engraftment of cellular immunotherapy.

BACKGROUND OF THE INVENTION

Cellular immunotherapy must remain in the bloodstream or injection site for long periods of time to effectively target and participate in the destruction of cancerous or autoimmune activated cells or infectious agents. Unfortunately, cellular immunotherapy disappears quickly, usually within one hour after injection, from the bloodstream or injection site unless preconditioned with cytotoxic chemotherapy or radiation therapy (Muranski Nat Clin Pract Oncol. 2006 December; 3(12): 668- 681; Kalos M et al. Sci Transl Med. Aug 10;3(95) (2011); Rosenberg et al., Clin. Cancer. Res. (2011)). The prevailing thought has been that preconditioning improves the effectiveness of adoptive cell transfer or therapy (ACT) by eliminating Tregs and competing elements of the immune system called cytokine sinks, which will use the cytokines needed for optimal activation of ACT (Muranski Nat Clin Pract Oncol. 2006 December; 3(12): 668-681 page 2 paragraph 3, page 4 paragraph 4; US 9,855,298 B2 Jan/2018, bottom of page 29, Detailed description of the invention, first paragraph). Several investigators have noted that cellular immunotherapy binds and accumulates rapidly in the lungs, liver, spleen, and secondary lymphoid organs (Kershaw MH et al. Clin Cancer Res. Oct 15;12(20 Pt 1):6106-15 (2006)); (Ritchie DS et al. Mol Ther. Nov, 21(11):2122-9 (2013); (Cheadle J Immunol April 15, 2014, 192 (8) 3654-3665) Kershaw concluded that the cell-based immunotherapy signal in the lungs and spleen was caused by the cells being adherent and non-selectively trapped (p. 6114, paragraph 3), while Cheadle concluded that the accumulation in the spleen observed in mice was chronic toxicity manifesting as granuloma formation (p. 3654, abstract).

Because of the toxicity associated with chemotherapy or radiation, and the contribution of chemotherapy to neuroedema and cytokine release syndrome after ACT, there is a need to develop safer and less cytotoxic methods to precondition patients to allow cellular immunotherapies to remain in the bloodstream or injection site in over long periods of time.

Although chemotherapy and radiation therapy have often been used to precondition patients before ACT, most leading authorities in the field state that steroids or other immunosuppressive drugs are specifically avoided at least 3 days before NK administration (Klingemann H, Transfusion. 2013 Feb; 53(2):412-8 p. 3, Study Design, paragraph 3), and in clinical trials of adoptive cell therapy, the use of steroids is usually an exclusion criterion for patient enrollment. For example, see exclusion criterion #2 of the ACTIVATE clinical trial, which specifically excludes systemic steroid or other immunosuppressive therapy within 7 days of ACT, which in this clinical trial are autologous tumor infiltrating lymphocytes that have been expanded in culture (clinical trial identifier : NCT03158935 - current online address: https://clinicaltrials.gov/ct2/show/NCT03158935). Also see US9855298 1/2018 (Bot et al), in which example 3 exclusion criteria p, column 54, specifically excludes patients from ACT treatment if they have a current or anticipated need for systemic corticosteroid therapy. This demonstrates that it was believed in the art that corticosteroids were harmful prior to ACT and did not involve preconditioning with glucocorticoids immediately prior to ACT, as described in this patent application. Although US2013/0287748 A1 10/2013 (June et al) in paragraph 0227 discloses In other embodiments, the T cells of the invention [claimed in US2013/0287748 A1] can be used in combination with chemotherapy, radiation, immunosuppressants, such as cyclosporine, azathioprine, methotrexate, mycophenolate and FK506, antibodies or other immunoablative agents such as PATH CAM, anti-CD3 antibodies or other antibody therapies, cytoxin, fludaribine, cyclosporine, FK506, rapamycin, mycophenolic acid, steroids, FR901228, cytokines and irradiation. These drugs inhibit either the calcium-dependent phosphatase calcineurin (cyclosporine and FK506) or inhibit the p70S6 kinase, which is important for growth factor-induced signaling (rapamycin) (Liu et al., Cell 66:807-815, 1991; Henderson et al. al., Immun. 73:316-321, 1991; Bierer et al., Curr. Opin. Immun. 5: 763-773, 1993), June does not explain whether the use of

- 1 043393 listed agents in combination with a disclosed T-cell therapy for prior, simultaneous or subsequent use, for example, to relieve symptoms. Pre-conditioning is not offered.

June mentions Liu, who used cyclosporine, FK506, and rapamycin at concentrations of 300 nM, and Henderson, who used concentrations of about 100 nM, which corresponds to low in vivo doses, below 0.05 mg/kg.

Previous studies of the use of steroids to precondition the patient prior to ACT have shown that this approach is ineffective. Hinrichs (J Immunother. 2005 Nov-Dec; 28(6):51724.) evaluated dexamethasone as a preconditioning treatment before ACT. When compared with total body irradiation (TBI), Hinrichs demonstrated that HED 0.8 mg/kg administered on day -6, day -4 and day -2 lymphodepleted the equivalent of 5 Gy TBI. Hinrichs demonstrates that pretreatment with systemic intraperitoneal dexamethasone at 10 mg/kg (0.81 mg/kg HED) on days -6, -4, and -2 before ACT caused equivalent lymphodepletion compared with radiation, but this pretreatment did not enhance destruction of the tumor through ACT. In contrast, Hinrichs reveals that radiation pretreatment actually enhances tumor killing by ACT. The Hinrichs article reported that dexamethasone caused lymphodepletion, as evidenced by a 99% reduction in spleen cell content. However, although Hinrichs reported 99% lymphodepletion, no enhancement of tumor killing was observed with ACT. Hinrichs, on the other hand, observed that radiation actually helps kill ACT tumors. Repeat lymphodepletion experiments reported by Hinrichs show that Hinrichs doses of 10 mg/kg intraperitoneal dexamethasone (HED 0.81 mg/kg) on day -6, day -4 and day -2 do not effectively lymphodeplete peripheral blood lymphocytes. With Hinrichs dosing, only peripheral blood B cells were significantly lymphodepleted, from 10,680 (vehicle control) to 3,733 live events measured by flow cytometry of CD3-CD19+ cells, representing a 65% reduction. In contrast, the CD3+ T cell count decreased from 3370 to 2441 live events, representing only a minor decrease of 33%. The CD3+ CD4+ T cell count decreased from 1779 to 902 live events, representing only a slight decrease of 50%. The CD3+ CD8_ T cell count decreased from 1318 to 1277 live events, representing only a minor decrease of 3%. The number of CD3+CD4+CD25+FoxP3+ Tregs decreased from 198 to 70 live events, representing only a minor decrease of 65%. The number of natural killer (NK) cells decreased from 1153 to 958 live events, representing only a slight decrease of 17%.

In some studies, patients were preconditioned with a chemotherapy agent administered in combination with dexamethasone. For example, Shi et al. (Br J Haematol. 2008 Dec;143(5):641-53.) preconditioned relapsed multiple myeloma with fludarabine (FLU, 25 mg/m ² from day -5 to day -2), and dexamethasone (DEX, 40 mg/m days from day -5 to day 2). This dose of dexamethasone corresponds to about 1.14 to 1.6 mg/kg in the 72 hours before ACT administration. Lymphodepletion was complete, as shown in Fig. in 5 Shi et al., with a decrease in absolute WBC from 10.9e9/L to 0.7e9/L, representing a 94% reduction. Shi et al did not suggest the use of higher doses of dexamethasone. Cell Therapy Catapult preconditioned patients with fludarabine x 5 days 30 mg/ ^m2 intravenously (IV) and methylprednisolone x 1 day 500 mg (IV) for their phase I/II WT1 TCR gene-modified therapy study in patients with MDS and AML (https: //clinicaltrials.gov/ct2/show/NCT02550535). This dose of methylprednisolone corresponds to a 100 mg dose of dexamethasone, which is about 1.4 to 2 mg/kg. Additionally, the Shi publication and the Cell Therapy Catapult study performed preconditioning with repeated doses of chemotherapy. In addition, methylprednisone increases the number of Tregs, which is an undesirable response in cancer patients because Tregs limit tumor killing by T cells (Braitch Acta Neurol Scand. 2009 Apr; 119(4): 239-245; Mathian PLoS One. 2015; 10( 12): 0143689).

Because of the toxicity associated with chemotherapy or radiation and the contribution of cytotoxic preconditioning to neuroedema syndrome and cytokine release following ACT, safer and less cytotoxic methods need to be developed to precondition patients to allow cellular immunotherapy to remain in the bloodstream or injection site in over long periods of time.

The essence of the invention

The present inventors have shown that accumulation of cellular immunotherapy in the spleen is a specific binding event, in contrast to the previous view discussed above that accumulation in the spleen was due to non-selective sequestration. The present inventors believe that known methods based on chemotherapy and radiation therapy non-selectively destroy spleen cell abundance, maintaining the administered cellular immunotherapies in the bloodstream or at the injection site for extended periods of time and improving patient outcome.

This patent application shows that non-chemotherapeutic agents such as glucocorticoids and other non-toxic lymphodepleting agents

- 2 043393

NTLA) can be used to make cellular immunotherapy more effective without the need for chemotherapy (or at least can reduce the need for chemotherapy to one day of chemotherapy treatment). For example, the present application shows that acute doses of dexamethasone, typically from about 300 to about 840 mg, can be very effective. In particular, the present invention discloses the benefit for cancer patients of pre-treatment of the patient with a steroid, such as dexamethasone, shortly before the administration of cellular immunotherapy.

Thus, the present invention satisfies the need to replace preconditioning with chemotherapy and radiotherapy by providing methods and compositions for inhibiting the binding of cellular immunotherapies to lymphoid tissue, comprising administering the cellular immunotherapies to an individual in combination with a therapeutic agent or agents that inhibit the binding of cellular immunotherapies to lymphoid tissue, in particular , germinal centers and marginal zones in the lymph nodes and germinal centers and marginal zones in the spleen. The therapeutic agent or agents also lymphodeplete peripheral blood lymphocytes through a biological rather than a cytotoxic mechanism. The term in combination with may mean before and/or together with and/or after cellular immunotherapy.

Accordingly, in a first aspect, the present invention relates to a method of enhancing adoptive cell therapy (ACT) in a patient by administering to the patient a non-toxic lymphodepleting agent (NTLA) at a dose that is effective to cause significant lymphodepletion and/or cause ablation of germinal centers of secondary lymphoid organs wherein the method does not include administering radiation therapy or administering a chemotherapy agent for more than 1 day in the approximately 2 weeks preceding the initiation of ACT.

In a second aspect, the present invention provides NTLA for use in a method of enhancing adoptive cell therapy (ACT) in a patient, the method comprising administering to the patient a dose of NTLA that is effective to cause significant lymphodepletion and/or cause removal of germinal centers of secondary lymphoid organs, wherein the method does not involve administering a chemotherapeutic agent for 1 day or more.

In a third aspect, the present invention provides a method of administering adoptive cell therapy (ACT) to a patient in need thereof, the method comprising performing a method of enhancing ACT by pre-treating the patient in accordance with the invention; and then performing ACT by administering therapeutic cells to the patient. In some embodiments, NTLA is a steroid. The steroid may be a glucocorticoid. In some embodiments, the steroid is selected from the group consisting of dexamethasone, dexamethasone base, prednisone, methylprednisone, and dexamethasone analogues. In other embodiments, the NTLA is selected from the group consisting of tacrolimus and cyclosporine.

In some embodiments, a dose of NTLA results in at least 60% CD3+ lymphodepletion. Preferably, the dose results in at least 70%, at least 80%, or at least 90% lymphodepletion. In preferred embodiments, the ACT comprises administering either a cell used to enhance the immune system to treat a disease in said patient, or a cell derived from an immune line that directly treats the disease.

In embodiments in which the NTLA is dexamethasone, the dexamethasone can be administered at a dose of at least about 3 mg/kg, at least about 4 mg/kg, at least about 5 mg/kg, at least about 6 mg /kg, at least about 7 mg/kg, at least about 8 mg/kg, at least about 9 mg/kg, at least about 10 mg/kg, at least about 11 mg/kg, at least at least about 12 mg/kg, at least about 13 mg/kg, at least about 14 mg/kg, at least about 15 mg/kg, at least about 16 mg/kg, at least about 17 mg/kg kg, at least about 18 mg/kg, at least about 19 mg/kg, at least about 20 mg/kg, at least about 21 mg/kg, at least about 22 mg/kg, at least about 23 mg/kg, at least about 24 mg/kg, at least about 25 mg/kg, or at least about 26 mg/kg. The dose of NTLA dexamethasone may be selected from a range limited by the dosage range of dexamethasone as described herein, for example, in this paragraph. For example, NTLA dexamethasone can be expressed as being administered at a dose selected in the range of about 9 to about 12 mg/kg. In some embodiments, dexamethasone can be administered at a dose of up to about 26 mg/kg.

Preferably, NTLA is administered before the start of ACT. NTLA can be administered at least 12 hours before the start of ACT. NTLA can be administered at one or more time points from about 72 to about 12 hours before the start of ACT.

In a fourth aspect, the present invention provides a method for improving the binding and accumulation of cellular immunotherapy at binding sites in secondary lymphoid organs, comprising: identifying a patient suffering from cancer; administering to said patient a cellular immunotherapy comprising either a cell used to enhance the immune system in treating said cancer or a cell derived from an immune line that directly treats said cancer; and administration of a non-toxic lymphodepleting agent (NTLA), which depletes and removes tissue

- 3 043393 binding sites in secondary lymphoid organs, where the specified cellular immunotherapy binds and accumulates, and is selected from the group consisting of tacrolimus, delivered by injection or oral dose of 0.48 mg/kg to 10 mg/kg for about 1- 4 weeks, cyclosporine administered at about 15-100 mg/kg/day or about 7.5-50 mg/kg/bid for about 7-28 days, dexamethasone base or an equivalent dose of another glucocorticoid, from about 3 to 26 mg/kg for a single acute dose over about 12 to 72 hours, and a TNF inhibitor that is administered over about 3 to about 4 weeks; wherein the administration of NTLA occurs prior to the administration of said cellular immunotherapy, for example, to enhance the binding and accumulation of said cellular immunotherapy at binding sites in secondary lymphoid organs.

In preferred embodiments of the aspects described herein, the patient is a human. NTLA can be administered at least 12 hours before the start of ACT. In some embodiments, NTLA is administered for about 72 hours before the start of ACT. In some embodiments, ACT includes administering anti-tumor T cells and/or anti-tumor NK cells to a patient. In preferred embodiments, the cells administered for ACT include T cells. ACT can be an adoptive T-cell therapy. Preferably, the method does not involve administering radiation therapy or administering a chemotherapy agent for more than 1 day within about 2 weeks prior to the start of ACT. In some embodiments, the patient is not receiving radiation therapy or chemotherapeutic agents. In some embodiments, NTLA induces an increase in the plasma level of one or more cytokines in the patient, selected from the group consisting of IL-2, IL-7, IL-12 and IL-15, to levels preferably 20 pg/ml or greater. NTLA may not affect IL-6 levels.

Enhancing ACT may involve enhancing cancer killing in a cancer patient or reducing the number of cells that cause autoimmune diseases in a patient with an autoimmune disorder or reducing the infectious agent load in a patient with an infectious disease.

Preferably, NTLA is administered before the start of ACT. For example, NTLA can be administered at least 12 hours before the start of ACT or at another interval before ACT, as described herein. In some embodiments, NTLA is administered at one or more time points from about 12 to about 72 hours before the start of ACT.

In some embodiments of the present invention, a method according to any of the preceding claims, wherein the ACT is an adoptive T cell therapy, for example, based on the transfusion of CAR T cells. In some embodiments, the patient is a cancer patient and the ACT includes administering anti-tumor T cells and/or anti-tumor NK cells.

ACT may be based on autologous cells (ie, cells that have been collected from the patient, before optional modification or stimulation before transfer/reintroduction) or heterologous (ie, cells or cell lines derived from a different donor).

In some embodiments of the present invention, chemotherapeutic agents are not administered to the patient.

A non-toxic lymphodepleting therapeutic agent, is an agent that causes lymphodepletion and inhibits germinal centers in the spleen without killing other rapidly dividing cells such as hair cells, mucosal cells, intestinal cells, and which does not cause sepsis, organ dysfunction, capillary leakage, myocarditis, lethal inflammatory syndrome, fatal infusion reactions or subsequent new cancers.

The non-toxic lymphodepleting therapeutic agent can be administered without cytotoxic preconditioning or in combination with cytotoxic preconditioning. In combination with means administration before and/or together with and/or after cytotoxic lymphodepleting chemotherapy, preferably only with a one-day administration of cytotoxic chemotherapy. The addition of a nontoxic lymphodepleting therapy may reduce the total dose or required duration of cytotoxic lymphodepleting chemotherapy to reduce side effects and toxicity to the patient. The non-toxic lymphodepleting therapeutic agent can also be administered in combination with other cytotoxic preconditioning drugs, which include rituximab and similar molecules that bind lymphocytes and induce antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated cytotoxicity (CMC) in combination with temodar, in combination with interleukins or toll-like receptor agonists, which can activate endogenous cytotoxic pathways, in combination with radiolabeled antibodies that trigger the destruction of immune cells (immunotoxins), such as anti-CD45 antibodies, such as Iomab-B, or in combination with total irradiation whole body (TBI).

Brief description of the figures

Fig. 1: Acute high dose Dex eliminates AST binding niches in mouse spleen and secondary lymphoid organs. Black-and-white immunofluorescence images of fresh thick sections of spleen stained with FITC-PNA to quantify germinal centers in mice receiving IP control placebo and from mice IP treated with HED 9.3 mg/kg dexamethasone base 96 h before collection spleen. The graph shows bar charts of the average quantity

- 4,043,393 germ cells per spleen area plus standard error of the mean (SEM).

Fig. 2: Acute high-dose Dex dose-dependently eliminates ACT binding niches in the mouse spleen. Shown is a bar graph graph of mean germinal center staining intensity measured using immunofluorescence staining of fresh thick sections of spleen stained with FITC-PNA. Immunofluorescence intensity was calculated using threshold analysis and MetaMorph image analysis. Columns represent means plus SEM. Mice were administered placebo, 3 mg/kg dexamethasone base HED, 6 mg/kg dexamethasone base HED, 9 mg/kg dexamethasone base HED, or 12 mg/kg dexamethasone base HED 48 h before spleen collection.

Fig. 3: Acute high dose Dex eliminates AST binding niches in rat spleen (MZ: marginal zone). Bar graph of marginal zone widths measured on 5-micron spleen sections from rats treated intravenously or orally with placebo, 20 mg/kg (HED 3.23 mg/kg), 40 mg/kg (HED 6.45), or 80 mg /kg (HED 12.9 mg/kg) dexamethasone base 48 hours before spleen collection.

Fig. 4: Acute high dose Dex eliminates AST binding niches in rat spleen. Shown is a bar graph plot of area per spleen, which represents BCL-6 staining of 5-μm fixed spleen sections as an indicator of the number of germinal centers, given as the average per section. Rats were intravenously or orally treated with placebo, 20 mg/kg (HED 3.23 mg/kg), 40 mg/kg (HED 6.45), or 80 mg/kg (HED 12.9 mg/kg) dexamethasone bases for 48 h before collecting the spleen.

Fig. 5: Acute high dose of Dex reduces rat lymphocyte count. Shown are graphs of individual absolute lymphocyte counts and mean values, measured by complete blood chemistry, 48 hours after intravenous or oral administration of placebo, 20 mg/kg (HED 3.23 mg/kg), 40 mg/kg (HED 6) to rats. ,45) or 80 mg/kg (HED 12.9 mg/kg) dexamethasone base.

Fig. 6: Acute high dose Dex does not reduce neutrophil counts in rats. Presented are graphs of the numbers and mean values of individual absolute neutrophils, measured by full blood chemistry, 48 hours after intravenous or oral administration of placebo, 20 mg/kg (HED 3.23 mg/kg), 40 mg/kg (HED 6, 45) or 80 mg/kg (HED 12.9 mg/kg) dexamethasone base. Data in Fig. 3, 4, 5 and 6 were obtained on the same rats.

Fig. 7: Acute high dose Dex reduces CD3 and CD4 positive lymphocytes in mouse (Dexamethasone (AVM0703) doses shown as HED). Plots of individual CD3+ and CD4+ lymphocytes and means measured by flow cytometry as relative values and normalized to relative absolute values using full blood chemistry at 48 h after RO mice were treated with placebo, HED 3 mg/kg, HED 6 mg/kg, HED 9 mg/kg, or HED 12 mg/kg dexamethasone base.

Fig. 8: Acute high dose Dex reduces CD8 positive lymphocytes and Tregs in mouse (dexamethasone (AVM0703) doses shown as HED). Shown are plots of individual CD8+ and Tregs and mean values measured by flow cytometry as relative measures and normalized to relative absolute measures using full blood chemistry at 48 h after RO mice were treated with placebo, HED 3 mg/kg , HED 6 mg/kg, HED 9 mg/kg, or HED 12 mg/kg dexamethasone base. Treg lymphocytes were identified as CD3+CD4+CD25+FoxP3+.

Fig. 9: Acute high dose Dex reduces murine NK cells and B cells (dexamethasone doses (AVM0703) shown as HED). Plots of individual natural killer (NK) cells and B cells and means measured by flow cytometry as relative scores and normalized to relative absolute scores using a complete blood chemistry panel, 48 h after mice received placebo. 3 mg/kg HED, 6 mg HED/kg, HED 9 mg/kg, or HED 12 mg/kg dexamethasone base. NK cells were identified as CD3-CD49b+. B cells were identified as CD3-B220+.

Fig. 10: Acute high doses of Dex reduce the absolute number of mouse lymphocytes while sparing neutrophils (dexamethasone doses (AVM0703) shown as HED). Plots of individual absolute neutrophils and total lymphocytes, and mean values measured by full blood chemistry, 48 hours after mice received placebo, HED 3 mg/kg, HED 6 mg/kg, HED 9 mg/kg, or HED 12 mg/kg dexamethasone base.

Fig. 11: Acute high-dose Dex of mouse red blood cell and platelet storage (dexamethasone doses (AVM0703) shown as HED). Plots of individual absolute red blood cell and platelet values and mean values measured by full blood chemistry 48 hours after mice were treated with placebo, 3 mg/kg HED, 6 mg/kg HED, 9 mg/kg HED, or 12 mg/kg HED. kg HED of dexamethasone base. Data in Fig. 8, fig. 9, fig. 10, fig. 11 were derived from the same cohorts of mice.

Fig. 12: Fifty percent (2 of 4) of human patients receiving 3 mg/kg dexamethasone base experienced depletion of CD3, CD4, and CD8-positive lymphocytes. Individual before and after treatment, 48 hours after oral administration of 3 mg/kg dexamethasone base four times a day

- 5 043393 patients, values and line graphs of CD3+, CD4+ and CD8+ lymphocytes measured using flow cytometry. Each patient's pre-treatment values are linked to post-treatment values by a connecting line. CD4+ cells are also CD3+. CD8+ cells are also CD3+.

Fig. 13: Twenty-five percent (1 of 4) of human patients receiving 3 mg/kg dexamethasone base experienced depletion of Tregs and B cells. Lines represent individual pre- and post-treatment, 48 hours after oral administration of 3 mg/kg dexamethasone base to four patients, Treg and B cell values and line graphs measured by flow cytometry. Each patient's pre-treatment values are linked to post-treatment values by a connecting line. Tregs are identified as CD3+CD4+CD25+FoxP3+. B lymphocytes are identified as CD3CD19+.

Fig. 14: Seventy-five percent (3 of 4) of people treated with 3mg/kg dexamethasone base experienced NK cell depletion while retaining hematopoietic stem cells. Lines represent individual pre- and post-treatment, 48 hours after oral administration of 3 mg/kg dexamethasone base to four patients, values and line plots of NK cells and hematopoietic stem cells (HSC) measured by flow cytometry. The pre-treatment values for each patient are linked to the post-treatment values by a connecting line. NK cells are identified as CD3-CD16/56+. HSCs are identified as CD34+CD38-.

Fig. 15: 100% of human patients receiving 3 mg/kg dexamethasone base demonstrated increased serum levels of IL-2 and/or IL-15, but no increase in IL-6 was observed. Bar graphs of each patient before and after treatment, 48 hours after oral administration of 3 mg/kg dexamethasone base to four patients, plasma interleukin-2 and interleukin-15 levels measured using the ProCartaPlex-9 plx Luminex test (Fig. 12, Fig. 13, 14 and 15 show data from the same four human patients).

Fig. 16: Oral administration of 3 mg/kg dexamethasone base increased bone marrow MSC numbers at 48 hours. Data bar graphs for historical data for 31 unexposed controls plus standard deviation and two patients treated with 3 mg/kg dexamethasone base at 48 hours before aspirating concentrated bone marrow from the iliac crest using a MarrowCellution™ needle. Bone marrow was added directly to fibroblast medium (CFU-F) for colony-forming unit analysis without further manipulation 24 h after collection and shipment at controlled room temperature. The CFU-F colony count is a measure of the number of mesenchymal stem cells (MSCs) in the starting material. At 48 hours after oral administration of 3 mg/kg dexamethasone base, iliac bone marrow MSC scores were approximately twice as high as those of 31 historical controls.

Fig. 17: Comparison of 12 mg/kg oral Dex base dose on day -2 with a single dose of cyclophosphamide 166 mg/kg (HED 500 mg/m ² ) and fludarabine 10 mg/kg on day -5 combined with 12 mg/kg Dex base on day -2, and up to 2 days repeat cyclophosphamide 166 mg/kg on days -5 and -4 and 4 days fludarabine 10 mg/kg (HED 30 mg/ ^m2 ) on days -5, -4, -3, - 2. Fig. 17 is a dosing schedule for mice with 2-day Cy and 4-day Flu (light gray) versus 1-day Cy plus 1-day Flu dexamethasone base HED 12 mg/kg on day -2 (dark gray) or with 12 mg/kg dexamethasone base HED on day -2 alone (black). Below the dosing schedule are bars showing the percentage change from vehicle controls in body weight, CD3+ lymphocytes, CD4+ lymphocytes, CD8+ lymphocytes, Tregs, B lymphocytes, NK cells, neutrophils, absolute lymphocytes, platelets, and red blood cells.

Fig. 18: single dose of cyclophosphamide 166 mg/kg (HED 500 mg/m ² ) and fludarabine 10 mg/kg on day -5 combined with 12 mg/kg Dex base on day -2, equivalently lymphodeplete CD3+ and CD4+ lymphocytes compared to 2 days of repeat cyclophosphamide 166 mg/kg on days -5 and -4 and 4 days of fludarabine 10 mg/kg (HED 30 mg/m ² ) on days -5, -4, -3, -2. In fig. 18 shows plots of individual CD3+ and CD4+ lymphocytes and means measured by flow cytometry as relative values and normalized to relative absolute values using full blood chemistry 48 hours after mice were IP treated with PBS (Vehicle 1 ) or by repeated administration of IP cyclophosphamide 166 mg/kg on days -5 and -4 and 4 IP fludarabine 10 mg/kg (HED 30 mg/m ² ) on days -5, -4, -3, -2 ( Flu Cy) or a single IP dose of cyclophosphamide 166 mg/kg (HED 500 mg/ ^m2 ) and fludarabine IP 10 mg/kg on day -5, with an oral dose of 12 mg/kg Dex on day -2 (Flu Cy AVM0703) , or oral placebo (Vehicle 2), or with oral 12 mg/kg dexamethasone base.

Fig. 19: a single dose of cyclophosphamide 166 mg/kg (HED 500 mg/ ^m2 ) and fludarabine 10 mg/kg on day -5 in combination with 12 mg/kg Dex base on day -2, equivalently lymphodepleted CD8+ and Treg lymphocytes compared with 2 days of repeated administration of cyclophosphamide 166 mg/kg on days -5 and -4 and 4 days of fludarabine 10 mg/kg (HED 30 mg/m ² ) on days -5, -4, -3, -2. In fig. 19 shows plots of individual Tregs and CD8+ lymphocytes and average values measured by flow cytometry as relative measures and normalized to relative absolute measures using full blood chemistry 48 hours after mice were treated with IP

- 6 043393 with PBS (Carrier 1) or repeated IP cyclophosphamide 166 mg/kg on days -5 and -4 and 4 days IP fludarabine 10 mg/kg (HED 30 mg/m ² ) on days -5, -4 , -3, -2 (Flu+Cy) or a single IP dose of cyclophosphamide 166 mg/kg (HED 500 mg/m ² ) and fludarabine IP 10 mg/kg on day -5, with an oral dose of 12 mg/kg Dex base on day -2 (Flu Cy AVM0703), or with oral placebo (Vehicle 2), or with 12 mg/kg oral dexamethasone base.

Fig. 20: a single dose of cyclophosphamide 166 mg/kg (HED 500 mg/ ^m2 ) and fludarabine 10 mg/kg on day -5 combined with 12 mg/kg Dex base on day -2, equivalently lymphodepleted NK cells and B lymphocytes compared with 2 days of repeated cyclophosphamide 166 mg/kg on days -5 and -4 and 4 days of fludarabine 10 mg/kg (HED 30 mg/m ² ) on days -5, -4, -3, -2. Fig. 20 presents plots of individual B cells and NK cells and averages measured by flow cytometry as relative values and normalized to relative absolute values using a complete blood chemistry panel 48 hours after mice were IP treated with PBS. (Vehicle 1) or by repeated administration of IP cyclophosphamide 166 mg/kg on days -5 and -4 and 4 days IP fludarabine 10 mg/kg (HED 30 mg/m ² ) on days -5, -4, -3 , -2 (Flu Cy) or using a single intraperitoneal dose of cyclophosphamide 166 mg/kg (HED 500 mg/m ² ) and IP fludarabine 10 mg/kg per day -5, with an oral dose of 12 mg/kg Dex base per day - 2 (Flu Cy AVM0703) with either oral placebo (vehicle 2) or oral 12 mg/kg dexamethasone base.

Fig. 21: a single dose of cyclophosphamide 166 mg/kg (HED 500 mg/m ² ) and fludarabine 10 mg/kg on day -5 combined with 12 mg/kg Dex base on day -2, equivalently lymphodepleted absolute lymphocytes but spared neutrophils, compared with 2 days of repeated administration of cyclophosphamide 166 mg/kg on days -5 and -4 and 4 days of repeated administration of fludarabine 10 mg/kg (HED 30 mg/m ² ) on days -5, -4, -3, -2. In fig. 21 shows graphs of individual absolute neutrophils and absolute lymphocytes and mean values measured by full blood chemistry 48 hours after mice were IP treated with PBS (Vehicle 1) or with a repeat IP of 166 mg/kg cyclophosphamide. on days -5 and -4 and 4 days IP administration of 10 mg/kg fludarabine (HED 30 mg/ ^m2 ) on days -5, -4, -3, -2 (Flu Cy) or a single dose IP of cyclophosphamide 166 mg/m2 kg (HED 500) mg/m ² ) and IP fludarabine 10 mg/kg on day -5, with an oral dose of 12 mg/kg Dex base on day -2 (Flu Cy AVM0703), or oral placebo (Carrier 2), or orally 12 mg/kg dexamethasone base.

Fig. 22: single dose of cyclophosphamide 166 mg/kg (500 mg/ ^m2 ) and fludarabine 10 mg/kg (HED 30 mg/ ^m2 ) on day -5 combined with 12 mg/kg Dex base on day -2, preserved red blood cells and platelets. In fig. 22 shows plots of individual absolute platelets and absolute red blood cells and the average values measured by complete blood chemistry 48 hours after mice were IP treated with PBS (Vehicle 1) or with repeated IP cyclophosphamide 166 mg/kg per day. -5 and -4 and 4 days IP fludarabine 10 mg/kg (HED 30 mg/m ² ) on days -5, -4, -3, -2 (Flu Cy) or a single dose IP cyclophosphamide 166 mg/kg (HED 500) mg/m ² ) and IP fludarabine 10 mg/kg on day -5, with an oral dose of 12 mg/kg Dex base on day -2 (Flu Cy AVM0703), or oral placebo (Vehicle 2), or oral 12 mg /kg dexamethasone base.

Fig. 23: Single dose of cyclophosphamide 166 mg/kg (500 mg/m ² ) and fludarabine 10 mg/kg on day -5 combined with 12 mg/kg Dex base on day -2 maintained body weight, a measure of toxicity compared to 2 days repeated 166 mg/kg cyclophosphamide on days -5 and -4 and 4 days of fludarabine 10 mg/kg on days -5, -4, 3, -2. In fig. 23 shows graphs of differences in individual body weights and means calculated by subtracting body weights 48 hours after mice were IP treated with PBS (Vehicle 1) or repeated IP cyclophosphamide 166 mg/kg on days -5 and - 4 and 4 days IP fludarabine 10 mg/kg (HED 30 mg/m ² ) on days -5, -4, -3, -2 (Flu Cy) or a single IP dose of cyclophosphamide 166 mg/kg (HED 500 mg/m ² ) and IP fludarabine 10 mg/kg on day -5, with an oral dose of 12 mg/kg Dex base on day -2 (Flu Cy AVM0703), or oral placebo (Carrier 2), or oral 12 mg/kg dexamethasone base, from body weight before treatment.

Description of the invention

Review.

Presented herein are novel therapeutic compositions and methods that maintain cellular immunotherapy in the bloodstream or injection site for extended periods of time without the use of cytotoxic preconditioning. More specifically, the compositions and methods described herein lymphodeplete and reduce or remove binding sites in secondary lymphoid organs at which cellular immunotherapy binds and sequesters, without the use of cytotoxic preconditioning.

Cytotoxic chemotherapeutic preconditioning agents trigger cell death through mechanisms or means that are not receptor mediated. Cytotoxic chemotherapy agents trigger cell death by interfering with functions essential for cell division, metabolism, or cell survival. Because of this mechanism of action, cells that are growing rapidly (meaning they are proliferating or dividing) or are metabolically active will preferentially

- 7,043,393 killed compared to cells that do not. The status of various cells in the body as dividing or energy-using (ie, having metabolic activity to maintain cell function) determines the dose of the chemotherapy agent that causes cell death. One skilled in the art will appreciate that NTLA, which is used in this invention, is not a cytotoxic chemotherapeutic agent. Cytotoxic chemotherapeutic agents are not exclusively alkylating agents, antimetabolites, plant alkaloids, topoisomerase inhibitors, anticancer drugs and arsenic trioxide, carmustine, fludarabine, IDA ara-C, myalotang, GO, mustargen, cyclophosphamide, gemcitabine, bendamustine, total body irradiation, cytarabine , etoposide, melphalan, pentostatin and radiation.

Examples of alkylating agents include not only cisplatin and carboplatin, but also oxaliplatin. Temador is an alkylating agent. ACNU is also an alkylating agent. They disrupt cell function by forming covalent bonds with amino, carboxyl, sulfhydryl and phosphate groups in biologically important molecules.

Examples of antimetabolites are not exclusively azathioprine, mercaptopurine, capecitabine, fluorouracil, which become the building blocks of DNA. They prevent these substances from being incorporated into DNA during the S phase (cell cycle), stopping normal development and division. They also influence RNA synthesis. Due to their effectiveness, these drugs are the most widely used cytostatics.

Alkaloids do not exclusively refer to vinca alkaloids and taxanes. Vinca alkaloids do not exclusively refer to vincristine, vinblastine, vinorelbine and vindesine. Taxanes do not exclusively refer to taxol, paclitaxel and docetaxel.

Topoisomerases are important enzymes that maintain DNA topology. Inhibition of type I or type II topoisomerases interferes with both transcription and DNA replication by interfering with proper DNA supercoiling. Some type I topoisomerase inhibitors are not exclusively camptothecins: irinotecan and topotecan. Examples of type II inhibitors are not exclusively amsacrine, etoposide, etoposide phosphate and teniposide.

Antineoplastic drugs do not exclusively refer to dactinomycin, doxorubicin, epirubicin and bleomycin.

Other cytotoxic preconditioning agents include not exclusively: rituximab and similar antibody molecules that activate antibody-dependent cellular cytotoxicity and complement mediated cytotoxicity upon binding to their target cells; radiolabeled antibodies that trigger the destruction of immune cells (immunotoxins), such as anti-CD45 antibodies, such as Iomab-B; immunotoxins such as Mylotarg, Denileukin diftitox (ONTAK), BL22 and 8H9; and pharmacological doses of interleukins such as IL-2, IL12 or IL15, which activate cytotoxic T lymphocytes.

Agents that lymphodeplet and remove binding sites in secondary lymphoid organs where cellular immunotherapy binds and accumulate, but do not precondition cytotoxic agents, are considered non-toxic lymphodepleted agents (NTLAs).

NTLAs, which reduce the binding of cellular immunotherapy to the spleen and other lymph nodes and lymphodeplete, thus increasing the number of cellular immunotherapy cells at the injection site or in the bloodstream, which can in turn find and participate in the destruction of cancerous or neoplastic cells or cells, causing autoimmune diseases or infectious agents. Therapeutic agents that exert this effect through a biological mechanism of action rather than a cytotoxic mechanism of action are considered NTLAs.

NTLAs that inhibit the binding of cellular immunotherapy to lymphoid tissues, in particular the germinal centers of lymphoid tissues, and cause lymphodepletion through a biological mechanism of action that are not preconditioning cytotoxic agents are not exclusively immunosuppressants, in particular agents that include dexamethasone, glucocorticoid receptor modulating agents, CD40L or CD40 antagonists or CD26 antagonists. Thus, some of the NTLAs used in this invention may be referred to as NTLA immunosuppressants. NTLAs that inhibit the binding of cellular immunotherapy to lymphoid tissues, in particular germinal centers of lymphoid tissues, and cause lymphodepletion through a biological mechanism of action that are not preconditioning cytotoxic agents are also not exclusively steroids, and include, but are not limited to, glucocorticoids; dexamethasone, prednisone, methylprednisone, beclomethasone, betamethasone, budesonide, cortisone, hydrocortisone, prednisolone, mometasone furoate, triamcinolone acetonide and methylprednisolone and agents that enhance the expression or activate CCR7, an agent that inhibits the binding of CD40L to CDR40 (an agent that inhibits antagonistic antibodies anti-CD40 or anti-CD40L), antagonists or inhibitors of lymphocyte activation molecule-associated signaling protein, and antagonists or inhibitors from the following list: interleukin 1, interleukin 2, interleukin 4, interleukin 5, interleukin 6, interleukin 12, interleukin

- 8 043393, interleukin 21, interleukin 23, IgE, vascular adhesion protein (VAP), vascular endothelial growth factor (VEGF), BAFF (BLyS), complement, CD2, CD23, CD25a, CD40, CD154 (CD40L), CD62L, CD147 , LFA1, (CD11a), CD18, adenosine deaminase, tumor necrosis factor (TNF).

When administering a glucocorticoid or glucocorticoid receptor modulating therapeutic agent-NTLA that inhibits the binding of cellular immunotherapy to lymphatic tissues and causes lymphodepletion, it is preferable to administer the therapeutic agents about 1-14 days before the cellular immunotherapy treatment, more preferably about 1-7 days before the treatment cellular immunotherapy and most preferably about 36-48 hours prior to cellular immunotherapy treatment.

Corticosteroids that are NTLA immunosuppressants at certain doses, such as dexamethasone, prednisolone, methylprednisolone, dexamethasone sodium phosphate and betamethasone, will cause lymphodepletion and prevent cellular immunotherapy from binding to binding sites in secondary lymphoid organs and thus retain cellular immunotherapy in the circulation or at the injection site so they can find and kill cancer cells, tumor cells or cells that cause autoimmune diseases, or infectious agents. Long-term engraftment of cellular immunotherapy will also be enhanced.

Glucocorticoids and glucocorticoid receptor (GR) modulating agents exert their effects through both membrane glucocorticoid receptors and cytoplasmic GRs, which activate or repress gene expression. It appears that some of the desirable lymphodepletion effects of glucocorticoids and GR-modulating agents are mediated through membrane GRs or other nongenomic effects in addition to their genomic effects. Interestingly, co-treatment with dexamethasone can reduce glucocorticoid resistance (Serafin Blood 2017 130: 2750-2761).

The effects of glucocorticoids are complex and depend on the affinity of each specific glucocorticoid for the GR and mineralocorticoid receptor (MR). In addition, there are currently 9 known cytosolic GR isoforms and additional membrane-expressed GR receptors that have been identified but not fully characterized. Glucocorticoids have been reported to have varying effects on lymphocyte levels depending on the concentration of glucocorticoid administered and the duration of treatment. In general, at low doses commonly used for chronic therapy, glucocorticoids redistribute lymphocytes from the peripheral blood to the bone marrow; at moderate doses, glucocorticoids are reported to cause leukocytosis, which is thought to redistribute white blood cells from the bone marrow, spleen, and thymus to the peripheral blood, and in large doses, glucocorticoids have a lymphotoxic effect on lymphocytes, causing apoptosis and necroptosis. The duration of effect also depends on the dose level, for example, Fauci (Clin. Exp. Immunol. (1976) 24, 54-62.) reports that a single oral dose of dexamethasone 0.24 mg/kg suppresses peripheral blood T and B lymphocytes by 80 %, with recovery beginning within 12 hours and normal levels observed within 24 hours. However, the present invention demonstrates that acute oral doses of 3 mg/kg or more are required to reduce peripheral blood T and B cells 48 hours after administration, with a return to baseline levels occurs 5-14 days after dosing.

Desirable in vivo effects of typical NTLA would include reduction of the germinal center and marginal zones in secondary lymphatic organs, especially direct tumor killing of some cancers; multiple myeloma, renal cell carcinoma, leukemia and lymphoma, non-small cell lung cancer (NSCLC), prostate cancer and breast cancer; depletion of all types of peripheral blood lymphocytes, lack of redistribution of lymphocytes to the VM or other organs and increase in plasma cytokines, including IL-2 and/or IL-7 and/or IL-12 and/or IL-15 to levels of preferably 20 pg /ml or higher, among other things. Typical NTLAs do not increase plasma levels of IL-6, one of the main factors causing ACT cytokine release syndrome (CRS). Acute doses of dexamethasone at or above 6 mg/kg HED reduce germinal centers and marginal zones in secondary lymphoid organs; Acute doses of dexamethasone of about 1.6 mg/kg HED over 48 hours result in about 50% direct tumor killing when used against multiple myeloma and other neoplastic cell lines, which is maintained but not increased at doses up to about 12 mg/kg HED ; Acute doses of dexamethasone greater than about 3 mg/kg HED are required for lymphodepletion, demonstrated by the observation that 50% of patients receiving 3 mg/kg HED had lymphocytosis (Fig. 12); An increase in plasma levels of the cytokines IL-2 and IL-15 is observed at dexamethasone base doses of about 3 mg/kg HED or higher (Fig. 15). Based on the desired in vivo effects in the indications disclosed in this application, the most preferred acute doses of dexamethasone base that can be converted to equivalent NTLA doses of other glucocorticoids based on known calculations or as described herein will most likely be HED 9 mg/kg and higher.

The dosage of NTLA dexamethasone or an equivalent dose of another glucocorticoid should be from about 3 mg/kg to about 26 mg/kg as a single acute dose from about 12 to about 72 hours before administration of cellular immunotherapy or a total dose of about 3 mg/kg to about 26 mg/kg , introduced between approx.

- 9 043393 up to about 72 hours before the administration of cellular immunotherapy. The single acute dose is most preferably administered about 36 to about 48 hours before administration of the cellular immunotherapy.

A single acute dose of NTLA is administered orally or infused over about one hour. The total dose may be administered as repeated intravenous or oral doses in any amount such that the total dose reaches from about 3 mg/kg to about 26 mg/kg over a period of about 12 to about 72 hours before administration of the cellular immunotherapy.

Equivalent doses of another glucocorticoid or glucocorticoid receptor modulating agent can be readily and easily calculated using publicly available conversion algorithms for corticoids. For example, a 12 mg/kg dose of dexamethasone corresponds to 1) a 75 mg/kg dose of prednisolone, which would require repeat dosing of two to three doses over about 48 hours before administration of ACT because it has a shorter pharmacological half-life, 2 ) dose of betamethasone 10 mg/kg, the pharmacodynamic (biological) half-life of which is similar to dexamethasone. However, betamethasone reduces red blood cells at doses of about 24 mg/50 kg (Gaur 2017).

The NTLA agent containing dexamethasone is preferably administered intravenously or orally about 36 to 48 hours prior to administration of the cellular immunotherapy at a dose of about 3.0 to about 12.0 mg of dexamethasone base per kg of patient body weight. The most preferred dose for young children is from about 3.0 to about 12.0 mg/kg dexamethasone base, and for adolescents and adults is from about 6.0 to about 12.0 mg/kg, with the most preferred dose of dexamethasone base ranges from about 9.0 mg/kg to about 12.0 mg/kg. Dexamethasone, like other glucocorticoid steroids in equivalent doses, inhibits the formation and proliferation of germinal centers in lymphoid tissues and leads to lymphodepletion of peripheral blood.

An NTLA agent containing hydrocortisone is administered intravenously or orally every about 12 hours at a dose of about 75 to about 300 mg/kg, from about 12 to 72 hours before administration of cellular immunotherapy. An NTLA agent containing cortisone is administered intravenously or orally every about 12 hours at a dose of about 93 to about 375 mg/kg from about 12 to about 72 hours before administration of cellular immunotherapy. An NTLA agent containing prednisolone is administered intravenously or orally every about 24 hours at a dose of about 19 to about 75 mg/kg from about 12 to 60 hours before administration of cellular immunotherapy. An NTLA agent containing methylprednisolone is administered intravenously or orally every 24 hours at a dose of about 15 to about 60 mg/kg for about 12 to about 60 hours before administration of cellular immunotherapy. The NTLA agent containing triamcinolone is administered intravenously or orally every about 24 hours at a dose of about 15 to about 60 mg/kg from about 12 to 60 hours before administration of cellular immunotherapy. The NTLA agent containing paramethasone is administered as a single acute dose or in cumulative doses of about 7.5 to about 30 mg/kg administered over about 12 to 72 hours prior to cellular immunotherapy. The NTLA agent containing betamethasone is administered as a single acute dose or in cumulative doses of about 2.5 to 10 mg/kg administered over about 12 to 72 hours prior to cellular immunotherapy.

Clinically effective doses of NTLA, particularly dexamethasone, achieve greater than 60% CD3+ lymphodepletion. More preferred clinically effective doses of NTLA, particularly dexamethasone, achieve greater than 70% CD3+ lymphodepletion. The most preferred clinically effective doses of NTLA, especially dexamethasone, achieve greater than 80% CD3+ lymphodepletion. One of ordinary skill in the art will appreciate that CD3+ lymphodepletion can be easily measured by measuring a complete blood count (CBC) with differentials and/or the percentage of cells that are CD3 positive using flow cytometry. Flow cytometry is a technology that is used to analyze the physical and chemical characteristics of particles in a liquid as it passes through at least one laser. Cell components are fluorescently labeled and then excited with a laser to emit light at different wavelengths. Flow cytometry allows the identification and characterization of distinct subsets of cells in a heterogeneous sample.

Clinically effective doses of NTLA, particularly dexamethasone, achieve greater than 60% Treg lymphodepletion. More preferred clinically effective doses of NTLA, particularly dexamethasone, achieve greater than 70% Treg lymphodepletion. The most preferred clinically effective doses of NTLA, particularly dexamethasone, achieve greater than 80% Treg lymphodepletion. Clinically effective doses of dexamethasone and other preferred NTLA agents are neutrophil sparing and do not inhibit neutrophil function (Schleimer RP, J Pharmacol Exp Ther 1989;250:598-605) and are sparing on red blood cells (RBCs), platelets, mesenchymal stem cells (MSCs) ) and hematopoietic stem cells (HSC). Neutrophil persistence in humans is an absolute neutrophil count (ANC) greater than 500 per mm ³ . Because of the preservation of neutrophils, red blood cells, and platelets, the preferred NTLAs, especially the NTLA dexamethasone, reduce or eliminate the need for transfusions. NTLA dexamethasone also preserves bone marrow mesenchymal stem cells (MSCs) and does not affect the ability of bone marrow MSCs to differentiate into chondrocytes, osteocytes, or adipocytes. NTLA dexamethasone also increases the endogenous number of MSCs in the VM or their ex vivo survival in both humans and horses. Preferred NTLAs, in particular the NTLA dexamethasone, increase plasma levels of IL-2, IL-7, IL-12 and IL-15, but not IL-6 levels.

- 10 043393

Dexamethasone is approved for use with a starting dose of dexamethasone sodium phosphate injection that varies from 0.5 to 9 mg per day depending on the disease being treated, resulting in a daily dose of 0.01 to 0.18 mg/kg per 50 kg body weight. For less severe diseases, doses of less than 0.5 mg may be sufficient, while for severe diseases, doses greater than 9 mg may be required. In modern medical practice, there is a tendency to use high (pharmacological) doses of corticosteroids to treat unresponsive shock. For cerebral edema, dexamethasone sodium phosphate injection is usually given initially at a dose of 10 mg intravenously and then 4 mg every six hours intramuscularly until symptoms of cerebral edema subside. This total dose would correspond to a total 24-hour dose of about 0.34 to 0.48 mg/kg and a total 72-hour dose of 0.8 to 1.12 mg/kg over 72 hours, which is not the NTLA dose described in herein, which represent total doses of about 3 mg/kg to about 26 mg/kg administered from about 12 to about 72 hours before ACT.

For acute allergic disorders, dexamethasone sodium phosphate injection, USP 4 mg/ml is recommended: first day, 1 or 2 ml (4 or 8 mg), intramuscular, then dexamethasone sodium phosphate tablets, 0.75 mg; second and third days - 4 tablets in two divided doses every day; fourth day, 2 tablets in two divided doses; fifth and sixth days, 1 tablet per day; seventh day, no treatment; eighth day, control visit. Dexamethasone is used in the emergency department for severe acute childhood asthma at a dose of 2 mg/kg, a dose that is lower than the NTLA doses defined in this invention.

The human CD26 gene contains 26 exons and is located on chromosome 2q.24.3. This gene spans a region of about 70 kb. At the 5' end is a 300 bp sequence that consists of at least 72% cytosine and guanine residues, meaning that the sequence contains potential binding sites for growth factors such as nuclear factor kappa light chain enhancer of activated B cells (NF-κB) and hepatocyte nuclear transcription factor 1 (HNF1).

The absence of a TATA box and high CG content, which characterize the CD26 gene, are typical features of the promoter region of a housekeeping gene. As this leads to the present invention, CD26 antagonists do not affect the activity of the DPPIV molecule. The encoded glycoprotein, in the form of a monomer, has a size of 110 kDa and is multifunctional. CD26 exists in both a soluble and membrane-bound form, and functions as a serine protease, as a receptor, as an adhesion molecule for collagen and fibronectin, as a co-stimulatory signal for T lymphocytes, and is involved in apoptosis. Hypoxic conditions promote CD26 expression, and hypoxia-inducible protein-1a (HIP-1a) is a strong inducer for CD26 gene expression and protein production. Several cytokines, including IFN and IL-1e, retinoic acid and HNF-1, can also stimulate CD26 activation in fibroblasts, epithelial cells, endothelial cells and leukocytes. Membrane-bound CD26 contains a transmembrane domain that is located 28 residues from the NH2 terminus and is a surface marker of leukocytes. The protein exhibits catalytic proteolytic activity only as a dimer and can be found on the surface of T and B cells, NK cells, some types of macrophages and hematopoietic stem and progenitor cells. In addition, fibroblasts, endothelial, acinar and epithelial cells of various tissues such as kidney and liver also express CD26. Both ends of the protein contribute to the formation of the so-called β-propeller domain (amino acids 55-497). The β-propeller structure contains seven sheets and contains only hydrophobic bonds and salt bridges, meaning the region is extremely flexible. In addition, the protein contains an α/β-hydroxylase domain (amino acids 39-51 and amino acids 506-766), which is covalently linked to the β-propeller domain. Taken together, these properties imply that the catalytic pocket is located in a locked hole. The other side of the β-propeller domain faces the extracellular environment. It is possible that the flexibility of the β-propeller domain plays a role in facilitating the passage of substrates to the catalytic pocket of CD26. However, experimental evidence currently only supports the entry of substrates through the side opening of the enzyme. In addition to functional homodimeric CD26, active heterodimers with FAPa have also been described.

CD26 contains several regions that can be N-glycosylated. Studies, however, suggest that glycosylation of these sequences is not important for protein dimerization, adenosine deaminase (ADA) binding, or catalytic activity.

CD26, also called DPP4, is a multifunctional protein involved in T cell activation by costimulation through its association with adenosine deaminase (ADA), caveolin-1, CARMA-1, CD45, mannose 6-phosphate receptor/insulin-like growth factor II receptor ( M6P/IGFII-R) and C-X-C motif-containing receptor 4 (CXC-R4). CD26 is a T cell activation antigen. CD26 antagonists prevent costimulation of CD26 T cells. Without T cell activation, B cells cannot be activated and germinal center formation cannot occur.

CD26 is expressed in all organs, primarily on the apical surfaces of epithelial and acinar cells and at lower levels in lymphocytes and capillary endothelial cells

- 11 043393 kah. Immunohistochemical analysis identified CD26 in human tissue sections from the gastrointestinal tract, biliary tract, exocrine pancreas, kidney, uterus, placenta, prostate and epidermis, adrenal glands, parotid glands, sweat, salivary and mammary glands, and on the endothelium of all organs. including the liver, spleen, lungs and brain. Similar studies of rat tissue produced identical data using immunohistochemistry and showed that capillary endothelial cells in all organs, including lymphoid organs, muscle and brain, express CD26.

CD26 in addition to its DPPIV enzymatic activity can directly bind adenosine deaminase, fibronectin, collagen and other extracellular matrix proteins, gpl20, fibroblast activation protein alpha, CARD11, gelatin, CAV1, BCL10, GPC3, CXRC4, TAT, coronavirus-EMC IBGF protein, IGF2R and PTPRC and CD45. CD26 also has signal transduction activity (http://www.uniprot.org/uniprot/P27487). The leucine_<340>, valine_<341>, alanine_<342> and arginine_<343> residues on the CD26 molecule are essential amino acids for ADA binding. These interactions were determined to involve fibronectin and collagen: collagen binds to a region in cysteine domain 14 between residues 238 and 495, whereas fibronectin binds residues 469 to 479. Residues 340–343 on the CD26 molecule were found to be important for ADA21 binding. GP120 blocks ADA binding to CD26. The MERS-CoV RBD receptor-binding subdomain binds to the DPP4 bpropeller by contacting blades 4 and 5 and the small convex helix in the linker blade. Structural and mutational analyzes identified Y499, L506, W533, and E513 in the RBD as critical for receptor binding and viral entry, and their mutations significantly suppressed its interaction with DPP4.

In certain embodiments of the invention, it would be desirable to have a CD26 antagonist that prevents binding of cellular immunotherapy in secondary lymphoid organs, but does not affect or interfere with the proteolytic activity of DP26 in DPPIV.

The complete cDNA and derived amino acid sequence for human CD26 were first published in 1992. The CD265 gene encodes a type II transmembrane protein of 766 amino acids, which is attached to the lipid bilayer by a single hydrophobic segment located at the N-terminus and has a short cytoplasmic tail of six amino acids. The flexible rod binds the membrane anchor to a large glycosylated region, a cysteine-rich region, and a C-terminal catalytic domain. Amino acid sequence alignment reveals a high degree of conservation between different species, with the C-terminal segment showing the highest level of identity.

The present invention also provides a means for achieving adequate lymphodepletion by combining NTLA, particularly NTLA dexamethasone, with a reduced intensity of cytotoxic preconditioning administered as a daily dose to reduce the toxicity of the cytotoxic preconditioning or by significantly reducing the acute dose of the cytotoxic preconditioning. Standard pre-chemotherapy regimens include cyclophosphamide (about 200 to about 2100 mg/m ² /day from about day -14 to about day -2) with or without fludarabine (from about 10 mg/m ² /day to about 9000 mg/ m ² /day from about day -14 to about day -2) in various combinations and daily dosage. Single treatment with cyclophosphamide (Cy) 167 mg/kg (equivalent to HED about 500 mg/ ^m2 ) for mice on day -5 and fludarabine (Flu) 10 mg/kg (equivalent to HED about 30 mg/ ^m2 ) for mice per day - 5 plus a 12 mg/kg dose of HED base dexamethasone on day -2 was equally effective for lymphodepletion compared with the more standard dose of cyclophosphamide 167 mg/kg on days -5 and -4 and fludarabine 10 mg/kg on days -5, -4 , -3, -2, however, the toxicity of preconditioning was reduced, as evidenced by lower reductions in BW in dexamethasone plus CyFlu alone compared with standard CyFlu rechallenge. A reduced cytotoxic preconditioning dose would be a single dose of a standard dose chemotherapy regimen used in repeat dosing, or a cumulative dose of a cytotoxic preconditioning agent below the cumulative standard preconditioning chemotherapy regimens. For example, a reduced dose of cyclophosphamide would be a single dose of cyclophosphamide ranging from about 200 to about 3000 mg/m ² or a cumulative dose below about 200 mg/m ² .

To reduce preconditioning toxicity, a single dose of any standard preconditioning therapy or combination preconditioning therapy may be administered for 0 to 9 days, followed by a dose of NTLA, particularly NTLA dexamethasone. NTLA dexamethasone should be administered in a range of about 3 mg/kg to about 26 mg/kg as a single acute dose from about 12 to about 72 hours before administration of cellular immunotherapy or in a total dose of about 3 mg/kg to about 26 mg/kg in the interval from about 12 about 72 hours before the introduction of cell therapy. Preconditioning agents that can be used at lower doses in combination with NTLA dexamethasone ranging from about 3 mg/kg to about 26 mg/kg single acute dose administered ranging from about 12 to about 72 hours before administration of cellular immunotherapy or from about 3 mg/kg to about 26 mg/kg total dose administered over about 12

- 12 043393 up to about 72 hours before the administration of cell therapy, not exclusively include abiraterone, alemtuzumab, anastrozole, aprepitant, aranose, arsenic trioxide, atezolizumab, azacitidine, bevacizumab, bleomycin, bortezomabine, cabazitaxel, capecitabine, cetuximab, cisplatin, crizotinib, cyclophosphamide, cytarabine, chlorosotocin, chlorambucil, denosumab, docetaxel, doxorubicin, eribulin, erlotinib, etoposide, everolimus, exemestane, ailgrastim, fluorouracil, fotemustine, fulvestrant, gemcitabine, HPV vaccine, imatinib, imiquimod, ipilimumab, ixabepilone, lapatinib, flax Alidomide, Letrozole, leuprolide, mesna, melphalan, methotrexate, mechlorethamine, nivolumab, oxaliplatin, paclitaxel, palo nosetron, pembrolizumab, pemetrexed, radium-223, rituximab, sipuleucel-T, sorafenib, sunitinib, intrapleural talc, tamoxifen, temozolomide, temsirolimus, thalidomide, trastuzumab, vinorelbine, zoledronic acid, abitrexate (methotrexate injection), Abraxane® (paclitaxel injection), Adcetris® (brentuximab vedotin injection), Adriamycin® (doxorubicin), Adrucil® injection (5-FU (fluorouracil)), Afinitor® (everolimus), Afinitor® Disperz (everolimus), Alimta® (PEMETREXED), Alkeran® injection (melphalan injection), Alkeran® (Melphalan) tablets, Aredia® (pamidronate), Arimidex® (anastrozole), Aromasin® (exemestane), Arranon® (nelarabine ), Arzerra® (injectumumab injection), Avastin® (bevacizumab) (belinostat injection), Bexar (tositumomab), BiCNU® (carmustine), Blenoxan® (bleomycin), Blincyto® (blinatumomab injection), Bosulf® (bosutinib) injection Busulfex® (busulfan injection), Campat® (alemtosumab), Camptosar® (irinotecan), Caprelka® (vandetanib), Casodex® (bicalutamide), SiNU® (lomustine), SiNU® (lomustine) unit pack, Cerubidin® (daunorubicin) , Clolar® (clofarabine injection), Cometric® (cabozantinib), Cosmegen® (dactinomycin), Cotellic® (cobimetinib), Cyramza® (ramucirumab injection), Cytosar® (cytarabine), Cytoxan® (Cytoxan), Cytoxan® injection (injection cyclophosphamide), Dacogen® (decitabine), Daunose® (daunorubicin lipid complex injection), DepoCit® (cytarabine lipid complex injection), Docefrez® (docetaxel), Doxil® (doxorubicin lipid complex injection), Droxia® (hydroxyurea), DTIC® (decarbazine), Eligard® (leuprolide), Ellens® (Ellens (epirubicin)), Eloxatin® (oxaliplatin), Elspar® (asparaginase), Emcyt® (estramustine), Erbitux® (cetuximab), Erived®zh (vismodegib), Erwinase® (Erwinia chrysanthemi asparaginase), Etiol® (amifostine), Etopofos® (etoposide injection) (Eulexin (Flutamide), Fareston® (Toremifene), Faridak® (Panobinostat), Faslodex® (Fulvestrant), Femara® (letrozole), Firmagon® (degarelix injection), Fludara® (Fludarabine), Folex® (methotrexate injection), Folotin® (pralatrexate injection), FUDR® (Fudry®), Gazyva® (obinutuzumab injection), Gemzar® (Gemcitabine), Gilotrif® ( Afatinib), Gleevec® (imatinib masilate), Gliadel® capsule (carmustine capsule), Halaven® (eribulin injection), Herceptin® (trastuzumab), Hex (Altretamine), Hycamptin® (topotecan), Hydrea® (hydroxyurea), Ibrance® (palbocilib), Iclusig® (ponatinib), Idamycin® PFS (idarubicin), Ifex® (ifosfamide), Imbruvice® (ibrutinib), Inlyta® (axitinib), Intron® A alfab (interferon alfa-2a), Iressa® (gefitinib ), Istodax (romidepsin injection), Ixempra® (ixabepilone injection), Jakavi® (rixolitinib), Jevtana® (cabazitaxel injection), Kadcyla® (ado-trastuzumab emtansine), Keytruda® (pembrolizumab injection), Kyprolis® (carfilzomib), Laevima® (lenvatinib), Leukeran® (chlorambucil), Leukin® (sargramostim), Leustatin® (cladribine), Lonsurf® (trifluridine and tipiracil), Lupron® (Leuprolide), Lupron® DepotPED (Leuprolide) ), Lysodren® (mitotane), Markibo® (vincristine lipid complex injection), Matulan® (procarbazine), Megeys® (megestrol), Mekinist® (Trametinib), Mesnex® (Mesna), Mesnex® (Mesna injection), Metastron® (strontium-89 chloride), Mexate® (methotrexate injection), Mustargen® (mechlorethamine), Mutamycin® (mitomycin), Mileran® (busulfan), Mylotarg® (gemtuzumab ozogamicin), Navelbrine® (vinorelbine ), Neosar® injection (cyclophosphamide injection), Neulasta® (pegfilgrastim), Neupogen® (filgrastim), Nexavar® (sorafenib), Nilandron® (nilutamide), Nipent® (pentostatin), Nolvadex® (tamoxifen), Novantrone® (mitoxantrone) , sonigidzo), Odomozo Oncaspar® (pegaspargase), Oncovin® (vincristine), Ontak® (denileukin difitox), Onxol® (paclitaxel injection), Opdivo® (nivolumab injection), Panretin® (aliretinoin), Paraplatin® (carboplatin), Perjeta® (pertuzumab injection), Platinol® (cisplatin), Platinol® (cisplatin injection), Platinol® AQ (cisplatin), Platinol® AQ (cisplatin injection), Pomalyst® (pomalidomide), Proleukin® (aldesleukin), Purinetol® ( mercaptopurine), Reclast® (Zoledronic acid), Revlimid® (Lenalidomide), Revmatrex® (Methotrexate), Rituxan® (Rituximab), Roferon A alpha (interferon Alpha-2a), Rubeke® (doxorubicin), Sandostatin® (octreotide), Sandostatin® LAR Depot (octreotide), Soltamox® (tamoxifen), Sprycel® (dasatinib), Stivarga® (Regorafenib), Supprelin® LA, Sutent® (Sunitinib), Silatron® (PEGinterferon Alfa-2b injection), Sylvant® (injection siltuximab), Sinribo® (omacetaxine injection), Tabloid® (thioguanine), Taflinar® (dabrafenib), Tarceva® (erlotinib), Erlotinib® (bexarotene) capsules, Tacinya® (decarbazine), Taxol® (paclitaxel injection), Taxotere® (docetaxel), Temodar®

- 13 043393 (temozolomide), Temodar® (temozolomide injection), Tepadin® (thiotepa), Thalomid® (thalidomide), Teratsis® BCG (BCG), Thioplex® (thiotepa), TICE® BCG (BCG), Toposar® (injection etoposide), Toris® (temsirolimus), Treanda® (bendamustine hydrochloride), Trelstar® (triptorelin injection), Trexall® (methotrexate), Trizenox® (arsenic trioxide), Tykerb® (lapatinib), Unituxin® (dinutuximab injection), Valstarra (valrubicin intravesical), Vantas® (histrelin implant), Vectibix (panitumumab), Velban® (vinblastine), Velkad (bortezomib), Vepezid® (etoposide), Vepezid® (etoposide injection), Vesanoid® (tretinoin), Vidaza® ( azacit), Vincasar® PFS (vincristine), Vincrex® (vincristine), Votrient® (pazopanib), Vumon® (teniposide), Wellcovorin® IV (leucovorin injection), Xalkori® (crizotinib), Xeloda® (capecitabine), Xtandi® (enzalutamide), Yervoy® (ipilimumab injection), Yondelis® (trabectin injection), Zaltrap® (ziv-aflibercept injection), Zanosar® (streptozocin), Zelboraf® (vemurafenib), Zevalin® (ibrutumomab tiuxetan), Zoladex® (goserelin ), Zolinze® (vorinostat), Zomete® (zoledronic acid), Zortress® (everolimus), Zydelig® (idelalisib), Zykadia® (ceritinib), Zytiga® (abiraterone), ABVD (a combination of doxorubicin (Adriamycin®), bleomycin, vinblastine and dacarbazine (DTIC)), AC (a combination of Adriamycin® (doxorubicin) and cyclophosphamide) ACE (a combination of Adriamycin® (doxorubicin), cyclophosphamide and etoposide (epozine, etopophos, Vepesid)), abiraterone (Zytiga®), Abraxane® (set -paclitaxel), Abstral® (fentanyl), Actinomycin D, Actik®, Adriamycin, Afatinib (Jotrif®), Afinitor® (everolimus), aflibercept (Zaltrap®), Aldara® (imiquimod cream), Aldesleukin (IL-2, Proleukin ® or interleukin 2), Alemtuzumab (MabCampat®), Alkeran® (melphalan), Amsacrine (Amsidin®, m-AMSA), Amsidin®, anastrozole (Arimidex®), Ara S (cytarabine), Aredia®, Arimidex®, Aromasin ®, arsenic trioxide (Trisenox™, ATO), Asparaginase (crizantaspase, Erwinase®), axitinib (Inlyta®), azacitidine (Vidaza®), BEACOPP, BEAM, bendamustine (Levact®), bevacizumab (Avastin®), bexarotene (Targretin® ®), bicalutamide (Casodex®), bleomycin, [bleomycin, etoposide and platinum (BEP)], borteseomib (Velcad®), Bosulif®, bosutinib (Bosulif®), brentuximab (Adcetris®), brufen, buserelin (Suprefact®) , Busilvex®, busulfan (Mileran®, Busilvex®), CAP-OX (oxaliplatin and capecitabine (XELOX)), CAP oxaliplatin and capecitabine (XELOX)), CAV (cyclophosphamide, doxorubicin (Adriamycin®), vincristine), CAVE (cyclophosphamide , doxorubicin (Adriamycin®), vincristine, etoposide), CCNU (lomustine), CHO (a combination of cyclophosphamide, doxorubicin hydrochloride (Adriamycin®), vincristine (Oncovin®), CMF (a combination of cyclophosphamide, methotrexate and fluorouracil (5FU)), CMV ( combination of cisplatin, methotrexate and vinblastine), CT (combination of cyclophosphamide, thalidomide), CV (combination of cyclophosphamide, vincristine (Oncovin®), cabazitaxel (Evtan®), cabozantinib (Kometrik®), Kelix®, Calpola®, Campto®, capecitabine ( Xeloda®), cabazitanib (Kometric®), Carbo® MV (a combination of carboplatin, methotrexate and vinblastine), CarboTaxol®, Carboplatin®, Carboplatin® and etoposide, Carboplatin® and paclitaxel, Carmustine (BCNU, Gliadel®), Casodex®, Celebrex ®, celecoxib (Celebrex®), ceritinib (Zykadia®), Cerubidin®, cetuximab (Erbitux®), ChlVPP, chlorambucil (Leukeran®), Cisplatin®, Cisplatin® and Teysuno®, Cisplatin® and capecitabine (CX), Cisplatin® , etoposide and ifosfamide (PEI), Cisplatin®, fluorouracil (5-FU) and trastuzumab, cladribine (Leustat, LITAK®), Clasteon®, clofarabine (Evoltra®), co-codamol (Kapak®, Solpadol®, Tilex®) , Kometric®, Cosmegen®, Crizantaspase®, crizotinib (Xalkori®), cyclophosphamide, Ciprostat®, cyproterone acetate (Cyprostat®), cytarabine (Ara C, cytosine arabinoside), cytarabine in cerebrospinal fluid, cytosine arabinoside, NAR (NA combination (high dose Ara C, also known as cytarabine) and cisplatin), DTIC (dacarbazine), dabrafenib (Tafinlar®), Dacarbazine (DTIC), Dacogen®, dactinomycin (Actinomycin D, Cosmegen®), dasatinib (Sprycel®), daunorubicin, De Gramont , Decapeptyl® SR, decitabine (Dacogen®), degarelix (Firmagon®), denosumab (Prolia®, Exjiva®), Depocyt®, diamorphine, disodium pamidronate, disprole, docetaxel (Taxotere®), docetaxel, cisplatin and fluorouracil (TPF) , Doxiphos®, Doxil®, doxorubicin (Adriamycin®), doxorubicin and ifosfamide (Doxiphos®), Drogenil®, Durogesic®, E-CMF (Epi-CMF), EC, ECF, EOF, EOX, EP, ESHAP, Effentora® , Efudix®, Eldizin®, Eloxatin®, enzalutamide (Xtandi®), epirubicin (Farmorubicin®), epirubicin, carboplatin and capecitabine (ECarboX), epirubicin, cisplatin and capecitabine (ECX), Epozin®, Erbitux®, eribulin (Halaven® ), Erlotinib (Tarceva®), Ervinazu®, Estracit, Estramustine (Estracyt®), Etopofos®, etoposide (epozine, Etopofos®, Vepesid), etoposide, leucovorin and fluorouracil (ELF), everolimus (Afinitor®), Evoltra®) , FAD, FC, FEC, chemotherapy FEC-T, FMD, FOLFIRINOX, Faslodex®, Femara®, fentanyl, Firmagon®, Fludara®, fludarabine (Fludara®), [fludarabine, cyclophosphamide and rituximab (FCR)], fluorouracil (5FU ), flutamide, [Folic acid, fluorouracil and irinotecan (FOLFIRI)], [Folic acid, fluorouracil and oxaliplatin (FOL., FOX)], fulvestrant (Faslodex®), G-CSF, gefitinib (Iressa®), GemCarbo (gemcitabine and carboplatin), gemcitabine (Gemzar®), gemcitabine and capecitabine (GemCap), gemcitabine and cisplatin (GC), gemcitabine and paclitaxel (GemTaxol), Gemzar®, Giotrif®, Gliadel®, Gleevec®, Gonapeptil® Depot, goserelin

- 14 043393 (Zoladex®), goserelin (Zoladex®, Novgos®), granulocyte colony-stimulating factor (GCSF), Halaven®, Herceptin®, Hycamtin®, Hydrea, hydroxyurea (Hydrea®), hydroxyurea, IDEX, ICE, IL-2 , IPE, ibandronic acid, ibritumomab (Zevalin®), ibuprofen (Brufen®, Nurofen®), iclusig, idarubicin (Zavedos®), idelalisib (Zydelig®), ifosfamide (Mitoxana®), Imatinib (Gleevec®), imiquimod cream ( Aldara®), Imnovid®, Instanil®, interferon (Intron A®), interleukin, Intron A®, Ipilimumab (Yervoy®), Iressa®, irinotecan (Campto®), irinotecan and capecitabine (XELIRI®), irinotecan de Gramont, de Gramont modified irinotecan, Javlor™, Zhevtana®, Kadcyla®, Capac®, Keytruda®, Lanvis™, lapatinib (Tyverb®), lenalidomide (Revlimid®), letrozole (Femara®), Leukeran®, leuprorelin (Prostap®, Lutrate®), Leustat®, Levakt®, Liposomal doxorubicin, Litak®, Lomustine (CCNU, Gleostin®), Lynparza®, Lysodren®, MIC, MM, MMM, MST Continus, MVAC, MVP, MabCampat®, MabThera®, Maxtrex ®, medroxyprogesterone acetate (Provera®), Megace®, megestrol acetate (Megece®), melphalan (Alkeran®), melphalan, thalidomide, Mepact®, mercaptopurine (Xaluprine®), methotrexate (Maxtrex®), Mifamurti®), mitomycin C , mitotane, Mitoxana®, mitoxantrone (Mitosanthrone®), Morphgesic® SR, morphine, Mileran®, Myocet®, nabpaclitaxel, nab-paclitaxel (Abraxane®), Navelbine®, nelarabine (Atriance®), Nexavar®, nilotinib (Tasigna® ), nintedanib (Vargatef®), Nipent™, nivolumab (Opdivo®), Novgos®, Nurofen®, Ofatumumab (Arzerra®), Olaparib (Lynparza®), Oncovin®, Oncotron®, Opdivo®, Oramorph®, oxaliplatin (Eloxatin ®), oxaliplatin and capecitabine (XELOX), PAD, PC (paclitaxel and carboplatin, CarboTaxol®), PCV, PE, PMitCEBO, POMB/ACE, paclitaxel (Taxol®), paclitaxel and carboplatin, pamidronate, Panadol®, panitumumab (Vectibix ®), paracetamol, pazopanib (Votrient®), pembrolizumab (Keytruda®), Pemetrexed (Alimta®), pemetrexed and carboplatin, pemetrexed and cisplatin, pentostatin (Nipent®), Perjeta®, Pertuzumab (Perjeta®), Pixantrone (Pixuvri® ), Pixuvri®, pomalidomide (Imnovid®), Ponatinib (Iclusig®), potactazole, procarbazine, Proleukin®, Prolia®, Prostap®, Provera®, purinetol, R-CHOP, R-CVP, R-DHAP, R-ESHAP , R-GCVP, RICE, raloxifene, raltitrexed (Tomudex®), regorafenib (Stivarga®), Revlimid, rituximab (MabThera®), Sevredol®, sodium clodronate (Bonefos®, Clasteon®), Solpadol®, sorafenib (Nexavar®) , Stanford V, streptozocin (Zanosar®), sunitinib (Sutent®), Sutent®, TAS, TIP, Tafinlar®, tamoxifen, Tarceva®, Targ Retin®, Tacinya®, Taxol®, Taxotere®, Taxotere® and cyclophosphamide (TC ), Temodal®, temozolomide (Temodal®), temsirolimus (Torisel®), Tepadina®, Teysuno®, thalidomide, Thiotepa (Tepadina®), thioguanine (thioguanine, 6TG, 6-thioguanine), Tomudex®, topotecan (Hycamtin®, Potactasol®), Torisel®, trabectin (Yondelis®), trastuzumab (Herceptin®), trastuzumab emtansine (Kadcyla®), Treosulfan®, tretinoin (Vesanoid®, ATRA), triptorelin (Decapeptyl® SR, Gonapeptyl® Depot), Trisenox® , Tylex®, Tyverb®, VIDE, Vandetanib (Caprelsa®), Vargatef®, VeIP, Vectibix®, Velbe®, Velcade®, vemurafenib (Zelboraf®), Vepesid®, Vesanoid®, Vidaza®, Vinblastine (Velbe®), vincristine, [vincristine, actinomycin D (dactinomycin) and cyclophosphamide (VAC)], [vincristine, actinomycin and ifosfamide (VAI)], doxorubicin (VA)], Vindesine (Eldizin®), Vinflunine (Javlor®), vinorelbine (Navelbine ®), Vismodegib (Erived®zh), Votrient®, XELOX®, Xalkori®, Xeloda®, Exjiva®, Xtandi®, Yervoy®, yondelis, Z-DEX, Zaltrap®, Zanosar®, Zavedos®, Zelboraf®, Zevalin ®, Zoladex® (breast cancer), Zoladex® (prostate cancer), zoledronic acid (Zometa®), Zometa®, Zomorph®, Zydelig®, Zytiga®, abemaciclib, abiraterone acetate, abitrexate (Methotrexate®), Abraxane® ( nanoparticle composition stabilized with albumin, paclitaxel), ABVD, ABVE, ABVE-PC, AC, acalabrutinib, AC-T, Adcetris® (brentuximab vedotin), ADE, ado-trastuzumab emtansine, Adriamycin (doxorubicin hydrochloride), afatinib dimaleate, afinitor ( Everolimus®), Akinseo® (netupitant and palonosetron hydrochloride), Aldara® (imiquimod), Aldesleukin, Alecensa® (alectinib), alectinib, alemtuzumab, Alimta® (pemetrexed disodium), Aliquopa® (copanlisib hydrochloride), Alkeran® injection ( melphalan hydrochloride), Alkeran® (melphalan) tablets, Aloxy® (palonosetron hydrochloride Alunbrig® (brigantinib), ambochlorin (chlorambucil), amifostine, aminolevulinic acid, anastrozole, aprepitant, Aredia® (disodium pamidronate), Arimidex® (anastrozole), Aromasin ® (exemestane), Arranone® (nelarabine), arsenic trioxide, Arzerra® (ofatumumab), Erwinia chrysanthemi asparaginase, atezolizumab, Avastin® (bevacizumab), Avelumab, axicabtagene siloleucel, axitinib, azacitidine, Bevesio® (avelumab), VEACORR, Becenum (Carmustine™), Beleodac (Belinostat™), Belinostat™, bendamustine hydrochloride, VER, Besponsa™ (inotuzumab ozogamicin), bevacizumab, bexarotene, bicalutamide, BiCNU (Carmustine™), bleomycin, blinatumomab, Blincyto® (blinatumomab), bortezomib, Bosulif® (bosutinib), bosutinib, brentuximab vedotin, brigatinib, BuMel, busulfan, busulflex (busulfan), cabazitaxel, cabometyx (cabozantinib-S-malate), cabozantinib-S-malate, CAF, calquence (acalabrutinib), Campath (alemtuzumab) , camptosar (irinotecan hydrochloride), capecitabine, SAROKH, carak (topical fluorouracil), carboplatin, carboplatin-taxol, carfilzomib, carmubris (carmustine), carmustine, carmustine implant, cazodex (bicalutamide), CEM, ceritinib, cerubidine (daunorubicin, requivals, cyvarid

- 15 043393 hydrochloride), CEV, chlorambucil, cisplatin, cladribine, clafen (cyclophosphamide), clofarabine, clofarex (clofarabine), clolar (clofarabine), CMF, cobimetinib, Kometric (cabozantinib-S-malate), copanlisib hydrochloride, COPDAC, COPP , COPP-ABV, cosmegen (dactinomycin), cotellic (cobimetinib), crizotinib, CVP, cyclophosphamide, cyphos (ifosfamide), cyramza (ramucirumab), cytarabine, cytarabine liposomal, cytosar-U (cytarabine), cytoxan (cyclophosphamide), dabrafenib, dacarbazine, dacogen (decitamib), dactinomycin, daratumumab, darzalex (daratumumab), dasatinib, daunorubicin hydrochloride and cytarabine liposomal, decitabine, sodium defibrotide, defitelio (sodium defibrotide), degarelix, denileukin diftitox, denosumab, DepoCyt (cytarabine liposomal), dexraz oxane hydrochloride , dinutuximab, docetaxel, Doxil (doxorubicin hydrochloride liposomal) doxorubicin hydrochloride, doxorubicin hydrochloride liposomal, Dox-SL (doxorubicin hydrochloride liposomal), DTIC-Dome (dacarbazine), durvalumab, efudex (fluorouracil - topical), Elitek (rasburicase), Ellens ( epirubicin hydrochloride), elotuzumab, eloxantin® (oxaliplatin), eltrombopag olamine, Emend® (aprepitant), Emplicity® (elotuzumab), enasidenib mesylate, enzalutamide, epirubicin hydrochloride, EPOCH, Erbitux® (cetuximab), eribulin mesylate, Erived®zh ( vismodegib), erlotinib hydrochloride, erwinase (Erwinia chrysanthemi Asparaginase), Etiol® (amifostin), Etofos® (etoposide phosphate), etoposide, etoposide phosphate, Evacet™ (doxorubicin hydrochloride liposomal), everolimus, Evista® (raloxifene hydrochloride), Evomela® (melphalan hydrochloride), exemestane, 5-FU (fluorouracil injection), 5-FU (fluorouracil - topical), Fareston® (toremifene), Faridak® (Panobinostat), Faslodex® (Fulvestrant), FEC, Femara® (letrozole) , Filgrastim, Fludara® (fludarabine phosphate), fludarabine phosphate, Fluoroplex® (fluorouracil - topical), fluorouracil injection, fluorouracil - topical, flutamide, Folex® (methotrexate), Folex® PFS (methotrexate), Folfiri®, Folfiribevacizumab, Folfiri- cetuximab, Folfirinox, Folfox, Folotin® (Pralatrexate), FU-LV, fulvestrant, Gardasil® (recombinant quadrivalent FIPV vaccine), Gardasil® 9 (recombinant nine-valent FIPV vaccine), Gazyva® (obinutuzumab), gefitinib, gemcitabine hydrochloride, gemcitabine-cisplatin, gemcitabine-oxaliplatin, gemtuzumab ozogamicin, Gemzar® (gemciteblatimate hydrate), Gilotrif® (afatinib dimaleate), Gleevec® (imatinib mesylate), Gliadel® (carmustine implant), Gliadel® Wafer (carmustine implant), glucarpidase, acetate goserelin, Halaven® (eribulin mesylate), Gemangeol® (propranolol hydrochloride) Herceptin® (trastuzumab), [bivalent HPV vaccine, recombinant], nine-valent HPV vaccine, recombinant], quadrivalent HPV vaccine, recombinant], Hycamtin® (hydrochloride topotecan), Hydrea® (hydroxyurea), hydroxyurea, hyper-CVAD, Ibrance® (Palbociclib), ibritumomab tiuxetan, ibrutinib, ICE, Iclusig® (ponatinib hydrochloride), Idamycin® (idarubicin hydrochloride), idarubicin hydrochloride, idelalisib, Idhifa® ( enasidenib mesylate), Ifex® (ifosfamide), ifosfamide, Ifosfamidum® (ifosfamide), IL-2 (aldesleukin), imatinib mesylate, Imbruvica® (ibrutinib), Imfinzi® (durvalmab), imiquimod, Imligic® (talimogene laherparepvec), Inlyta ® (axitinib), inotuzumab ozogamicin, [interferon alfa-2b, recombinant], interleukin-2 (aldesleukin), intron A (recombinant interferon alfa-2b), ipilimumab, Iressa® (gefitinib), irinotecan hydrochloride, irinotecan hydrochloride liposomal, Istodax ® (romidepsin), ixabepilone, ixazomib citrate, Ixempra® (ixabepilone), Jakavi® (raxolitaxab phosphate), JEB, Jevtana® (cabazitaxel), Kadcyla® (ado-trastuzumab emtansine), Keoxifene® (raloxifene hydrochloride), Kepivan® ( palifermin), Keytruda® (pembrolizumab), Kisqali® (ribociclib), Kymriach® (tisagenucleucel), Kyprolis® (carfilzomib), lanreotide acetate, lapatinib ditosylate, Lartruvo® (olaratumab), lenalidomide, lenvatinib mesylate, Lenvima® (lenvatinib mesylate) , letrozole, leucovorin calcium, Leukeran® (chlorambucil), leuprolide acetate, Leistatin® (cladribine), Levulan® (aminolevulinic acid), linfolysin® (chlorambucil), LipoDox® (doxorubicin hydrochloride liposomal), Lomustine, Lonsurf® (trifluridine and tripiracil hydrochloride), Leipron® (leuprolide acetate), Leipron® Depot (leuprolide acetate), Leipron® Depot-Ped (leuprolide acetate), Lynparza® (olaparib), Markibo® (liposomal vincristine sulfate), Matulan® (procarbazine hydrochloride), mechlorethamine hydrochloride, megestrol acetate, Mekinist® (trametinib), melphalan, melphalan hydrochloride, mercaptopurine, mesna, Mesnex® (mesna), Metazolaston® (temozolamide), methotrexate, methotrexate LPF (methotrexate), methylnaltrexone bromide, mexate (methotrexate), mexate-AQ ( methotrexate), midostaurin, mitomycin C, mitoxantrone hydrochloride, Mitozitrex® (mitomycin C), MOPP, Mozobil® (Prelixafor), Mustargen® (mechlorethamine hydrochloride), Mutamycin® (mitomycin C), Mileran® (busulfan), Milosar® (azacytidine ), Mylotarg® (gemtuzumab ozogamicin), paclitaxel bound to albumin nanoparticles, Navelbine® (vinorelbine tartrate), necitumumab, nelarabine, Neosar® (cyclophosphamide), neratinib maleate, Nerlynx® (neratinib maleate), netupitant and palonosetron hydrochloride, Neulasta® (pegfilgrastim), Neupogen® (Filgrastim), Nexavar® (Sorafenib tosylate), Nilandron® (nilutamib), nilotinib, nilutamide, Ninlaro® (ixazomib citrate), Niraparib tosylate monohydrate, Nivolumab, Nolvadex® (tamoxifen citrate), Nplat® ( romiplostim), obinutuzumab, Odomzo® (sonidegib), OEPA, ofatumumab, OFF,

- 16 043393 olaparib, olaratumab, omacetaxine mepesuccinate, Oncaspar® (pegaspargase), ondansetron hydrochloride, Onivide® (irinotecan hydrochloride liposomal), Ontak® (denileukin diftitox), Opdivo® (nivolumab), ORPA, osimertinib, oxaliplatin, paclitaxel, composition with nanoparticles with albumin-stabilized paclitaxel, PAD, palbociclib, palifermin, palonosetron hydrochloride, palonosetron hydrochloride and netupitant, pamidronate disodium, panitumumab, panobinostat, Paraplat® (carboplatin), Paraplatin® (carboplatin), pazopanib hydrochloride, PCV, REV, pegaspargase, pe gfilgrastim, peginterferon Alpha-2b, PEG-Intron (peginterferon alfa-2b), pembrolizumab, pemetrexed disodium, Perjeta® (pertuzumab), pertuzumab, Platinol® (cisplatin), Platinol®-AQ (cisplatin), plerixafor, pomalidomide, Pomalyst® (pomalidomide) , ponatinib hydrochloride, Portrazza® (necitumumab), pralatrexate, procarbazine hydrochloride, Proleukin® (aldesleukin), Prolia® (denosumab), Promacta® (eltrombopag olamine), propranolol hydrochloride, Proven®zh (sipuleucel-T), Purinetol® (mercaptopurine ), Purixan® (mercaptopurine), radium-223 dichloride, raloxifene hydrochloride, ramukirumab, rasburicase, R-CHOP, R-CVP, recombinant bivalent human papillomavirus (HPV) vaccine, recombinant nine-valent human papillomavirus (HPV) vaccine, recombinant quadrivalent human papillomavirus (HPV) vaccine, recombinant interferon alfa-2b, regorafenib, Relistor® (methylnaltrexone bromide), R-EPOCH, Revlimid® (lenalidomitrexate), Revmatrex® (methotrexate), ribociclib, R-ICE, Rituxan® (rituximab), Rituxan® Hicela (rituximab and human hyaluronidase), rituximab, rituximab and human hyaluronidase, rolapitant hydrochloride, romidepsin, romiplostim, rubidomycin (daunorubicin hydrochloride), Rubraca® (rucaparib camsilate), rucaparib camsilate, ruxolitinib phosphate, Ridapt ® ( midostaurin), Sclerosol® intrapleural aerosol (talc), siltuximab, sipuleucel-T, Somatulin® Depot (lanreotide acetate), sonidegib, sorafenib tosylate, Sprycel® (dasatinib), STANFORD V, sterile talc powder (talc), Steritalc® (talc ), Stivarga® (regorafenib), sunitinib malate, Sutent® (sunitinib malate), Silatron® (peginterferon alfa-2b), Silvant® (siltuximab), Sinribo® (omacetaxine mepesuccinate), Tabloid® (thioguanine), TAS, tafinlar ( dabrafenib), Tagrisso® (osimertinib), talc, talimogene laherparepvec, tamoxifen citrate, Tarabine® PFS (cytarabine), Tarceva® (erlotinib hydrochloride), Targretin® (bexarotene), Tasinya® (nilotinib), Taxol® (paclitaxel), Taxotere ® (docetaxel), Tecentriq® (atezolizumab), Temodar® (temozolomide), temozolomide, temsirolimus, thalidomide, Thalomid® (thalidomide), thioguanine, thiotepa, tisagenucleus, Tolac® (fluorouracil-topical), topotecan hydrochloride, toremifene, Torisel® (temsirolimus), Totect® (dexrazoxane hydrochloride), TPF, trabectedin, trametinib, trastuzumab, Treanda® (bendamustine hydrochloride), trifluridine and tipiracil hydrochloride, Trizenox® (arsenic trioxide), Tykerb® (lapatinib ditosylate), Unituxin® (dinutuximab) , uridine triacetate, VAC, valrubicin, Valstar® (valrubicin), vandetanib, VAMP, Varubi® (rolapitant hydrochloride), Vectibix® (panitumumab), VeIP, Velban® (vinblastine sulfate), Velcade® (bortezomib), Velsar® (vinblastine sulfate), vemurafenib, Venxlexta® (venetoclax), venetoclax, Verzenio® (abemaciclib), Viadur® (leuprolide acetate), Vidaza® (azacytidine), vinblastine sulfate, Vincasar® PFS (vincristine sulfate), vincristine sulfate, vincristine sulfate liposomal, vinorelbine tartrate, vismodegib, Vistogard® (uridine triacetate), Voraxaz® (glucarpidase), Vorinostat, Votrient® (pazopanib hydrochloride), Vixeos® (daunorubicin hydrochloride and cytarabine liposomal), Wellcovorin® (leucovorin calcium), Xalkori® (crizotinib), Xeloda® (capecitabine), XELIRI, XELOX, XGiva® (Denosumab), Xofigo® (radium 223 dichloride), Xtandi® (Enzalutamide), Yervoy® (ipilimumab), Yescarta® (axicabtagene ciloleucel), Yondelis® (trabectin), Zaltrap ® (zivaflibercept), Zarxio® (filgrastim), Zejula® (niraparib tosylate monohydrate), Zelboraf® (vemurafenib), Zevalin® (ibritumomab tiuxetan), Zaincard® (dexrazoxane hydrochloride), ziv-aflibercept, Zofran® (ondansetron hydrochloride) Zoladex ® (goserelin acetate), Zoledronic acid, Zolinza® (Vorinostat), Zometa® (zoledronic acid), Zydelig® (idelalisib), Zykadia® (ceritinib), Zytiga® (Abiraterone Acetate), Monoclonal antibodies - FDA-approved abciximab (Reopro) , adalimumab (Humira®, Amjevita®), adotrastumumab, emtansine (Kadcyla®), alefacept (Ameviv®), alemtuzumab (Campas®, Lemtrada®), alirocumab (Praluent®), atezolizumab (Tecentriq®), avelumab (Bavencio®) , basiliximab (Simulect®), belimumab (Benlysta®), blinatumomab (Blincyto®), brentuximab vedotin (Adcentris), bevacizumab (Avastin®), bezlotoxumab (Zinplava®), Brodalumab (Siliz®), Canakinumab (Ilaris®), pandetide capromab (Prostaskin®), Catumaxomab (Removab®), canakinumab (Ilaris®), certolizumab pegol (Cimzia®), cetuximab (Erbitux®), cixitumumab, daclizumab (Zenapax®, Zinbrita®), daratumumab (Darzalex®), denosumab ( Prolia®, Exjiva®), dinutuximab (Unituxin®), dupilumab (Dupixent®), durvalumab (Imfinzi®), eculizumab (Soliris®), elotuzumab (Repata®), efalizumab (Raptiva®), emicizumab (Hemlibra®), ertumaxomab (Rexomune®), etaracizumab (Abegreen®), evolocumab (Repata®), gemtuzumab (Ozotamixim®), gemtuzumab ozogamicin (Mylotarg®), girentuximab (Rencarex®), golimumab (Simponi®, Simponi® Aria), guselkumab, ibritumomab tiuk

- 17 043393 setane (Zevalin®), idarucizumab (Praxbind®), imciromab (Myoscint®), infliximab/inflectra (Remicad®), ipilimumab (Yervoy®), ikekizumab (Taltz®), mepolizumab (Bosatria®), natalizumab (Tysabri) ®), necitumumab (Portrazza®), nivolumab (Opdivo®), obiltoxaximab, obinutuzumab (Gazyva®), ocrel izumab (Ocrevus®), ofatumumab (Arzerra®), olaratumab (Lartruvo®), omalizumab (Xolair®), palivizumab ( Synagis®, Abbosynagis®), panitumumab (Vectibix®), pembrolizumab (Keytruda®), pertuzumab (Omnitarg®), ramucirumab (Cyramza®), ranibizumab (Lucentis®), rasibacumab, reslizumab, rituximab (Rituxan®, MabThera®), rovelizumab (LakeArrest®), ruplizumab (Antova®), secukinumab (Cosentyx®), siltuximab (Sylvant®), tocilizumab (Actemra®, RoActemra®), tositumomab (Bexar®), trastuzumab (Herceptin®), trastuzumab emtansine (Kadcyla® ), ustekinumab (Stelara®), vedolizumab (Entyvio®), PERTUZUMAB, interferon alpha, galiximab, SMART humanized anti-IL-12 antibody, dinutuximab, oregovomab, epratuzumab, anti-CD22 recombinant immunotoxin moxetumomab pasudotox, CAT-5001 (formerly SS1P ), labetuzumab, anti-alpha5Beta1-integrin, NVS antibody, efmoroctocog alpha, 3f8 (CAS # 339169-93-6), 8H9 MAb, abagovomab, abituzumab, abrilumab, actoxumab, adecatumumab, aduanumab, afasevicumab, afelimomab, afutuzumab, alazizu mab pegol . ab, bertilimumab, besilesomab (Scintimune®), biciromab (FibriSint® ), bimagrumab, bimekizumab, bivatuzumab mertansine, bleselumab, blontuvetmab (Blontress®), blosozumab, bococizumab, brazikumab, briakinumab, brolucizumab, brontictuzumab, burosumab, cabiralizumab, cantuzumab mertansine, cantuzumab ravtansine, caplacizumab, carlumab, carotuximab, cB11R96-doxorubicin immunoconjugate, cedelizumab , cergutuzumab, amunaleukin, cituzumab bogatox, clazakizumab, clenoliximab, clivatusumab tetraxetane (hPAM4-cid), codrituzumab, coltuximab ravtansine, conatumumab, concizumab, crenezumab, crotedumab, CR6261, dacetuzumab, dalotuzumab, dapriolizumab pegol, dectrecumab, demcizumab, denintuzumab mafodotin, depatuxizumab mafodotin, derlotuximab biotin, detumomab, diridavumab, domagrozumab, dorlimomab aritox, drositumab, duligotumab, dusigitumab, ecromeximab, edobacomab, edrecolomab, efalizumab, efungumab, eldelumab, elgemtumab, elsilimomab, emactuzumab, em ibetuzumab, enavatuzumab, enfortumabvedotin, enlimomabpegol, enoblituzumab, enokizumab, enoticumab, ensituximab, epitumomabcituxetan, epratuzumab, erenumab, erlizumab, etrolizumab, evinacumab, exbivirumab, fanolesomab (NeutroSpec), faralimomab, farletuzumab, fasinumab, FBTA05 (lymphomune), felvizumab, fezakinumab, fibatuzumab, ficlatuzumab , figitumumab, firivumab, flanvotumab, fleticumab, fontolizumab (HuZAF), foralumab, forovirumab, fresolimumab, fulranumab, futuximab, galcanezumab, galiximab, ganitumab, gantenerumab, gavilimomab, gevokizumab, glembatumumab, vedotin, gomiliximab, ibalizumab, icrucumab, igovomab (Indimacis-1 25™), IMAB362, imalumab, imgatuzumab , INTLAcumab, indatuximab ravtansine, indusatumab vedotin, inbilizumab, intetumumab, inolimumab, inotuzumab ozogamicin, iratumumab, isatuximab, itolizumab, keliximab, labetuzumab (CEA-cid), lampalizumab, lanadelumab, landogrosumab, laprituxime ab emtansine, lebrikizumab, lemalesomab, lendalizumab, lenzilumab, lerdelimumab, lexatumumab, libivirumab, lifastuzumab, vedotin, liglizumab, lilotomab satetraxetane, lintuzumab, lirilumab, lodelcizumab, lorvotuzumab mertansine, lucatumumab, lulizumab pegol, lumiximab, lumretuzumab, MABp1 (Xilonix™), mapatumumab, margetuximab, maslimomab, mapatumumab, margetuximab, maslimomab , mavrilimumab, matuzumab, metelimumab, milatuzumab, minretumomab, mirvetuximab soravtansine, mitumomab, mogamulizumab, monalizumab, morolimumab, motavizumab (Numax™), moxetumomab pasudotox, muromonab-CD3 (orthoclone OKT3), nacolomab tafenatox, namilumab , naftumomab estafenatox, naratuximab emtansine, narnatumab, navixizizumab, navivumab, nebacumab, nemolizumab, nerelimomab, nesvacumab, nimotuzumab (Teratsim®, Teralok®), nofetumomab merpentane (Verluma®), ocaratuzumab, odulimomab, olokizumab, onartuzumab, ontuxizumab, opicinumab, oportuzumab Monatox, Oregovomab, Orticumab, Otelizizumab , otlertuzumab, oxelumab, ozanezumab, ozoralizumab, pagibaximab, pamrevlumab, pancomab, panobakumab, parsatuzumab, pascolizumab, pasotuxizumab, pateclizumab, patritumab, pemtumomab, perakizumab, pexelizumab, pidilizumab, pinatuzumab, vedotin , pintumomab, placulumab, plosalizumab, pogalizumab, polatuzumab, vedotin , ponezumab, presalizumab, priliximab, pritoxaximab, pritumumab, PRO 140, kilizumab, racotumomab, radretumab, rafivirumab, ralpancizumab, refanezumab, regavirumab, rilotumumab, rinukumab, resankizumab, rivabazumab pego, robatumumab, roldumab, romosozumab, ritonalizumab, rovalpituzumab tesirine, sakituzumab, govitecan, samalizumab, sapelizumab, sarilumab, satumomab, pandetide, seribantumab, setoxaximab, sevirumab, sibrotuzumab, SGN-CD19A, SGN-CD33A, sifalimumab, simtuzumab, siplizumab, sirukumab, sofituzumab, vedotin, solanezuma b, solitomab, sonepcizumab, sontuzumab, stamulumab, sulesomab (LeikoScan®), suvizumab, tabalumab, takatuzumab, tetraxetane, tadocizumab, talizumab, tamtuvetmab, tanezumab, taplitumomab paptox, tarestumab, tefibazumab (Aurexis), telimomab aritox, tenatumomab, teneliximab, teplizumab, tepotumumab, tesidolumab , tetulomab, tezepelumab, TGN1412 , ticilimumab, tildrakizumab, tigatuzumab, timolumab, tizotumab, vedotin, TNX-650, Torali

- 18 043393 zumab, tosatoxumab, tovetumab, tralokinumab, TRBS07 (ectomab), tregalizumab, tremelimumab, alarmrumab, tucotuzumab, celmoleukin, tuvirumab, ublituximab, ulocuplumab, urelumab, urtoxazumab, utomilumab, vadastuximab thalirine, vandort uzumab vedotin, vantictumab, vanucizumab, vapaliximab, varlilumab, vatelizumab, veltuzumab, vepalimomab, vesenkumab, visilizumab (Nuvion), vobarilizumab, volociximab, vorsetuzumab mafodotin, votumumab (HumaSPECT®), xentuzumab, zalutumumab (HuMax-EGFr), zanolimumab (HuMax-CD4), zatuxi mab, ziralimumab, aritoximolibab, Fab, digoxin immune (sheep), recombinant cholera toxin B subunit, difitox denileukin, ranimustine (approved in Japan), resimmune (A-dmDT390-bisFv (UCHT1), MOC31PE, BL22, anti-CD22 recombinant immunotoxin BL22 (CAT-3888 ) and immunotoxin CMD-193.

NTLA, particularly NTLA dexamethasone, dosed in the range of about 3 mg/kg to about 26 mg/kg single acute dose administered from about 12 to about 72 hours before administration of cellular immunotherapy, or a total dose of about 3 mg/kg to about 26 mg/kg administered approximately 12 to 72 hours prior to administration of cell therapy increases plasma levels of IL-2 and IL-15.

NTLA, particularly NTLA dexamethasone, dosed in the range of about 3 mg/kg to about 26 mg/kg single acute dose, or a total dose of about 3 mg/kg to about 26 mg/kg, administered over about 72 hours, alone or in combination with reduced intensity of cytotoxic preconditioning may be useful for the treatment of autoimmune diseases. To treat an autoimmune disease, ACT can target the disease-causing immune cells to destroy the autoimmune recognition cells. Additionally, for autoimmune diseases, ACT can target Tregs, via a CAR or TCR, or express an antibody to an antigen expressed specifically or selectively in the area or organ of the body where the autoimmune attack occurs. Tregs may not exclusively be CD4+ Treg, CD4+ CD45RA+Treg, CD4+CD25+CD45RA Treg, FoxP3+Treg, CD4+ CD25 FoxP3 CD152+Treg, CD4+CD25+CD152+Treg, CD8+Treg, CD8+CD28-Treg , CD4+CD25int/high, CD127low, CTLA4+, GITR+, FoxP3+, CD127low, CD4+CD25- -induced Tregs or Type I Tregs.

Natural regulatory T cells, initially recognized by their constitutive expression of CD4 and CD25, can be further identified by the expression of the transcription factor foxP3 and surface CD152. Their formation and some of their suppressive activity are dependent on TGF-beta, and they have been shown to induce IDO in appropriate DCs via CD152-mediated CD80/86 ligation. Anergic CD4+ T cells generated by antigenic stimulation in the absence of costimulation appear to be characterized by an intrinsic increase in their threshold for antigenic stimulation, which may be supported by the expression of E3 ubiquitin ligases such as GRAIL, c-cbl, and Itch. Anergic cells can act as regulatory T cells by competing for sites of antigen presentation and adsorbing stimulatory cytokines such as IL-2. Tr1 cells are an induced subset of CD4 helper T cells that depend on IL-10 for their differentiation and some of their regulatory properties. They do not express foxP3, but may express markers associated with Th2 cells and the repressor of GATA (ROG). Like natural Tregs, they express high levels of surface CD152 and can induce IDO and trypophan catabolism in their respective DCs. CD8+ CD28− suppressor T(Ts) cells were first characterized in humans but have recently also been demonstrated in rodents. Like Tr1 cells, they are induced in the presence of IL-10, and IL-10 may be involved in the suppression of dendritic cell costimulation and the activation of ILT-3 and ILT-4 (in human DCs), which appear to play an important role in antigen presentation, induces tolerance in further cohorts of T cells.

Regulatory T cells (Treg) play an important role in maintaining immune homeostasis. Tregs suppress the function of other T cells to limit the immune response. Alterations in Tregs number and function have been associated with several autoimmune diseases, including multiple sclerosis, active rheumatoid arthritis, and type 1 diabetes. High levels of Tregs have been found in many cancers, including lung, pancreatic, and breast cancers. Tregs can also prevent antitumor immune responses, leading to increased mortality.

To date, two main classes of Tregs have been identified: CD4 and CD8 Tregs. CD4 Tregs consist of two types: natural Tregs (nTregs), which constitutively express CD25 and FoxP3, and so-called adaptive or inducible Tregs (iTregs).

Natural Tregs originate from the thymus as CD4+ cells ^expressing high levels of CD25 along with the transcription factor (and lineage marker) FoxP3. nTregs represent approximately 5–10% of the total CD4+ T cell population and can be first detected during the single-positive stage of T cell development. They are positively selected thymocytes with relatively high avidity to autoantigens (Fehervari Z, Sakaguchi S. Development and function of CD25+CD4+ regulatory T cells. Curr Opin Immunol. 2004; 16:203-208.)

The signal to develop into Treg cells is thought to come from the interaction between the T cell receptor and the MHC II complex with a self-peptide expressed on the thymic stroma. nTregs are essentially cytokine independent.

Adaptive or inducible Tregs originate from the thymus as single CD4 positive

- 19 043393 cells. They differentiate into CD25 and FoxP3-expressing Tregs (iTregs) after adequate antigenic stimulation in the presence of cognate antigen and specialized immunoregulatory cytokines such as TGF-β, IL-10, and IL-4. (Chatenoud L, Bach JF. Adaptive human regulatory T cells: myth or reality? J Clin Invest. 2006; 116:2325-2327.)

FoxP3 is currently the most accepted marker for Tregs, although small populations of FoxP3 ^- Tregs have been reported. The discovery of the FoxP3 transcription factor as a marker for Treg allowed scientists to better define Treg populations, leading to the discovery of additional Treg markers, including CD127.

NTLA, particularly NTLA dexamethasone, at a dose of about 3 mg/kg to about 26 mg/kg as a single acute dose, or a total dose of about 3 mg/kg to about 26 mg/kg administered over about 72 hours, alone or in combinations with reduced-intensity cytotoxic preconditioning may be useful for the treatment of residual HIV disease and for the treatment of germinal center lymphomas such as Burkitt's lymphoma.

Follicular helper CD4 T cells, T _FH , found in B cell follicles in secondary lymphoid organ tissues, are easily infected by the AIDS virus and are the main source of persistent virus, despite relative control of viral replication. This persistence is due, at least in part, to the relative exclusion of effective antiviral CD8 T cells from B cell follicles. Persistence of the AIDS virus in individuals under effective drug therapy or in those whose viremia is spontaneously controlled remains a barrier to definitive treatment. Infected follicular helper CD4 T cells, T _FH , present within B cell follicles represent the main source of this residual virus. Although effective CD8 T cell responses can control viral replication in combination with drug therapy or in rare cases spontaneously, most antiviral CD8 T cells do not enter B cell follicles, and those that do fail to reliably control viral replication in the T _FH population . Thus, these areas are a refuge and reservoir for the reproduction of AIDS viruses. Here we demonstrate that engineering unselected CD8 T cells to express CXCR5, a chemokine receptor on T _FH associated with B cell follicle localization, redirects them to B cell follicles. Lymphodepletion and reduction in the number of germinal centers and marginal zones in the spleen will result in the remaining HIV-infected cells entering the bloodstream, where they can be killed by existing treatments. Latently infected resting CD4 T cells have been found in the peripheral blood, gastrointestinal (GI) tract, and lymph nodes of HIV-1-infected individuals and likely also exist in other organs containing lymphoid tissue.

Highly active antiretroviral therapy (HAART) allows long-term suppression of plasma HIV-1 loads in infected individuals, but low-level virus persists and recovers after cessation of therapy. During HAART, this virus resides in latently infected cells, such as resting CD4 T cells, and in other cell types that can support replication of residual virus. Therapeutic eradication will require elimination of the virus from all reservoirs.

Burkitt's lymphoma is a germinal center lymphoma that arises and develops in the secondary lymphatic system, always associated with a c-Myc activating chromosomal translocation. It is one of the fastest growing types of cancer and can double every 14 to 18 hours.

Clinical observations of the ability of the Bruton's tyrosine kinase inhibitor ibrutinib in the treatment of chronic lymphocytic leukemia have shown that redistribution of CLL cells from the lymphatic system into the bloodstream is the mechanism of action contributing to its benefit in CLL. Circulating CLL cells are nonproliferative, with lineage proliferation being limited to the lymphatic microenvironment. Consequently, redistribution into the bloodstream reduces the spread of cancer. Likewise, redistribution of ALL from the bone marrow into the bloodstream also increases sensitivity to standard chemotherapy (Chang BY, Blood 2013 122: 2412-24;).

Among B-cell malignancies, CLL is the most sensitive to ibrutinib, and unfortunately, ibrutinib is unlikely to provide significant benefit to people with Burkitt lymphoma and other germinal center lymphomas. However, the same result for redistribution of B-cell cancers into the circulation, where they are more responsive to chemotherapy and less proliferative, can be achieved for germinal center lymphomas, such as Burkitt's lymphoma, using agents that remove the germinal centers of secondary lymphoid organs.

Glucocorticoids have been reported to have multiple and conflicting effects on lymphocytes depending on the dose, duration of use, and species studied. Glucocorticoids have been studied as lymphocytosis-inducing agents, agents that increase the number of circulating lymphocytes, since 1943 (for review, see Burger JA, Blood 2013 121:1501-9), typically using prednisone 0.5 to 1 mg /kg, which is equivalent to a dexamethasone dose of 0.1-0.2 mg/kg. In contrast, high-dose methylprednisone (HDMP), used for refractory CLL,

- 20 043393 apparently do not cause lymphocytosis with methylprednisone equivalent to a dose of 0.5-1.0 mg/kg at which prednisone acted. Lymphotoxic steroids at high doses are generally considered to be about 100 mg per day in terms of prednisone, which would be equivalent to dexamethasone at a dose of 16 mg, which is about 0.23 to 0.32 mg/kg, and, as we have demonstrated, is not dose of NTLA. NTLA dexamethasone does not reduce germinal centers in mice until HED 3 mg/kg is administered. Prednisone does not have a significant effect on splenic weight or germinal centers unless used in mice at doses greater than 2.5 mg/kg PO for 13 weeks (Yan SX ¹ , Acta Pharmacol Sin. 2015 Nov; 36(11): 1367- 76.), a human dose that would have unacceptable mineralocorticoid activity at a dose of 30 mg per day (~0.48 - 0.72 mg/kg), is considered a high dose in human patients with lupus.

To treat Burkitt's lymphoma (BL) with standard chemotherapy regimens such as COPADM, prednisone is included in various cycles, typically at a dose of 60 mg/ ^m2 , which converts to 1.62 mg/kg prednisone and is equivalent to a dose of dexamethasone 0. 3 mg/kg, which is not an NTLA dose. Dexamethasone is also used clinically to treat B-cell cancers, usually at an oral daily dose of 40 mg for 4-5 days or 6 mg/ ^m2 for 5 days. For some indications, such as ALL, dexamethasone is given daily for several weeks and may be associated with osteonecrosis, especially in adolescent boys. The risk of osteonecrosis can be largely eliminated by dosing dexamethasone every other week and may particularly occur in ALL due to the asparaginase regimen that is part of the treatment for ALL (Chang BY, Blood 2013 122: 2412-24).

BL is an aggressive B-cell lymphoma found in the germinal centers of the spleen and secondary lymphoid organs. Epstein-Barr virus (EBV) infection occurs in almost all African patients with BL, and chronic malaria is thought to reduce resistance to EBV, allowing it to spread. The disease typically involves the jaw or other facial bone, distal ileum, cecum, ovaries, kidney, or mammary gland. In addition, BL affects immunocompromised people, such as people with HIV.

BL is classified into three main clinical variants: endemic, sporadic, and immunodeficiency-associated variants, with the endemic variant (also called the African variant) most commonly occurring in children living in malaria-endemic regions of the world.

The use of NTLAs, which remove germinal centers to selectively direct BL and other germinal center cancer cells out of the germinal centers and into the bloodstream, where they can be more easily killed by chemotherapy or other agents, could significantly, safely, and cost-effectively improve treatment outcomes for BL.

NTLA, particularly NTLA dexamethasone, at a dose of about 3 mg/kg to about 26 mg/kg as a single acute dose, or a total dose of about 3 mg/kg to about 26 mg/kg administered over about 72 hours, alone or in combinations with reduced intensity cytotoxic preconditioning, preferably one day of cytotoxic preconditioning dosing, may be useful for preconditioning before allogeneic or autologous bone marrow transplantation or hematopoietic stem cell transplantation (HSCT).

The doses of DEX (dexamethasone base) in the examples in this application are given as human equivalent doses (HED). AVM0703 (also called AugmenStem™ or PlenaStem™) in these examples is Dex (dexamethasone base) as dexamethasone sodium phosphate in a specialized buffer.

The specific NTLA drugs listed below at standard or novel high doses may interfere with the binding and accumulation of cellular immunotherapy in secondary lymphoid organs and cause peripheral blood lymphodepletion because they are also immunosuppressants:

Tacrolimus is a calcineurin inhibitor delivered as NTLA by injection or oral dose of about 0.48 mg/kg/day to about 10 mg/kg/day for about 1 to about 4 weeks. The doses of tacrolimus required for NTLA are higher than those typically used for its approved indications. Tacrolimus (Prograf™) is approved for adult kidney transplantation. In combination with azathioprine at a dose of 0.2 mg/kg/day and in combination with an MMF/IL-2 receptor antagonist 0.1 mg/kg/day in adult liver transplantation at a dose of 0.1 to 0.15 mg/kg /day, for pediatric liver transplantation at a dose of 0.15-0.20 mg/kg/day and for adult heart transplantation 0.075 mg/kg/day, which are much lower doses than in the present invention for NTLA. Tacrolimus suppressed interleukin 2. Tacrolimus Sandoz® is approved for: Primary immunosuppression in liver, kidney, pancreas, lung, or heart allograft recipients. LIVER: Administration should begin approximately 6 hours after completion of the operation. When initiating oral therapy, an initial dose of 0.10-0.20 mg/kg/day should be administered in two divided doses. KIDNEY, PANCREAS or KIDNEY-PANCREAS: Administration should begin approximately 6 hours after completion

- 21 043393 operations. When initiating oral therapy, an initial dose of 0.15 to 0.30 mg/kg/day should be administered in two divided doses. HEART: Administration should begin no earlier than 6 hours after completion of the operation. When initiating oral therapy, the initial dose of 0.075 mg/kg/day should be administered in two divided doses. LUNGS: Administration should begin no earlier than 6 hours after completion of the operation. When initiating oral therapy, an initial dose of 0.10 to 0.30 mg/kg/day should be administered in two divided doses. Tacrolimus is associated with an increased risk of malignancies, especially lymphomas. Tacrolimus inhibits neutrophil function (Suzuki 1993). Ulrich et al (Toxicol Lett 149, 123-31, 2004) showed that 1 to 4 weeks of daily dosing of FK506 (tacrolimus) at doses ranging from 0.48 mg/kg/day to 10 mg/kg is required to reduce the number of germinal centers /day.

Cyclosporine is a cyclic polypeptide immunosuppressant administered orally as NTLA in an amount of about 20 to about 100 mg/kg/day for about 7 to about 28 days. The daily dose is divided into two and administered every 12 hours. The doses of cyclosporine required for NTLA are usually higher than the doses typically used for the approved indications. Sandimmune® (cyclosporine) is approved for an initial single oral dose of 15 mg/kg and should be given 4-12 hours before transplantation. Although most clinical trials have used a single daily dose of 14 to 18 mg/kg, a few centers still use the highest dose, with the lower end of the scale being most preferred. There is a trend towards using even lower initial doses for kidney transplantation, ranging from 10 to 14 mg/kg/day. The initial single daily dose is continued postoperatively for 1 to 2 weeks and then reduced by 5% per week to a maintenance dose of 5 to 10 mg/kg/day. Some centers have successfully reduced the maintenance dose to 3 mg/kg/day in selected renal transplant patients without an apparent increase in the incidence of rejection. Cyclosporine inhibits neutrophil function (Suzuki 1993). If blood concentrations via cyclosporine are used, the target range for Neoral® is the same as for Sandimmune®. Cyclosporine causes significant nephrotoxicity. Moriyama et al (J Vet Med Sci 74, 1487-1491 2012) showed that 7 to 28 days of cyclosporine at a dose of 20 to 100 mg/kg are required to reduce the number of germinal centers.

Anakinra (trade name KINERET®, BioVitrum, Stockholm, Sweden) is a recombinant, non-glycosylated version of human IL-1ra (RA for receptor antagonist) supplied as an injectable concentrate containing approximately 100 mg per unit dose, weekly, preferably for 3 -4 weeks before the introduction of cellular immunotherapy.

Infliximab (trade name REMICAD®, CENTOCOR ORTHO BIOTECH, Horsham, PA) is a monoclonal antibody against tumor necrosis factor alpha (TNFa). administered by intravenous infusion at a dose of about 3 mg/kg to about 10 mg/kg, weekly, preferably 3-4 weeks before the administration of cellular immunotherapy.

Golimumab (CNTO 148) is a human monoclonal antibody and is marketed under the brand name SIMPONI®, CENTOCOR ORTHO BIOTECH, Horsham, PA. Golimumab targets TNF-alpha. administered by intravenous infusion, subcutaneous injection once a month, preferably 3-6 months before the introduction of cellular immunotherapy.

Adalimumab (HUMIRA®, ABBOTT LABORATORIES, North Chicago, IL) is a TNF inhibitor, adalimumab binds to TNF, preventing it from activating TNF receptors; Adalimumab was constructed from a fully human monoclonal antibody, sold in both pre-loaded 0.8 ml syringes and pre-loaded pens, each containing 40 mg of adalimumab. To reduce the level of activity of germinal centers before the introduction of stem cells, at least 40 mg of adalimumab should be administered weekly, preferably for 3-4 weeks before the introduction of cellular immunotherapy.

Certolizumab pegol (trade name CYMZIA®, UCB Inc., Atlanta, GA) is a monoclonal antibody directed against necrosis factor alpha. More precisely, it is a pegylated Fab' fragment of a humanized monoclonal antibody to a TNF inhibitor. It was administered as two subcutaneous injections of 200 mg per week, preferably for 3-4 weeks before the introduction of cellular immunotherapy.

Eculizumab (trade name SOLIRIS®, ALEXION PHARMACEUTICALS, Cheshire, CT) is a monoclonal antibody directed against complement protein C5. This antibody blocks the breakdown of C5 and stops the process of complement-mediated cell destruction. Soliris® was administered as an intravenous infusion, given in doses of 600 mg or 900 mg, weekly, preferably for 3-4 weeks before the administration of cellular immunotherapy.

Mepolizumab (proposed trade name BOSATRIA, GLAXO SMITH KLINE, King of Russia, PA) is a humanized monoclonal antibody that recognizes interleukin-5 (IL-5), administered subcutaneously (SC) at a dose of 750 mg every four weeks, preferably for from 1 to 6 months before the introduction of cellular immunotherapy.

Omalizumab (trade name XOLAR®, GENENTECH/NOVARTIS) is a humanized antibody. Omalizumab is a recombinant DNA-derived gum

- 22 043393 nizirovanny monoclonal antibody IgGlk, which selectively binds to human immunoglobulin E (IgE). XOLAR® (omalizumab) 150 to 375 mg was administered to SC every 2 to 4 weeks, preferably 4 to 12 weeks before cellular immunotherapy administration.

Nerelimomab (BEIIX®) is a murine anti-TNF antibody and can be administered at a dose of 10 mg/kg subcutaneously per week, preferably for 1-3 months before the introduction of cellular immunotherapy.

Faralimomab is an anti-mouse TNF antibody and can be administered at a dose of 10 mg/kg per week, preferably for 3-4 weeks before the administration of cellular immunotherapy.

Elsilimomab (also known as B-E8) is a murine monoclonal antibody and immunosuppressant that blocks interleukin 6. According to the present invention, it can be administered at a dose of 10 mg/kg per week, preferably for 3-4 weeks before the administration of cellular immunotherapy.

Lebrikizumab (GENENTECH, South San Francisco, CA) is a humanized monoclonal antibody that is designed to specifically bind to IL-13 and can be administered at a dose of 10 mg/kg per week, preferably for 3 to 4 weeks prior to administration of cellular immunotherapy.

Ustekinumab (experimental name CNTO 1275, brand name STELARA®, CENTOCOR) is a human monoclonal antibody. It targets interleukin 12 and interleukin 23, natural proteins that regulate the immune system and immune-mediated inflammatory diseases. 2 injections, one month apart, 90 or 45 mg, preferably 2 months before cellular immunotherapy.

Efalizumab (trade name RAPTIVA®, GENENTECH, MERCK SERONO) is a recombinant humanized monoclonal antibody. Efalizumab binds to the CD11a subunit of lymphocyte function-associated antigen 1. According to the present invention, it can be administered once a week by subcutaneous injection at a dose of 20 mg/kg, preferably for 3-4 weeks before the administration of cellular immunotherapy.

Erlizumab, also known as rhuMAb, is a recombinant humanized monoclonal antibody developed by GENENTECH in partnership with ROCHE. According to the present invention, it can be administered once a week by subcutaneous injection at a dose of 20 mg/kg, preferably for 3-4 weeks before the administration of cellular immunotherapy. The drug works by blocking growth factor in the blood vessels. Specifically, erlizumab targets CD18 and LFA-1 integrin.

Pascolizumab is a humanized monoclonal antibody against IL-4. According to the present invention, it can be administered once a week by subcutaneous injection at a dose of 20 mg/kg, preferably for 3-4 weeks before the administration of cellular immunotherapy.

Lumiximab (BIOGEN IDEC) is a monoclonal antibody that targets CD23. According to the present invention, it can be dosed in doses ranging from 50 mg/ ^m2 to 450 mg/ ^m2 , up to 500 mg/ ^m2 weekly, preferably for 3-4 weeks before the administration of cellular immunotherapy. The drug is a chimeric antibody from Masas irus and Homo sapiens.

Teneliximab is a chimeric monoclonal antibody that binds to the immunostimulatory protein CD40. According to the present invention, it can be administered once a week by subcutaneous injection at a dose of 20 mg/kg, preferably for 3-4 weeks before the administration of cellular immunotherapy.

Toralizumab (IDEC 131, IDEC Pharmaceuticals Corporation) is a humanized monoclonal antibody to IL-6. According to the present invention, it can be administered once a week by subcutaneous injection at a dose of 20 mg/kg, preferably for 3-4 weeks before the administration of cellular immunotherapy.

Azelizumab is an anti-CD62L administered by intravenous infusion at doses ranging from 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg weekly, preferably for 3 to 4 weeks prior to administration of cellular immunotherapy.

Gavilimomab is a murine monoclonal antibody (also known as ABX-CBL, developed by ABGENIX. It binds to the CD147 antigen. According to the present invention, it can be administered intravenously at a dose of 20 mg/kg per week, preferably 3-4 weeks before the administration of cellular immunotherapy.

BG9588, a humanized anti-CD40L, administered at a dose of 20 mg/kg weekly, preferably for 3-4 weeks before cellular immunotherapy. Antibody administration to CD154, also called CD40 ligand or CD40L, is a protein that is predominantly expressed on activated T cells and is a member of the TNF superfamily of molecules. This protein binds to CD40 on antigen presenting cells (APCs), resulting in a variety of effects depending on the type of target cell. In general, CD40L plays a role as a co-stimulatory molecule and induces activation in the APC due to stimulation of the T cell receptor by MHC molecules on the APC. In total, CD40L has three binding partners: CD40, integrin α5β1 and αΠΒβ3.

- 23 043393 (Hu5c8) 5c8, a monoclonal antibody that binds CD154 (CD40 ligand), thereby blocking the interaction between CD40 and CD154, administered at a dose of 20 mg/kg weekly, preferably 3-4 weeks before the administration of cellular immunotherapy.

Belimumab (registered name BENLISTA®, formerly known as LymfoStat-B), is a fully human monoclonal antibody that specifically recognizes and inhibits the biological activity of B-lymphocyte stimulator (BLyS), also known as B-cell activating factor of the TNF family (BAFF)) HUMAN GENOME SCIENCES. According to the present invention, it can be administered at a dose of 10 mg/kg per week, preferably for 3-4 weeks before the administration of cellular immunotherapy.

Bertilimumab is a human monoclonal antibody that binds to eotaxin-1 (iCo Therapeutics Inc., Vancouver, BC). According to the present invention, it is administered at a dose of 10 mg/kg per week, preferably for 3-4 weeks before the administration of cellular immunotherapy.

Natalizumab is a humanized monoclonal antibody against the cell adhesion molecule α4 integrin. It is marketed jointly by Biogen Idec and Elan as TYSABRY®, and was formerly known as Antegren. Natalizumab was administered at a dose of 300 mg administered intravenously over approximately one hour every 4 weeks, preferably 1 to 6 months before the administration of cellular immunotherapy.

Tocilizumab or altizumab, developed by Hoffmann-La Roche and Chugai under the trade names ACTEMRA® and ROACTEMRA®, is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). According to the present invention, it can be administered by intravenous infusion at a dose of 8 mg/kg, preferably per week for 3-4 weeks before the administration of cellular immunotherapy.

Odulimomab is a murine monoclonal antibody directed against the alpha chain of lymphocyte function-associated antigen 1 protein, which is involved in immune responses. It was administered at 10 mg/kg of active drug weekly, preferably for 3-4 weeks before the administration of cellular immunotherapy.

Atorolimumab is a mouse monoclonal antibody directed against the Rh factor. According to the present invention, it can be administered at a dose of 10 mg/kg per week, preferably for 3-4 weeks before the administration of cellular immunotherapy.

Fontolizumab (trade name HuZAF®, PDL Biopharma) is a humanized monoclonal antibody against interferon gamma. According to the present invention, it can be administered intravenously at a dose of fontolizumab equal to 4.0 mg/kg or 10.0 mg/kg per week, preferably for 3-4 weeks before the administration of cellular immunotherapy.

Gantenerumab is an anti-amyloid beta monoclonal antibody (ROCHE). It was administered at a dose of 10 mg/kg of active drug weekly, preferably for 3-4 weeks before the administration of cellular immunotherapy.

Gomiliximab is a monoclonal antibody that targets the low-affinity IgE receptor (FcεRΠ or CD23). According to the present invention, it can be administered at a dose of 10 mg/kg per week, preferably for 3-4 weeks before the administration of cellular immunotherapy.

Morolimumab is a human monoclonal antibody against the human Rh factor. According to the present invention, it can be administered at a dose of 10 mg/kg per week, preferably for 3-4 weeks before the administration of cellular immunotherapy.

Pexelizumab is a single chain variable fragment monoclonal antibody targeting component 5 of the complement system. According to the present invention, it can be administered at a dose of 10 mg/kg per week, preferably for 3-4 weeks before the administration of cellular immunotherapy.

Reslizumab (CEPTION THERAPEUTICS Inc) is a humanized monoclonal antibody against IL-5. According to the present invention, it can be administered as an infusion at a preferred dose of reslizumab 3.0 mg/kg weekly, preferably for 3-4 weeks before the administration of cellular immunotherapy.

Rovelizumab, also known as LEUCARREST® and Hu23F2G, is a humanized anti-CD11/CD18 monoclonal antibody that inhibits white blood cells. According to the present invention, it can be administered at a dose of 10 mg/kg per week, preferably for 3-4 weeks before the administration of cellular immunotherapy.

Talizumab (TNX-901) is a humanized monoclonal antibody being developed by TANOX in Houston, Texas. It was designed to specifically target immunoglobulin E (or IgE) and IgE-expressing B cells without binding to IgE already bound to IgE receptors on mast cells and basophils. According to the present invention, it can be administered at a dose of 10 mg/kg per week, preferably for 3-4 weeks before the administration of cellular immunotherapy.

Omalizumab is an anti-IgE monoclonal antibody developed by TANOX, NOVARTIS and GENENTECH. According to the present invention, it can be administered at a dose of 10 mg/kg, preferably

- 24 043393 3-4 weeks before the introduction of cellular immunotherapy.

Vapaliximab is a chimeric monoclonal antibody against VAP-1. According to the present invention, it can be administered at a dose of 10 mg/kg, preferably 3-4 weeks before the administration of cellular immunotherapy.

Vepalimomab is a mouse monoclonal antibody against VAP1 (vascular adhesion protein 1). According to the present invention, it can be administered at a dose of 10 mg/kg, preferably 3-4 weeks before the administration of cellular immunotherapy.

Etanercept (trade name ENBREL®, AMGEN, Thousand Oaks, California) is a drug that treats autoimmune diseases by targeting tumor necrosis factor (TNF, part of the immune system), acting as a TNF inhibitor. Etanercept can be administered subcutaneously (SC) at a dose of 25 mg or 50 mg one to three times per week, preferably 3 to 4 weeks before the administration of cellular immunotherapy.

Pegsunercept is a pegylated soluble tumor necrosis factor receptor. According to the present invention, it can be administered at a preferred dose of 9 mg/kg subcutaneously, preferably 3-4 weeks before the administration of cellular immunotherapy.

Aflibercept is a protein consisting of segments of the extracellular domains of human vascular endothelial growth factor receptors 1 (VEGFR1) and 2 (VEGFR2) fused to the constant region (Fc) of human IgG1 with potential antiangiogenic activity and is being jointly developed by SANOFI-AVENTIS and REGENERON Pharmaceuticals. Aflibercept (VEGF Trap), an antiangiogenic agent, is a fusion protein specifically designed to bind all forms of vascular endothelial growth factor-A (called VEGF-A). In addition, aflibercept binds placenta growth factor (PLGF), which is also involved in tumor angiogenesis. Aflibercept can be administered by injection or intravenous infusion at preferred doses of 2 mg per kilogram (mg/kg) or 4 mg/kg, preferably 3 to 4 weeks before administration of cellular immunotherapy.

Alefacept (trade name AMEVIV®, ASTELLAS Pharma US, Inc. Deerfield, IL 60015) is a fusion protein: it combines part of an antibody with a protein that blocks the growth of certain types of T cells. Alefacept is an immunosuppressive dimeric fusion protein that consists of the extracellular CD2-binding portion of human antigen-3 (LFA-3) associated with lymphocyte function associated with the Fc portion (hinge domains, CH2 and CH3) of human IgG1. The preferred dosage is either 7.5 mg IV or 15 mg IM per week, preferably 3-4 weeks before cellular immunotherapy administration.

Rilonacept, also known as IL-1 decoy (marketed under the trade name AR KALIST®), is a dimeric fusion protein consisting of the extracellular domain of the human interleukin-1 receptor and the FC domain of human IgG1 that binds and neutralizes IL-1h. Treatment should begin with a loading dose of 320 mg, delivered as two 2 mL subcutaneous injections of 160 mg each, administered on the same day at two different sites, weekly, preferably 3 to 4 weeks before the administration of cellular immunotherapy. Pediatric patients aged 12 to 17 years: Treatment should begin with a loading dose of 4.4 mg/kg, up to a maximum of 320 mg, delivered as one or two subcutaneous injections with a maximum single injection volume of 2 mL, preferably 3 to 4 days before introduction of cellular immunotherapy. Manufactured by REGENERON.

Dacetumuzab (also known as SGN-40 or huS2C6, SEATTLE GENETICS, Inc.) is a humanized monoclonal antibody against CD40. The CD40 antigen is highly expressed in most B-lineage hematologic malignancies, including multiple myeloma, non-Hodgkin's lymphoma, and chronic lymphocytic leukemia. CD40 is also found on many types of solid tumors, including bladder, kidney and ovarian cancers, as well as on cells that play a role in immunological disorders. It was administered at a preferred dose of 10 mg/kg active drug weekly, preferably 3-4 weeks before the administration of cellular immunotherapy.

HCD122 is a fully human antagonistic monoclonal antibody against CD40. CD40 is a cell surface receptor that plays a key role in immune responses as well as cell growth and survival signaling through its activation by CD40 ligand (CD40L). It is commonly overexpressed and activated in B cell malignancies. According to the present invention, it can be administered at a dose of 10 mg/kg of active drug weekly, preferably 3-4 weeks before the administration of cellular immunotherapy. It was developed by XOMA/NOVARTIS ONCOLOGY.

Deficiency of adenosine deaminases will also reduce the formation of active germinal sites and will cause lymphodepletion, as will agents that trigger deoxy ATP accumulation (J Immunol 171: 5562-5570, 2003). Likewise, agents that upregulate or activate CCR7 result in decreased active germinal center formation and cause lymphodepletion.

Of all the disclosed immunosuppressant immunomodulators, the drug containing dexameth

- 25 043393 zones, which can be administered at a dose of about 3.0 to about 12.0 mg of dexamethasone per base/kg body weight from about 12 to 72 hours before the administration of cellular immunotherapy, most preferably administered at a dose of about 6.0 to 12.0 mg/kg is the most preferred method of lymphodepletion and preventing cellular immunotherapy from binding to secondary lymphoid organs so that they remain in the bloodstream where they can find and participate in the destruction of cancer cells, tumor cells or cells that cause autoimmune disorders, or infections due to - for dexamethasone's long biological half-life, short pharmacokinetic half-life and limited lack of toxicity.

Definitions.

Definitions used to describe embodiments of the invention.

Antibody-dependent cell-mediated cytotoxicity (ADCC), also called antibody-dependent cellular cytotoxicity, is a mechanism of cellular immune defense whereby an effector cell of the immune system actively lyses a target cell whose membrane surface antigens have been bound by specific antibodies. A type of immune response in which a target cell or microbe is coated with antibodies and destroyed by certain types of white blood cells. White blood cells bind to antibodies and release substances that kill target cells or microbes. Also called antibody-dependent cell-mediated cytotoxicity and antibody-dependent cellular cytotoxicity. Antibody-dependent cell-mediated cytotoxicity (ADCC) is the killing of an antibody-coated target cell by a cytotoxic effector cell through a nonphagocytic process characterized by the release of cytotoxic granule contents or expression of cell death-inducing molecules. ADCC is triggered by the interaction of target-bound antibodies (belonging to the IgG or IgA or IgE classes) with certain Fc receptors (FcR), glycoproteins present on the surface of effector cells that bind the Fc region of immunoglobulins (Ig). Effector cells that mediate ADCC include natural killer (NK) cells, monocytes, macrophages, neutrophils, eosinophils, and dendritic cells. ADCC is a rapid effector mechanism, the effectiveness of which depends on a number of parameters (density and stability of the antigen on the surface of the target cell; antibody affinity and FcR binding affinity). ADCC involving human IgG1, the most used IgG subclass for therapeutic antibodies, is highly dependent on the glycosylation profile of its Fc moiety and on Fcγ receptor polymorphism.

Complement-mediated cytotoxicity (CMC): CMC is a mechanism by which antibody-coated target cells recruit and activate components of the complement cascade, leading to the formation of a membrane attack complex (MAC) at the cell surface and subsequent cell lysis.

The biological mechanism of lymphodepletion refers to the induction of programmed cell death through apoptosis or necroptosis or pyroptosis, autophagy or oncosis. Various stimuli can induce a nonapoptotic form of cell death called necroptosis, which occurs when caspases required for apoptosis are inhibited. Pyroptosis is a caspase-dependent form of programmed cell death that differs from apoptosis in many respects. Unlike apoptosis, it depends on the activation of caspase-1 or caspase-11 (caspase-5 in humans). Autophagy is a lysosome-dependent process.

Apoptosis: A form of cell death in which a programmed sequence of events results in the destruction of cells without releasing harmful substances into the surrounding area. Apoptosis plays a critical role in the development and maintenance of body health by removing old cells, unnecessary cells and unhealthy cells.

The term and/or, as used herein, is to be understood as specifically disclosing each of the two specified features or components, with or without the other. Thus, the term and/or, when used in a phrase such as A and/or B, is intended to include A and B, A or B, A (separately) and B (separately). Likewise, the term and/or, when used in a phrase such as A, B, and/or C, is intended to cover each of the following: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (separately); B (separately); and C (separately).

The term about, when referring to a measured value such as magnitude or time duration and the like, refers to variations of +/- 20% or +/- 10%.

Administration refers to the physical administration of an agent to a subject using any of the various delivery methods and systems known to those skilled in the art. Typical routes of administration for the compositions disclosed herein include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes, such as by injection or infusion. The phrase parenteral administration as used herein means methods of administration other than enteral and local administration, typically by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcap

- 26 043393 sular, subarachnoid, intraspinal, epidural and intrasternal injections and infusions, as well as in vivo electroporation. In some embodiments, the composition is administered by a non-parenteral route, for example, orally. Other non-parenteral routes include topical, epidermal or mucosal routes of administration, such as intranasal, vaginal, rectal, sublingual or topical.

A pharmacological dose is a dose much higher than normal levels in the body.

As used herein, antitumor effect refers to a biological effect, which may be a reduction in tumor volume, a reduction in the number of tumor cells, a reduction in tumor cell proliferation, a reduction in the number of metastases, an increase in overall or disease-free survival, an increase in life expectancy, or an improvement in various physiological symptoms associated with tumor. The antitumor effect may also refer to the prevention of the occurrence of a tumor, for example by vaccination.

A therapeutic agent is an agent that increases the effectiveness of cellular immunotherapy compared to cellular immunotherapy without the specified therapeutic agent.

The term autologous refers to any material obtained from the same individual to which it must later be reintroduced, regardless of whether the individual is human or another animal.

The term allogeneic refers to any material obtained from one individual that is then administered to another individual of the same species, whether the individual is human or another animal.

The term dexamethasone (also referred to as Dex) does not refer exclusively to any formulation, whether a liquid solution, a liquid suspension, an oral solution, a tablet form, a tablet form dissolved in a liquid containing the active ingredient dexamethasone, an injectable form, a gel formulation, a patch, or any formulation containing the active ingredient dexamethasone.

The term glucocorticoid receptor modulating agents not only refers to glucocorticoid receptor agonists or glucocorticoid receptor modulators, including but not limited to: Compound A [CpdA; (2-((4-acetophenyl)-2-chloro-K-methyl) ethylammonium chloride)] and K-(4-methyl-1-oxo-1H-2,3-benzoxazin-6-yl)-4-( 2,3-dihydrobenzofuran-7-yl)-2-hydroxy-2(trifluoromethyl)-4-methylpentanamide (ZK216348), AL-438, Mapracorat, LGD-5552, RU-24858, Fosdagrocorat, PF-802, compound 10, MK5932, C108297, LGD5552 and ORG 214007-0.

Immunotoxins are proteins that contain a toxin along with an antibody or growth factor that specifically binds to target cells. Immunotoxins are created by chemically conjugating an antibody to a toxin of an entire protein lacking its natural binding domain. Immunological proteins that are smaller than monoclonal antibodies (MoAbs), such as growth factors and cytokines, have also been chemically conjugated and genetically fused to protein toxins. The toxins used in immunotoxin constructs are derived from bacteria, fungi, and plants and most act by inhibiting protein synthesis. Bacterial toxins commonly used in immunotoxins include diphtheria toxin (DT) and Pseudomonas exotoxin (PE). Plant toxins used in immunotoxins include ricin A chain (RTA) and ribosome inactivating proteins (RIPs), gelonin, phytolacca antiviral protein, and dodecandrone. Because it is an enzyme, one toxin molecule can affect many substrate molecules, causing destructive effects on the cell. Toxins such as diphtheria toxin (DT) and Pseudomonas exotoxin (PE) prevent protein synthesis by affecting elongation factor 2 (EF-2).

As used herein, the term systemic injection does not exclusively refer to a route of administration that rapidly, within seconds or several hours, results in circulating levels of cellular immunotherapy, and does not exclusively refer to intravenous, intraperitoneal, subcutaneous, transnasal, lingual, by bronchoscopy, intravenous, intraarterial, intramuscular, intraocular, intrastriatal, subcutaneous, intradermal, dermal patch, skin patch, patch, cerebrospinal fluid, portal vein, brain, lymphatic system, intrapleural, retroorbital, intradermal, spleen, intralymphatic routes of administration, among others.

As used herein, the term injection site does not exclusively refer to intratumoral or intraorgan sites, for example, kidney, liver, pancreas, heart, lung, brain, spleen or eye, intramuscular, intraocular, intrastriatal, intradermal, skin patch , patch, into the cerebrospinal fluid, into the brain, among other things.

As used herein, the term chimeric antigen receptor(s) (CAR) does not exclusively refer to constructs that contain an antibody antigen binding domain fused to a strong T cell activator domain. T cells modified with the CAR construct can bind to the antigen and are stimulated to attack the bound cells. Artificial T cell receptors (also known as chimeric T cell receptors, chimeric immunoreceptors, chimeric antigen receptors (CAR)) are engineered receptors that

- 27 043393 impart arbitrary specificity to an immune effector cell. The receptors are called chimeric because they are made up of parts from different sources.

As used herein, the term lymphodepletion does not exclusively refer to the reduction of the number of lymphocytes in the peripheral blood without causing redistribution of the lymphocytes to another organ, such as the bone marrow, thymus, lymph nodes, lung or spleen or other organ.

As used herein, the term cytotoxic lymphodepletion refers to the reduction in the number of lymphocytes in the peripheral blood through the mechanism of ADCC, CMC, or direct lysis or cytotoxic elimination of lymphocytes.

The terms cell immunotherapy, adaptive cell immunotherapy, adaptive cell therapy (ACT) or cell immunotherapy or cell therapy as used herein do not exclusively refer to treatments that involve a cell used to combat diseases of the immune system or a cell from an immune lineage, which directly combats diseases such as cancer, autoimmune diseases and infections with certain viruses. Cellular immunotherapy can be from an autologous or allogeneic source. In preferred embodiments, the adoptive immunotherapy used in the methods disclosed herein may be adoptive T cell immunotherapy, i.e. T cell therapy.

As used herein, the term preconditioning refers to preparing the patient with a cytotoxic lymphodepleting agent or NTLA prior to ACT.

The term immunotherapy, also called biologic therapy, as used herein, refers not only to a type of treatment for cancer, autoimmune disease, or infection designed to enhance the body's natural defenses to fight the cancer, autoimmune disease, or infection. It uses substances produced by the body or in a laboratory to improve or restore immune system function. The term immunotherapy refers to the treatment of a subject affected by or at risk of disease or relapse of disease, in a manner involving the induction, enhancement, suppression or other modification of an immune response. Examples of immunotherapy include, but are not limited to, T-cell therapy. T cell therapy may include adoptive T cell therapy, tumor lymphocyte immunotherapy (TIL), autologous cell therapy, engineered autologous cell therapy (eAST), and allogeneic T cell transplantation. However, one skilled in the art will understand that the conditioning methods disclosed herein will improve the effectiveness of any transplanted T cell therapy. Examples of T-cell therapy are described in US patent publications No. 2014/0154228 and 2002/0006409, Pat. US No. 5728388 and International Publication No. WO 2008/081035.

As used herein, the term immune modulation not only refers to cancer, autoimmune disease or infection, a series of procedures aimed at using the patient's immune system to achieve tumor control, cell- or virus-induced autoimmunity, stabilization and potential eradication of disease.

As used herein, the term immunomodulator not only refers to a chemical agent (eg, dexamethasone) or biological agent (eg, HUMIRA® and rituximab) that modifies the immune response or the functioning of the immune system (eg, by stimulating the production of antibodies) or inhibiting the activity of leukocytes) . Traditional immunomodulatory drugs, which are immunosuppressants, do not exclusively refer to glucocorticoids, calcineurin inhibitors, antimetabolites and alkylating agents. Antimetabolites not only refer to topurine analogues (eg, azathioprine and mycophenolate mofetil), but also to folate antagonists (eg, methotrexate and dapsone).

Immunosuppressants (also called immunosuppressants) can be chemical or biological agents that can suppress or prevent the immune response. For example, CD26 antagonists and dexamethasone are immunosuppressants. The NTLAs used in this invention may be NTLA immunosuppressants.

As used herein, the term T-cell therapy does not exclusively refer to immune cells or antibodies that can be produced in the laboratory under strictly controlled conditions and then administered to patients to treat diseases such as cancer, autoimmunity, or infection. T-cell therapy is a type of immunotherapy, and it involves taking a patient's own immune cells, specifically white blood cells called T cells, and reprogramming them to attack tumors.

Immunotherapy T cells can come from any source known in the art. For example, T cells can be differentiated in vitro from a population of hematopoietic stem cells, or T cells can be obtained from a subject. T cells can be obtained, for example, from peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from the site of infection, ascites, pleural effusion, spleen tissue and tumors. Except

- 28 043393 In addition, T cells can be obtained from one or more T cell lines available in the field. T cells can also be obtained from a unit of blood taken from a subject using any number of techniques known to one of ordinary skill in the art, such as FICOLL™ separation and/or apheresis. Additional methods for isolating T cells for T cell therapy are disclosed in US Patent Publication No. 2013/0287748, which is incorporated herein by reference in its entirety.

The term engineered autologous cell therapy, which can be abbreviated as eAST™, also known as adoptive cell transfer, is a process by which a patient's own T cells are taken and subsequently genetically modified to recognize and target one or more antigens expressed on the cell surface one or more specific cancer cells or malignant neoplasms. T cells can be engineered to express, for example, chimeric antigen receptors (CARs) or T cell receptors (TCRs). CAR-positive (+) T cells are engineered to express an extracellular single chain variable fragment (scFv) with specificity for a specific tumor antigen associated with an intracellular signaling moiety containing a co-stimulatory domain and an activating domain. The co-stimulatory domain can be derived from, for example, CD28, and the activating domain can be derived from, for example, CD3-zeta. In certain embodiments, the CAR has two, three, four or more co-stimulatory domains. The CAR scFv may be designed to target, for example, CD19, which is a transmembrane protein expressed by cells in the B cell lineage, including all normal B cells and B cell neoplasias, including, but not limited to, NHL, CLL and non T cell ALL. An example of CAR T-cell therapy therapies and constructs is described in US Patent Publications Nos. 2013/0287748, 2014/0227237, 2014/0099309 and 2014/0050708, and these references are incorporated by reference in their entirety.

The terms conditioning and preconditioning are used interchangeably herein and refer to preparing the patient or animal in need of T Cell Therapy for a suitable condition. Conditioning as used herein includes, but is not limited to, reducing the number of germinal centers and marginal zones, reducing the number of endogenous lymphocytes, removing cytokine sinks, increasing serum levels of one or more homeostatic cytokines or proinflammatory factors, enhancing T cell effector function, administered after conditioning, enhancing the activation and/or availability of antigen-presenting cells or any combination thereof prior to T-cell therapy.

The term adoptive immunotherapy or cell adoptive immunotherapy, as used herein, not only refers to immune cells that are collected from a patient (autologous or autogenous) or donor (allogeneic), related or unrelated, and grown in the laboratory. This increases the number of immune cells that are able to kill cancer cells, trigger autoimmune cells, or fight infections. These immune cells are returned to the patient to help the immune system fight the disease. This is also called cell adoptive immunotherapy. The immune cell may be a T cell and/or other cell of the immune system, not exclusively macrophages, monocytes, dendritic cells, neutrophils, granulocytes, phagocytes, mast cells, basophils, thymocytes or innate lymphoid cells, or any combination thereof.

The term agonist as used herein does not exclusively refer to any entity that activates a specific receptor or downstream signaling pathway necessary to mediate the effect(s) of the receptor. Agonists may be, but are not limited to, antibodies, antibody fragments, soluble ligands, small molecules, cyclic peptides, cross-linking agents.

As used herein, the term antagonist not only refers to any entity that interferes with the binding of opposing receptor structure(s) or the activation of a specific receptor or downstream signaling pathway necessary to mediate the action(s) of the receptor. Antagonists may be, but are not limited to, antibodies, antibody fragments, soluble ligands, Fc fusion receptors, chimeric receptors, small molecules, cyclic peptides, peptides.

As used herein, the term inhibitor does not exclusively refer to any entity that reduces the target effect of a particular receptor. Inhibitors can be small molecules, antisense agents, nucleic acids, including siRNA and microRNA.

As used herein, the term lymphocyte includes killer (NK) cells, T cells or B cells. NK cells are a type of cytotoxic (cell-toxic) lymphocyte that is a major component of the innate immune system. NK cells eliminate tumors and cells infected with viruses. It works through the process of apoptosis or programmed cell death. They are called natural killer cells because they do not require activation to kill cells. T cells play a major role in cell-mediated immunity (without participation

- 29 043393 antibodies). Their T cell receptors (TCRs) differentiate them from other types of lymphocytes. The thymus, a specialized organ of the immune system, is primarily responsible for the maturation of T cells. There are six types of T cells, namely: helper T cells (eg CD4+ cells), cytotoxic T cells (also known as TC, cytotoxic T lymphocytes, CTL, killer T cells, cytolytic T cells, CDS+ T -cells or killer T cells), memory T cells ((i) stem T scM - memory cells such as naïve cells are CD45RO-, CCR7+, CD45RA+, CD62L+(L-selectin), CD27+, CD28+ and IL -7Ra+, but they also express large amounts of CD95, IL-2R~, CXCR3 and LFA-1 and show numerous functional features characteristic of memory cells); (ii) central memory TcM cells express L-selectin and CCR7, they secrete IL-2, but not IFNy or IL-4, and (iii) effector memory TcM cells do not express L-selectin or CCR 7 but produce effector cytokines such as IFNy and IL-4), regulatory T cells (Treg, suppressor T cells or CD4+ CD25 regulatory T cells), natural killer T cells (NKT) and gamma delta T cells. B cells, on the other hand, play a major role in humoral immunity (involving antibodies). It produces antibodies and antigens and serves as antigen presenting cells (APCs) and becomes memory B cells after activation by antigen interaction. In mammals, immature B cells are produced in the bone marrow, hence its name.

The term autologous refers to any material obtained from the same individual to whom it will later be reintroduced.

The term allogeneic refers to any material obtained from another animal of the same species as the individual to which the material is administered. Two or more individuals are said to be allogenic to each other when the genes at one or more loci are not identical. In some aspects, allogeneic material from individuals of the same species may be genetically dissimilar enough to interact antigenically.

The term cancer refers to a disease characterized by the uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Examples of various types of cancer are described herein and include, but are not limited to, breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, kidney cancer, liver cancer, brain cancer, lymphoma , leukemia, lung cancer and the like. The terms cancer and malignant tumor are used interchangeably herein, for example, both terms cover solid and liquid, eg diffuse or circulating, tumors. As used herein, the term malignant tumor or cancer includes pre-malignant as well as malignant cancers and tumors.

A particular cancer may respond to chemotherapy or radiation therapy, or the cancer may be refractory. Refractory cancer refers to cancer that cannot be treated with surgery, and the cancer either does not initially respond to chemotherapy or radiation therapy, or the cancer becomes resistant over time.

As used herein, antitumor effect refers to a biological effect, which may be a reduction in tumor volume, a reduction in the number of tumor cells, a reduction in tumor cell proliferation, a reduction in the number of metastases, an increase in overall or disease-free survival, an increase in life expectancy, or an improvement in various physiological symptoms associated with tumor. The antitumor effect may also refer to the prevention of the occurrence of a tumor, for example by a vaccine.

The term progression-free survival, which may be abbreviated as PFS, as used herein, refers to the time from the date of treatment to the date of disease progression according to the revised IWG response criteria for malignant lymphoma or death from any cause.

Disease progression is assessed by measuring malignant lesions on radiographs or other methods should not be reported as adverse events. Death due to disease progression in the absence of signs and symptoms should be reported as the primary tumor type (eg, DLBCL).

Duration of response, which may be abbreviated as DOR as used herein, refers to the period of time between a subject's first objective response and the date of confirmed disease progression according to the revised IWG Response Criteria for Malignant Lymphoma or death.

The term overall survival, which can be abbreviated as OS, is defined as the time from the date of treatment to the date of death.

The dosages described herein may be presented as a dose based on body weight or a dose based on body surface area (BSA). A weight-based dose is a dose that is administered to a patient and is calculated based on the patient's weight, for example, mg/kg. The BSA-based dose is the dose that is administered to the patient and is calculated based on the patient's surface area, for example, mg/m ² . The two forms of dose measurement can be converted for human dosing by multiplying the weight-based dose by 37 or dividing the BSA-based dose.

- 30 043393 at 37.

The terms subject and patient are used interchangeably throughout this document to refer to a human or animal.

The terms reduction and reduction are used interchangeably throughout this document to indicate any change that is less than the original.

Decrease and decline are relative terms requiring comparisons before and after measurements. Diminution and decline include complete exhaustion.

Treating or treating a subject refers to any type of intervention or process carried out on a subject, or refers to the administration of an active agent to a subject for the purpose of modifying, alleviating, improving, suppressing, delaying or preventing the onset of progression, development, severity or recurrence of a symptom, complication or condition or biochemical signs associated with the disease. In one embodiment, treating or treating includes partial remission. In another embodiment, treating or treating involves complete remission.

The use of an alternative (for example, or) should be understood to mean either one, both, or any combination of alternatives. When the singular number is used herein, it should be understood that it refers to one or more of any given or listed component.

The terms about or substantially including refer to a value or composition that is within the acceptable range of error for a particular value or composition, as determined by one skilled in the art, which will depend in part on how the value or composition is measured or determined, i.e. . from the limitations of the measurement system. Thus, for example, about or substantially including may mean within 1 or more than 1 standard deviation, in accordance with practice in the art. Alternatively, about or substantially including may mean a range of up to 20% (ie ±20%). Thus, for example, about 3 mg may include any number between 2.3 mg and 3.6 mg (within 20%). Additionally, especially in relation to biological systems or processes, these terms can mean up to an order of magnitude or up to a factor of 5. When specific values or compositions are specified in the application and claims, unless otherwise indicated, it should be assumed that the value about or substantially including is within the acceptable error range for that specific value or composition.

As described herein, any concentration range, percentage range, ratio range, or integer range should be understood to include the value of any integer within the specified range and, as appropriate, fractions thereof (e.g., one-tenth and one-hundredth integer), unless otherwise stated.

Ranges: Various aspects of the invention are presented in range format. The description in range format is presented for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the range description should be considered to specifically disclose all possible subranges as well as the individual numerical values within that range. For example, the range from 3 to 12 includes 3.1, 3.2, 3.3, etc.

The spleen contains both white and red pulp. The red pulp of the spleen contains macrophages, which normally filter and remove aging or defective red blood cells (RBCs) and antibody-coated bacteria or red blood cells from the bloodstream. The white pulp of the spleen contains lymphoid compartments and is critical for immune surveillance and response: it synthesizes antibodies against invading pathogens and releases platelets and neutrophils in response to bleeding or infection. The spleen is thought to have several functions during development, including being the first site of hematopoiesis (after six weeks of pregnancy). Preclinical and clinical trials have shown that without pretreatment with cytotoxic chemotherapy, cellular immunotherapies are cleared from the circulation, primarily within one hour of administration, and accumulate in the spleen. Cytotoxic chemotherapy preconditioning should be immediately prior to administration of cellular immunotherapies to maintain cellular immunotherapies in the circulation, usually 48 hours before administration of cellular immunotherapies. When cytotoxic chemotherapy preconditioning is performed 4 weeks before or during pretreatment to allow bone marrow recovery, the conditioning does not effectively support cellular immunotherapy in the circulation Ritchie DS et al. Mol Ther. Nov;21(11):21229 (2013).

The periarteriolar lymphoid sleeves (PALS) of the white pulp of the spleen are populated primarily by T cells, whereas the lymphoid areas are populated primarily by B cells. Germinal centers (GC) are areas within lymph nodes or lymph nodes in the peripheral lymph tissues and in the white pulp of the spleen where intense mature B lymphocytes, also known as centrocytes, rapidly proliferate, differentiate, mutate through somatic hypermutation and class switching during antibody responses. Germinal centers are an important part of the B-cell humoral immune response. They develop dynamically after activation of B cells by T-dependent antigen. Histologically, GC is described microscopically

- 31 043393 distinguishable parts in lymphoid tissues. Activated B cells migrate from the primary lesion to the primary follicles of the follicular system and begin monoclonal expansion in the follicular dendritic cell (FDC) milieu.

After several days of proliferation, B cells mutate their antibody-encoding DNA and thus form diverse clones in the germinal center. This includes random substitutions, deletions and insertions due to somatic hypermutation. After some unidentified stimulus from the FDC, maturing B cells (centroblasts) migrate from the dark zone to the light zone and begin to expose their antibody to their surface, and at this stage they are called centrocytes. Centrocytes are in a state of activated apoptosis and compete for survival signals from FDCs that present antigen. This rescue process is thought to depend on the affinity of the antibody for the antigen. Functional B cells must then interact with helper T cells to obtain the final differentiation signals. This also includes isotype switching, for example from IgM to IgG. Interaction with T cells is thought to prevent the formation of autoreactive antibodies. The B cells become either antibody spreading plasma cells or memory B cells that will be activated upon subsequent exposure to the same antigen. They can also restart the entire process of reproduction, mutation and selection according to the recycling hypothesis.

B cells contained in the white pulp region of the spleen can be further divided into specific regions, identified by staining with specific molecular markers. The splenic marginal zone contains noncirculating mature B cells that border the white pulp, creating a separation between the white and red pulps, and express high levels of CD21 and IgM and CD24 and CD79a, as well as measurable levels of CD9 and CD22. The mantle zone surrounds normal germinal center follicles and expresses CD21, CD23 and CD38. The follicular zone is contained in the germinal centers and expresses high levels of IgD and CD23, intermediate levels of CD21 and CD24, and can also be identified by PNA staining. The germinal center is best differentiated for PNA binding and expresses higher levels of CD54 than the follicular zone. The germinal centers have a distinct population of helper T cells that appear to be distributed evenly throughout the germinal centers. Germinal centers have traditionally been associated with immune responses that require T helper cells, although this is not absolute. In the germinal centers, mutations of the hypervariable gene occur and B cells are generated that produce IgG with high affinity. Real macrophages and CD21-expressing dendritic cells have active germinal centers. Follicular centers can also be identified by the expression of CD45R (B220) (Cytotoxicologic Pathology, 35: 366-375, 2007). CD45R follicular centers are found around germinal centers expressing Bcl6 and Bcl2. BioEssays 29:166177, 2007; Cytotoxicol Pathol 34(5): 648-655, (2006)]

Cells of the immune system.

The response to pathogenic microorganisms or cancer cells is coordinated by complex interactions and activities of a large number of different cell types involved in the immune response. The innate immune response is the first line of defense and occurs soon after exposure to a pathogen. This is accomplished by phagocytic cells such as neutrophils and macrophages, natural killer (NK) cells, and granulocytes. The subsequent adaptive immune response induces antigen-specific defense mechanisms and may take several days. Cell types that play a critical role in adaptive immunity are antigen-presenting cells, including macrophages and dendritic cells. Antigen-dependent stimulation of various cell types, including T cell subsets, B cells, and macrophages, plays a critical role in host defense. Immune cells are not exclusively: B cells, dendritic cells, granulocytes, innate lymphoid cells (ILCs), megakaryocytes, monocytes/macrophages, myeloid-derived suppressor cells (MDSCs), natural killer (NK) cells, platelets, red cells blood (erythrocytes), T cells, thymocytes.

Cell types for cellular immunotherapy.

In certain embodiments of the invention, cellular immunotherapy can be either autologous or allogeneic, endogenous or exogenous. The cell types used for cellular immunotherapy may not exclusively, as single or combination cell therapy, be any of the following cell types: macrophages, phagocytes, tolerogenic dendritic cells, tumor infiltrating lymphocytes, adoptive cell transfer, adoptive cell therapy, adoptive T -cell therapy, chimeric antigen receptor cells, genetically engineered TCR cells, genetically engineered TCR-modified T cells, CAR-T cells, transfer of regulatory T cells, cellular adoptive immunotherapy, cellular immunotherapy, cellular immuno-oncology, in vivo complex ( IL-2C), consisting of IL-2 and anti-IL-2 monoclonal antibody (JES6-1), expanded Tregs, T cell receptor (TCR) immunogenicity for anti-T cell vaccination, autologous polyclonal anti-T cell vaccines ( TCV), adoptive transfer of B cell-dependent Tregs (B cells induced a specific subset of regulatory T cells), ado

- 32 043393 ptative transfer of GC-induced or ATF3-deficient G-MDSC (myeloid suppressor cells), genetically engineered lymphocytes, redirected autologous T cells, retargeted by RNA, natural killer T cells, NKG2D receptor cells, CD4+ cells, CD8+ cells, CD4+ T cells, CD8+ T cells, mixtures of CD4+ and CD8 T cells, MDSC, CTL, EBV-CTL, virus-specific cytocytotoxic T lymphocytes (CTL), cytokine-induced killer cells, antigen-pulsed dendritic cells cells, CMV-CTL, natural dendritic cells, dendritic cells, third-party donor-derived CTLs, autologous γδ T cell therapy, depleted CD45RA T cell infusion, laboratory-processed T cells, HER2Bi activated T cells, autologous tumor vaccine, dendritic cell (DC) vaccines loaded with allogeneic prostate cell lines, dendritic cell/AML vaccines, dendritic cell vaccines, genetically engineered lymphocytes, dendritic cell therapy, ESO-1 lymphocytes, tumor activated dendritic cells, autologous dendritic cells cell lysate-activated cells, genetically modified immune cells, bone marrow infiltrating lymphocytes, alpha-galactosylceramide-activated dendritic cells, alpha-galactosylceramide-activated natural killer T (NKT) cells, natural killer T (NKT) cells and dendritic cells , activated by alpha-galactosylceramide, autologous gamma/delta T cells, activated self lymphocytes, T lymphocytes immune to Epstein-Barr virus, derived from a normal HLA-matched or partially matched third-party donor, furin vector, autologous tumor cells, transfected granulocyte macrophage colony-stimulating factor vector plus bi-shRNAi, alpha-galactosylceramide-activated dendritic cells (Chiba-NKT), p53-activated dendritic cells, CMVpp65-specific T cells derived from a primary transplant donor, mixed natural T-phenotype cells cells and natural killer (NK) cells (CIK cells), antigen activated dendritic cells (APDC), DC-CLK, APC activated, alpha-GalCer, zoledronate activated autologous killer lymphocytes (Zak cells), Chiba NKT cells, autologous dendritic cells loaded with autologous tumor lysate or homogenate, CMVpp65-specific T cells obtained from third-party donors, D-CIK activated by autologous tumor, autologous dendritic cells with multi-epitope TARP peptide, adoptive transfer of T-reg cells (TRACT), modified DLI (donor double negative T cells), polarized dendritic cells type 1 (AlphaDC1), DC-CIK cells antigen-sensitized by autologous tumor tissue, peptide-activated dendritic cells, dendritic cytocytotoxic lymphocyte (DC-CTL) cells, MTCR-transduced autologous lymphocytes peripheral blood, cytokine-induced memory cell-like NK cells, LMP-specific DLI-modified T cells (double-negative related donor T cells), autologous dendritic cells loaded with autologous tumor homogenate, engineered autologous cell therapy (EATC) Vigil ®, novel antigen reactive cell therapy (NRT), autologous cytokine-induced killer cells, autologous dendritic cell fusions, peptide-specific CTLs, ACIT-1, PD-1 immunoglobulin immunotherapy, knockout engineered T cells, DC/fusion cells AML, (DC/PC3), laboratory-processed T cells, tumor-dendritic cell fusion cells, lethally irradiated autologous breast cancer cells, CD4-ZETA gene-modified T cells, EBV-specific immune effector cells (EBV- LE), herpes virus (HHV) specific immune effector (IE) cells, mRNA-transfected dendritic cells, allogeneic dendritic cell therapy, cytomegalovirus (CMV) Pp65-specific lymphocytes, alpha-galactosylceramide-activated peripheral blood mononuclear cells, T-depleted cells, donor dendritic cell vaccination, DC vaccine combined with cytokine-induced killer cells, DC vaccine combined with CIK cells, DC activated by HB-vac, haploidentical NK cell infusion, ZNK cells, WT1 and MUC1 dendritic cells , ONETregl cells, alpha-DCl, autologous ADCC T cells, memory T cell infusion, DC1, activated HER-2/Neu, stimulated autologous CD4+ T cells, gamma delta T cells, irradiated allogeneic lung adenocarcinoma cells, CD40LGVAX , irradiated allogeneic lung adenocarcinoma cells combined with a bystander cell line transfected with hCD40L and hGM-CSF, EGFRBi-armed autologous T cells, PD-L silenced DC, loaded with MiHA, MyDC/pDC, ROR-1.taNK, PDLl.taNK , adjuvant dendritic cell immunotherapy, D-CIK, DOT cells, autologous tumor lysate (TL) plus yeast cell wall particles (YCWP) plus dendritic cells, autologous EBV-specific cytocytotoxic T cells, autologous TLPLDC vaccine (tumor lysate, particle load, dendritic cells), regulatory T cells, personalized cell vaccine (PERCELLVAC), CAR-pNK cell, HER2.taNK, MUC16.taNK, DC1s-CTL, (PERCELLVAC2), (PERCELLVAC3), MASCT, CAR-pNK cells, CD33 .taNK, umbilical cord blood dendritic cells HCT, cord blood regulatory T cells, highly active natural killer cells, PD-1 knockout EBV-CTL, DC-CTL combined with CIK, antigen-containing dendritic cells, dendritic fusions

- 33 043393 cells/tumors, transfected dendritic cells, Her2 and TGF-beta CTL, blood T cells and EBV-specific CTL, autologous breast cancer cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF), genetically modified leukocytes, epitope -enhanced TARP peptide and TARP peptide activated dendritic cells, laboratory processed autologous lymphocytes, multiviral CTL, cytomegalovirus-specific T cell adoptive transfer (ERaDICATe), GM-K562 cells, kappa CD28 T lymphocytes, TGFB2 gene modified antisense-GMCSF autologous tumor cells, autologous tumor cells augmented with Bi-shRNA-furin and granulocyte-monocyte colony-stimulating factor (GMCSF), donor T cells sensitized with CMV-PP65 protein pentadecapeptides, vaccination with dendritic cells derived from monocytes activated with a peptide to propagate adoptively transferred CMVs -specific cytocytotoxic T lymphocytes, CMV-specific DLI from 3-6/6 HLA family member, autologous T cells in combination with autologous OS-DC, TAA-specific CTL, autologous lymphocytes, autologous tolerogenic dendritic cells, Langerhans dendritic cells , Langerhans dendritic cells, electroporated mRNA encoding tumor-associated antigen, autologous T cells, multiviral cytocytotoxic T cells, autologous tumor cells expressing IL2 ligand and CD40, engineered DCs with multiple antigens, dendritic cells activated by WT1 peptide and/or tumor lysate, autologous human cytomegalovirus (HCMV)-specific T-cell therapy, Ad/HER2/Neu dendritic cell, WT1 peptivator-activated dendritic cell, donor, multivirus-specific cytotoxic T-lymphocytes, ex-vivo expanded donor regulatory T cells, antigen presenting cells (APC), activated alpha-GalCer, cytokine-induced NK cells, similar to memory cells, re-stimulated tumor infiltrating lymphocytes, autologous dendritic Langerhans cells, memory cell-enriched T cells, expanded multiantigen-specific lymphocytes, TAA-specific CTLs, regulatory dendritic cells, well-matched third-party generated LMP, BARF1 and EBNA1 specific CTLs, activated bone marrow infiltrating lymphocytes, autologous tumor lysate-loaded dendritic cells, autologous multi-epitope TARP peptide-loaded dendritic cells, HPV-16/18 E6 /E7-specific T lymphocytes, Epstein-Barr virus-specific T cells, Activated T cells, donor MultiTAA-specific T cells, MultiTAA-specific T cells, type I-polarized autologous dendritic cells, vaccine-enriched autologous activated T -cells, polyvirus-specific cytocytotoxic T-lymphocytes (mCTL), allogeneic virus-specific T-cell lines (VST), donor regulatory T-cells, TCR-modified T-cells (TCR), MIC-cells, adoptive T-cell activated P53-specific T cell therapy, MUC1-DC-CTL, modified T cell receptor T cells, negative dendritic cell vaccine, tolDC, CD22-redirected autologous T cells, Dendristim, primary NK cells, lentivirus-based genetically modified cell therapy products CART-EGFRvIII, autologous dendritic cells activated by lysed allogeneic tumor lines, expanded multiantigen-specific lymphocytes, PD-1 knockout engineered T cells, GSC-loaded dendritic cells, adoptive transfer of Treg cells (TRACT) , E7 TCR T cells, PD-1 knockout engineered T cells, CAR-Treg (ENTX-DN), chimeric switch receptor modified T cells, neoantigen-doped dendritic cells (DC), pre-activated (PreT) T -cells, TSA-CTL (tumor-specific antigen-induced cytocytotoxic T lymphocytes), allogeneic cell immunotherapy (ACIT-1), autologous OS-DC, mature dendritic cells, CD8+ cells NKG2D AKT, natural killer (NK) cells - oNKord® , antigen presenting cells - sDCord®, an allogeneic GM-CSF-transfected pancreatic tumor vaccine.

Cellular immunotherapy can be genetically modified. Cellular immunotherapy can be CRISPR/Cas9, TALEN, piggy-bac transposon, transposase, Sleeping Beauty, serine recombinase, CRE-lox recombinase, RheoSwitch®, recombinase, lipofection, nucleofection, zinc finger nuclease, chemical, plasmid, biological, ARCUS, homingendonuclease or virus-modified. Cellular immunotherapy cells can be constructed using a plasmid carrying a gene vector for shRNA Furin and GMCSF (VIGIL®).

In certain embodiments of the invention, it would be desirable to exclude and avoid the use of certain types of cells for cellular immunotherapy, including:

macrophages, phagocytic cells, tolerogenic dendritic cells, tumor infiltrating lymphocytes, adoptive cell transfer, adoptive cell therapy, chimeric antigen receptor cells, genetically engineered TCR cells, regulatory T cell transfer, cell adoptive immunotherapy, cellular immunotherapy, cellular immune oncology , in vivo complex (IL-2C), consisting of IL-2 and anti-IL-2 monoclonal antibodies (JES6-1), expanded Tregs, immunogenicity

- 34 043393

T cell receptor (TCR) for T cell vaccinations, autologous polyclonal T cell vaccines (TCV) adoptive transfer of B cell-dependent Tregs (B cells induced a specific subset of regulatory T cells), adoptive transfer of GC-induced or ATF3-deficient Gs -MDSC (myeloid suppressor cells), genetically engineered lymphocytes, RNA redirected autologous T cells, natural killer T cells, NKG2D receptor cells, CD4+ cells, CD8+ cells, CD4+ T cells, CD8+ T cells, mixtures of CD4+ and CD8 T cells, MDSC, CTL, EBV-CTL, virus-specific cytotoxic T lymphocytes (CTL), cytokine-induced killer cells, antigen-activated dendritic cells, CMV-CTL, natural dendritic cells, dendritic cells derived from third-party CTL donors , autologous γδ T cell therapy, infusion of depleted CD45RA T cells, laboratory-engineered T cells, HER2Bi-armed activated T cells, autologous tumor DC vaccine, dendritic cell (DC)-based vaccines loaded with allogeneic prostate cell lines, vaccine-based dendritic cells/AML, dendritic cell vaccines, genetically modified lymphocytes, dendritic cell therapy, ESO-1 lymphocytes, tumor activated dendritic cells, autologous tumor lysate activated dendritic cells, genetically modified immune cells, bone marrow infiltrating lymphocytes, dendritic cells activated by alpha-galactosylceramide, natural killer T cells (NKT) activated by alpha-galactosylceramide, dendritic cells and natural killer T cells (NKT) activated by alpha-galactosylceramide, autologous gamma/delta T cells, activated self-lymphocytes , Epstein-Barr virus-immune T lymphocytes derived from a normal HLA-matched or partially matched third-party donor, autologous tumor cells transfected with granulocyte macrophage colony-stimulating factor plus bi-shRNAi furin vector, dendritic cells (Chiba-NKT) activated by alpha-galactosylceramide , P53-activated dendritic cells, CMVpp65-specific T cells derived from primary transplants, mixed phenotype T-cell and natural killer cells (CIK cells), antigen-activated dendritic cells (APDC), DC-CIK, APC , activated AlphaGalCer, zoledronate-activated autologous killer lymphocytes (Zak cells), Chiba NKT cells, autologous dendritic cells loaded with autologous tumor lysate or homogenate, CMVpp65-specific T cells derived from a third-party donor, D-CIK activated with autologous tumor lysate tumors, autologous dendritic cells with multi-epitope TARP peptide, adoptive transfer of T-reg cells (TRACT), DLI (donor double negative T cells), polarized dendritic cells type 1 (AlphaDC1), DC-CIK cells sensitized with autologous tumor antigen , peptide activated dendritic cells, transduced dendritic cytocytotoxic lymphocytes (DC-CTL), MTCR-transduced autologous peripheral blood lymphocytes, cytokine-induced NK cells like memory cells, LMP-specific DLI-modified T cells (double negative T-related donors) cells), autologous dendritic cells loaded with autologous tumor homogenate, VIGIL® engineered autologous tumor cell therapy, novel antigen-reactive immune cell therapy (NRT), autologous cytokine-induced killer cells, fused autologous dendritic cells, peptide-specific CTL, allogeneic immunotherapy ACIT-1 cells, PD-1 knockout engineered T cells, DC/AML fusion cells (DC/PC3), laboratory-processed T cells, tumor-dendritic cell fusions, lethally irradiated, autologous breast cancer cells, T CD4-ZETA gene-modified cells, EBV-specific immune effector cells (EBV-IE), herpes virus (HHV)-specific immune effector (IE) cells, mRNA-transfected dendritic cells, allogeneic dendritic cell therapy, lymphocyte-specific to cytomegalovirus (CMV) Pp65, alpha-galactosylceramide-activated peripheral blood mononuclear cells cultured with IL-2/GM-CSF, depleted T cells, donor dendritic cell vaccination, DC vaccine in combination with cytokine killer cells, DC vaccine in combination with CIK cells, HB-vac activated DC, haploidentical NK cell infusion, ZNK cells, WT1 and MUC1 peptide activated dendritic cells, ONETreg1 cells, alpha-DC1, autologous ADCC T cells, memory T cell infusion , DC1, activated HER-2/Neu, stimulated autologous CD4+ T cells, gamma delta T cells, irradiated allogeneic lung adenocarcinoma cells, CD40LGVAX, irradiated allogeneic lung adenocarcinoma cells combined with a bystander cell line transfected with hCD40L and hGM-CSF , autologous T cells armed with EGFRBi, PD-L silenced DCs loaded with MiHA, MyDC/pDC, ROR-1.taNK, PDL1.taNK, adjuvant dendritic cell immunotherapy, DCIK, DOT cells, autologous tumor lysate (TL) plus yeast cell wall particles (YCWP) plus dendritic cells, autologous EBV-specific cytocytotoxic T cells, autologous TLPLDC vaccine (tumor lysate loaded particle dendritic cells), regulatory T cells, personalized cell vaccine (PERCELLVAC), CAR-pNK -cell, HER2.taNK, MUC16.taNK, DC1s-CTL, (PERCELLVAC2), (PERCELLVAC3), MASCT, CAR-pNK cells,

- 35 043393

CD33.taNK, cord blood dendritic cells HCT, cord blood regulatory T cells, highly active natural killer cells, EBV-CTL, PD-1 knockout, DC-CTL in combination with CIK, antigen-containing dendritic cells, dendritic cell/tumor fusion cells, transfected dendritic cells, Her2 and TGF-beta CTL, blood T cells and EBV-specific CTL, autologous breast cancer cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF), genetically engineered leukocytes, epitope-enhanced peptide TARP and TARP peptide-activated dendritic cells, laboratory-processed autologous lymphocytes, multiviral CTLs, adoptive transfer of cytomegalovirus-specific T cells (ERaDICATe), GM-K562 cells, kappa CD28 T cells, gene-modified TGFB2-antisense-GMCSF autologous tumor cell, autologous tumor cells augmented with Bi-shRNA-furin and granulocyte-monocyte colony-stimulating factor (GMCSF), donor T cells sensitized with CMV-PP65 protein pentadecapeptides, vaccination with monocyte-derived peptide-activated dendritic cells to propagate adoptively transferred CMVs -specific cytocytotoxic T lymphocytes, CMV-specific DLI from a member of the 3-6/6 HLA-related family, autologous T cells in combination with autologous OS-DC, TAA-specific CTL, autologous lymphocytes, autologous tolerogenic dendritic cells, Langerhans dendritic cells, Langerhans dendritic cells electroporated with mRNA encoding tumor-associated antigen, autologous T cells, multiviral cytocytotoxic T cells, autologous tumor cells expressing IL2 ligand and CD40, engineered DCs with multiple antigens, dendritic cells activated by WT1 peptide and/or tumor lysate, autologous human cytomegalovirus (HCMV)-specific T-cell therapy, Ad/HER2/Neu dendritic cell, WT1 peptivator-activated dendritic cell, donor, multi-virus-specific cytotoxic T lymphocytes, ex-vivo expanded donor regulatory T -cells, antigen presenting cells (APC), activated alpha-GalCer, cytokine-induced NK cells, memory cell-like cells, re-stimulated tumor-infiltrating lymphocytes, autologous dendritic Langerhans cells, memory cell-enriched T cells, expanded multiantigen-specific lymphocytes , TAA-specific CTLs, regulatory dendritic cells, well-matched third-party generated LMP, BARF1 and EBNA1 specific CTLs, activated bone marrow infiltrating lymphocytes, autologous tumor lysate-loaded dendritic cells, autologous multi-epitope TARP peptide-loaded dendritic cells, HPV-16/18 E6/E7 specific T lymphocytes, Epstein-Barr virus specific T cells, Activated T cells, donor MultiTAA-specific T cells, MultiTAA specific T cells, type I polarized autologous dendritic cells, vaccine-enriched autologous activated T cells, polyvirus-specific cytocytotoxic T lymphocytes (mCTL), allogeneic virus-specific T-cell lines (VST), donor regulatory T cells, TCR-modified T cells (TCR), MIC cells, adoptive T-cell therapy with activated P53-specific T cells , MUC1-DC-CTL, T-cell receptor-modified T cells, dendritic cell-based negative vaccine, tolDC, CD22-redirected autologous T cells, Dendristim, primary NK cells, CARTEGFRvIII-based genetically modified cell therapy products lentiviruses, autologous dendritic cells activated by lysed allogeneic tumor lines, expanded multiantigen-specific lymphocytes, PD-1 knockout engineered T cells, GSC-loaded dendritic cells, adoptive transfer of Treg cells (TRACT), E7 TCR PD-knockout T cells 1 engineered T cells, CAR-Treg (ENTX-DN), chimeric switch receptor modified T cells, neoantigen-doped dendritic cells (DC), pre-activated (PreT) T cells, TSA-CTL (tumor-specific antigen-induced cytocytotoxic T -lymphocytes), allogeneic cell immunotherapy (ACIT-1), autologous OS-DC, mature dendritic cells, CD8+ NKG2D AKT cells, natural killer (NK) cells - oNKord®, antigen presenting cells sDCord®, allogeneic GM-CSF-transfected vaccine pancreatic tumors.

Chimeric antigen receptor targets.

In some embodiments of the invention, the chimeric antigen receptor (CAR) T cells or genetically modified cellular immunotherapy may be a single target or multiple target combinations of any of the targets listed below. The receptor/ligand or antibody expressed by a chimeric antigen receptor T cell or cellular immunotherapy may be mono- or bi-specific or multi-specific. In some embodiments of the invention, the cellular immunotherapy cannot be genetically modified for any specific target. In some embodiments of the present invention, the cellular immunotherapy will be started or activated in the laboratory to enhance the immune activity of the cellular immunotherapy before administering the cellular immunotherapy to the patient.

Expressed receptor/ligand or antibody target or cellular immunotherapy target

- 36 043393 may be selected from the following list of receptors/ligands or targets, which includes, but is not limited to: proto-oncogene tyrosine protein kinase ABL1, citrullinated antigen, ErbB2/HER2, CD16, WT-1, KRAS, glypican 3, CD3, CD20, CD226, CD155, CD123, HPV-16 E6, MelanA/MART-1, TRAIL, DR4 receptor-associated, LMP, MTCR, ESO, NY-ESO-1, gp100, 4SCARGD2/CD56, mesothelin (CAK1 or Pre Pro megakaryocytic antigen potentiating factor or MSLN); DNA synthesis inhibitor; histamine H1 receptor antagonist (HRH1); inhibitor of prostaglandin G/H synthase 2 (cyclooxygenase 2 or COX2 or prostaglandin endoperoxide synthase 2 or PHS II or prostaglandin H2 synthase 2 or PTGS2 or EC 1.14.99.1), CD19 (surface antigen B lymphocytes, antigen B4 or differentiation antigen CD19 or T- cell antigen Leu 12 or CD19), cell adhesion molecule 5 (carcinoembryonic antigen or CEA or meconium antigen 100 or CD66e or CEACAM5); interleukin 2 receptor (IL2R) agonist, epidermal growth factor receptor (proto-oncogene with ErbB 1 or receptor tyrosine protein kinase erbB 1 or HER1 or ERBB1 or EGFR or EC 2.7.10.1); DNA ligase inhibitor (EC 6.5.1.); DNA ligase (EC 6.5.1.), DNA polymerase inhibitor alpha (POLA or EC 2.7.7.7); DNA primase inhibitor (EC 2.7.7.6); ribonucleoside diphosphate reductase inhibitor (ribonucleotide reductase or RRM or EC 1.17.4.1); RNA polymerase II inhibitor (RNAP II or Pol II or EC 2.7.7.6), DNA polymerase inhibitor (EC 2.7.7.7); DNA topoisomerase II inhibitor (EC 5.99.1.3); CD22, meso, DNA primase (EC 2.7.7.6); programmed cell death protein 1 ligand inhibitor 1 (PD L1 or B7 homolog 1 or CD274); RNA polymerase II inhibitor (RNAP II or Pol II or EC 2.7.7.6), histone lysine N-methyltransferase inhibitor EZH2 (ENX 1 or Zeste homolog 2 enhancer or lysine N-methyltransferase 6 or EZH2 or EC 2.1.1.43); 1 programmed cell death protein 1 ligand (PD L1 or B7 homologue 1 or CD274), CXC chemokine receptor type 4 antagonist (FB22 or Fusin or HM89 or LCR1 or leukocyte seven transmembrane domain receptor or lipopolysaccharide-associated protein 3 or stromal derived receptor cells 1 NPYRL or CD184 or CXCR4); granulocyte colony-stimulating factor receptor (CD114 or GCSFR or CSF3R), adenosine deaminase (adenosine aminohydrolase or ADA or EC 3.5.4.4) agonist inhibitor; 17, a member of the tumor necrosis factor receptor superfamily (B-cell maturation antigen or CD269 or TNFRSF17), cytocytotoxic to cells expressing the inactive transmembrane tyrosine protein kinase receptor ROR1 (neurotrophic tyrosine kinase receptor-related protein 1, or ROR1 or EC 2.7.10.1); T cell surface CD3 epsilon chain glycoprotein (T3/Leu 4 T cell surface antigen epsilon chain or CD3E); dihydrofolate reductase inhibitor (DHFR or EC 1.5.1.3); ephrin inhibitor type A 2 (inhibitor of epithelial cell or tyrosine-protein kinase receptors ECK or EPHA2 or EC 2.7.10.1); glucocorticoid receptor agonist (GR or nuclear receptor subfamily 3, group C, 1 member, or NR3C1); mast cell/stem cell growth factor receptor set inhibitor (c-Kit proto-oncogene or tyrosine-protein kinase set or v-Kit Hardy Zuckerman 4 feline sarcoma viral oncogene homolog, or Piebald Trait protein or p145 c set or CD117, or KIT, or EC 2.7. 10.1); platelet-derived growth factor receptor beta inhibitor (platelet-derived growth factor receptor beta, or CD140 antigen-like family member B, or platelet-derived growth factor receptor 1, or CD140b, or PDGFRB, or EC 2.7. 10.1); tubulin inhibitor; CSK protein tyrosine kinase inhibitor (C-Src kinase or protein tyrosine kinase CYL or CSK or EC 2.7.10.2); inhibitor of tyrosine-protein kinase Fyn (Syn proto-oncogene or c-Fyn proto-oncogene or Src-like kinase or p59 Fyn or FYN or EC 2.7.10.2); tyrosine-protein kinase inhibitor Lck (leukocyte terminal Src kinase or YT16 protein or Lck proto-oncogene or T-cell specific protein tyrosine kinase or lymphocyte-specific protein tyrosine kinase or p56 LCK or LCK or EC 2.7.10.2); tyrosine-protein kinase inhibitor Yes (proto-oncogene c-Yes or p61 Yes or YES1 or EC 2.7.10.2), tumor necrosis factor inhibitor (cachectin or TNF alpha or 2 representative of the tumor necrosis factor ligand superfamily or TNF a or TNF), signal transporter inhibitor and transcription activator 3 (acute phase response factor or APRF or STAT3 binding protein), Bcr-Abl tyrosine kinase inhibitor (EC 2.7.10.2); dihydrofolate reductase (DHFR or EC 1.5.1.3); ephrin receptor type A 2 (epithelial cell kinase receptor or tyrosine-protein kinase ECK or EPHA2 or EC 2.7.10.1); mast/stem cell growth factor receptor Kit (c-Kit proto-oncogene kit or c-Kit protein tyrosine kinase or Hardy Zuckerman v-Kit 4 feline sarcoma viral oncogene homolog or Piebald Trait protein or p145 kit c-Kit or CD117 or KIT or EU 2.7.10.1 ); platelet-derived growth factor receptor beta, beta type (platelet-derived growth factor receptor, or CD140 antigen-like family member B, or platelet-derived receptor 1, or CD140b, or PDGFRB, or EC 2.7.10.1) ; tubulin; CSK protein tyrosine kinase inhibitor (c-Src kinase or protein tyrosine kinase CYL or CSK or EC 2.7.10.2); inhibitor of tyrosine-protein kinase Fyn (Syn proto-oncogene or cFyn proto-oncogene or Src-like kinase or p59 Fyn or FYN or EC 2.7.10.2); inhibitor of tyrosine protein kinase Lck (leukocyte terminal Src kinase or protein YT16 or proto-oncogene Lck or T-cell specific protein tyrosine kinase or lymphocyte-specific protein tyrosine kinase or p56 LCK or LCK or EC 2.7.10.2); protein tyrosine kinase inhibitor Yes (proto-oncogene c-Yes or

- 37 043393 р61 Yes or YES1 or EC 2.7.10.2); activator of caspase 9 (activator of apoptotic protease Mch 6 or activating apoptotic protease 3 or ICE-like apoptotic protease 6 or CASP9 or EC 3.4.22.62); prostate stem cell antigen (PSCA), melanoma antigen predominantly expressed in tumors (cancer/testis antigen 130 or Ora-interacting protein 4 or OIP4 or predominantly expressed melanoma antigen or PRAME), signal transporter and activator of transcription 3 (responsive factor acute phase or DNA binding protein inhibitor APRF or STAT3), CD44 antigen (CDw44 or epican or extracellular matrix receptor III or GP90, lymphocyte homing/adhesion receptor or HUTCH I, or heparan sulfate, proteoglycan or Hermes antigen, or hyaluronate receptor, or phagocytic glycoprotein 1, CDG 1) receptor tyrosine kinase AXL (anexelekto), GAS6, receptor tyrosine kinases TAM, TYRO-3 (also known as Brt, Dtk, Rse, Sky and Tif), AXL (also known as Ark, Tyro7 and Ufo) and MER (also known as Eyk, Nym and Tyro12), CTLA4, 8 member of the tumor necrosis factor receptor superfamily (CD30L receptor or Ki antigen 1 or lymphocyte activation antigen CD30 or CD30 or TNFRSF8), caspase activator 9 (apoptotic protease Mch 6 or apoptotic protease A activating factor 3 or ICE , such as apoptotic protease 6 or CASP9 or EC 3.4.22.62); Cytocytotoxicity for cells expressing ganglioside GD2; inhibitor of prostaglandin G/H synthase 1 (cyclooxygenase 1 or COX1 or prostaglandin endoperoxide synthase 1 or prostaglandin H2 synthase 1 or PTGS1 or EC 1.14.99.1); cytokines, interleukins, claudin 6 (scullin or CLDN6), NKG2D, MICA, MICB and ULBP 1-6, NKp30, B7H6 (NCR3LG1), Bag6, B7 family, activator of CD40 ligand (T cell antigen Gp39 or activator protein related TNF or tumor necrosis factor ligand superfamily member 5 or CD154 or CD40LG); Interleukin 12 activator (IL12), interleukin 3 receptor alpha subunit (IL3RAMast/pocT stem cell F), receptor activator Kit (c-Kit proto-oncogene or Hardy Zuckerman tyrosine protein kinase set or v-Kit, feline sarcoma virus oncogene homolog 4, or Piebald protein Trait or p145 c-Kit or CD117 or KIT or EC 2.7.10.1) antagonist; inhibitor of proto-oncogene receptor tyrosine protein kinase Ret (12 member of the catherin family or proto-oncogene cRet or RET or EC 2.7.10.1); FLT3 type receptor tyrosine kinase antagonist (FMS-like tyrosine kinase 3 or FL cytokine receptor or stem cell tyrosine kinase 1 or fetal liver kinase 2 or CD135 or FLT3 or EC 2.7.10.1); vascular endothelial growth factor receptor 1 antagonist (FMS-like tyrosine kinase 1 or receptor tyrosine kinase FLT or tyrosine protein kinase FRT or vascular permeability factor receptor or VEGFR1 or FLT1 or EC 2.7.10.1); vascular endothelial growth factor receptor 2 antagonist (fetal liver kinase 1 or receptor containing a kinase domain or protein tyrosine kinase receptor flk 1 or VEGFR2 or CD309 or KDR or EC 2.7.10.1); vascular endothelial growth factor receptor antagonist 3 (FMS-like tyrosine kinase 4 or receptor tyrosine kinase FLT4 or VEGFR3 or FLT4 or EC 2.7.10.1), caspase activator 9 (apoptotic protease Mch 6 or apoptotic protease activating factor 3 or ICE-like apoptotic protease 6 or CASP9 or EC 3.4.22.62), cytocytotoxic T-lymphocyte protein 4 antagonist (cytocytotoxic T-lymphocyte-associated antigen 4 or CD152 or CTLA4), myeloid cell surface antigen CD33 (sialic acid-binding lectin-like Ig 3 or gp67 or CD33) , hepatocyte growth factor receptor (c-Met proto-oncogene or tyrosine-protein kinase Met, or HGF/SF receptor, or scatter factor receptor, or MET or EC 2.7.10.1), epithelial cell adhesion molecule (adenocarcinoma-associated antigen or cell surface glycoprotein Trop 1 or epithelial cell surface antigen or epithelial glycoprotein 314 or KS 1/4 antigen or KSA or tumor-associated calcium signal transducer 1 or CD326 or EPCAM), ganglioside GD2, Lewis antigen Y (CD174), latent membrane protein 1 (p63 protein or LMP1), mucin 1 (breast carcinoma-associated antigen DF3 or episialin or H23AG or Krebs Von Den Lungen 6 or PEMT or peanut-reactive urinary mucin or polymorphic epithelial membrane mucin or tumor-associated epithelial membrane antigen or tumor-associated mucin or CD227 or MUC1 ), T cell receptor beta chain C region 1 (TRBC1), vascular endothelial growth factor receptor 2 (fetal liver kinase 1 or receptor having a kinase domain or protein tyrosine kinase receptor flk 1 or VEGFR2 or CD309 or KDR or EC 2.7.10.1), BCMA, PD-1, interleukin-6 receptor, NKR2, CX-072, T-lymphocyte protein 4 (cytocytotoxic T-lymphocyte-associated antigen 4 or CD152 or CTLA4); inhibitor of serine/threonine protein kinase B Raf (p94 or proto-oncogene B Raf or v Raf homologue B1 oncogene of murine sarcoma virus or BRAF or EU 2.7.11.1), mucin 16 (tumor marker associated with ovarian cancer CA125 or ovarian cancer antigen CA125 or MUC) ; Bcr-Ab1 tyrosine kinase inhibitor (EC 2.7.10.2); CSK protein tyrosine kinase inhibitor (c-Src kinase or protein tyrosine kinase CYL or CSK or EC 2.7.10.2); tyrosine-protein kinase inhibitor Fyn (Syn proto-oncogene or c-Fyn proto-oncogene or Src-like kinase or p59 Fyn or FYN or EC 2.7.10.2); inhibitor of tyrosine-protein kinase Lck (leukocyte terminal Src kinase or protein YT16 or proto-oncogene Lck or T-cell specific protein tyrosine kinase or lymphocyte-specific protein tyrosine kinase or p56 LCK or LCK or EC 2.7.10.2); tyrosine-protein kinase inhibitor Yes (protoncogene c-Yes or p61 Yes or YES1 or EC 2.7.10.2), cyclic inhibitor

- 38 043393 lens-dependent kinase 1 (p34 protein kinase or cell division protein kinase 1 or cell division control protein 2 homolog or CDK1 or EC 2.7.11.22 or EC 2.7.11.23); cyclin-dependent kinase 2 inhibitor (p33 protein kinase or cell division protein kinase 1 or CDK2 or EC 2.7.11.22); granulocyte-monocyte colony-stimulating factor receptor alpha subunit agonist (CDw116 or CD116 or CSF2RA), EGFRVIII, SYK tyrosine protein kinase inhibitor (spleen tyrosine kinase or p72 Syk or SYK or EC 2.7.10.2), alpha-fetoprotein (alpha 1 fetoprotein or alpha- fetoglobulin or AFP), cancer/testis antigen 1 (autoimmunogenic cancer/testis antigen or cancer/testis antigen 6.1 or 2 member of the L antigen family or CTAG1A or CTAG1B); HBV antigen, EGFR family member, herin, BTK tyrosine kinase inhibitor (Bruton's tyrosine kinase or B-cell precursor kinase or agammaglobulinemia tyrosine kinase or BTK or EC 2.7.10.2), CD4, epithelial cell adhesion molecule (adenocarcinoma-associated antigen or cell surface glycoprotein Trop 1 or epithelial cell surface antigen or epithelial glycoprotein 314 or KS 1/4 antigen or KSA or tumor-associated connective calcium signal transducer 1 or CD326 or EPCAM), shed endopeptidase FAP (170 kDa melanoma membrane-associated gelatinase, or dipeptedyl endopeptidase FAP or integral membrane serine protease or fibroblast activation protein alpha or gelatin degradation protease FAP or seprase or FAP or EC 3.4.21.26 or EC 3.4.14.5), neural cell adhesion molecule 1 (antigen recognized by monoclonal antibody 5.1H11 or CD56 or NCAM1); epidermal growth factor receptor (proto-oncogene with ErbB 1 or receptor tyrosine protein kinase erbB 1 or HER1 or ERBB1 or EGFR or EC 2.7.10.1), antagonist of the transmembrane receptor tyrosine protein kinase ROR1 (1 protein related to the neurotrophic tyrosine kinase receptor or ROR1 or EC 2.7. 10.1); Wilms tumor protein (WT33 or WT1); interleukin 13 receptor alpha-2 subunit (interleukin 13 binding protein or CD213a2 or IL13RA2), trophoblast glycoprotein (M6P1 or oncofetal antigen 5T4 or oncofetal trophoblast glycoprotein 5T4 or Wnt-activated inhibitory factor 1 or TPBG), (oncofetal antigen M6P1 or 5T4 or 5T4 oncofetal trophoblast glycoprotein or Wnt-activated inhibitory factor of the CDF family class 7 IL-1 or protein attachment group IL-5GB or IL-5GB, member-activating factor of the SLAP family class 7 or IL-5 member IL- 5, or member inhibited by WAP 12 or CD2-like receptor-activating cytocytotoxic cells or new Ly9 or protein 19A or CD2 subgroup 1 or CS1 or SLAMF7), B-cell lymphoma inhibitor 2 (Bcl 2); inhibitor of DNA (Cytosine 5) methyltransferase 1 (CXXC-type zinc finger protein 9 or DNA methyltransferase HsaI or MSMT or DNMT1 or EC 2.1.1.37), ROR1, CD19&CD40L, avidin (EGFRiiiv), folate receptor, CD30, pmel CD*8 T, CD33, NKR2, epithelial tumor antigen (ETA), tyrosinase, melanoma-associated antigen, abnormal ras products, p53, alpha-fetoprotein (AFP), CA-125, CA15-3, CA27-29, CA19-9, calcitonin , calretinin, CD34, CD99 MIC 2, CD117, chromogranin, cytokeratin (various types: TPA, TPS, Cyfra21-1), desmin, epithelial membrane antigen (EMA), factor VIII, CD31 FL1, glial fibrillary acidic protein (GFAP), fibrocystic disease fluid protein (GCDFP-15), HMB-45, human chorionic gonadotropin (hCG), immunoglobulin, inhibin, keratin (various types), lymphocyte marker (various types), BCR-ABL, Myo D1, muscle-specific actin (MSA), neurofilament, neuron-specific enolase (NSE), placental alkaline phosphatase (PLAP), prostate-specific antigen (PSA), PTPRC (CD45), S100 protein, smooth muscle actin (SMA), synaptophysin, thymidine kinase, thyroglobulin (Tg), thyroid transcription factor-1 (TTF1), tumor M2-PK, vimentin, SV40, adenovirus E1b-58kd, IGF2B3, ubiquitous (low), kallikrein 4, KIF20A, lengsin, Meloe, MUC5AC, immature laminin receptor , TAG-72, UPV E6, UPV E7, BING-4, calcium-activated chloride channel 2, cyclin B1, 9D7, Ep-CAM, EphA3, telomerase, SAP-1, BAGE family, CAGE family, GAGE family, family MAGE, SAGE family, XAGE family, LAGE-1 family, PRAME, SSX-2, pmel17, tyrosinase, TRP-1/-2, polypeptide P, MC1R, β-catenin, Prostate-specific antigen, BRCA1, BRCA2, CDK4, CML66, fibronectin, MART-2, Ras, TGF beta receptor II, T cell receptor (TCR), BLOC1S6, CD10/neprilysin, CD24, CD248, CD5/cluster of differentiation 5, CD63/Tspan-30/tetraspanin-30 , CEACAM5/CD66e, CT45A3, CTAG1A, CXORF61, DC, GPA33, HPSE, KLK3, LCP1, LRIG3, LRRC15, megakaryocyte potentiating factor, MOK, MUC4, NDNL2, OCIAD1, PMRSV, PTOV1, RCAS1/EBAG9, RNF43, ROPN1, RP LP1 , SARNP, SBEM/MUCL1, TRP1/TYRP1, CA19-9, inactive tyrosine protein kinase transmembrane receptor ROR1 (neurotrophic tyrosine kinase receptor-related protein or ROR1 or EC 2.7.10.1), tyrosine kinase receptor ALK (anaplastic lymphoma kinase or CD246 or ALK or EU 2.7.10.1), prostate stem cell antigen (PSCA), melanoma antigen predominantly expressed in tumors (cancer/testis antigen 130 or Ora-interacting protein 4 or OIP4 or predominantly expressed melanoma antigen or PRAME), signal transporter and activator inhibitor transcription factor 3 (acute phase response factor or DNA binding protein APRF or STAT3), CD44 antigen (CDw44 or epican or extracellular matrix receptor III or lymphocyte adhesion receptor GP90 or HUTCH I, or heparan sulfate, proteoglycan, or Hermes antigen, or hyaluronate receptor CDCD or phagocytic glycoprotein-1, CD44), activator of CD40 ligand (T

- 39 043393 cellular antigen Gp39 or TNF-related activation protein or tumor necrosis factor ligand superfamily member 5 or CD154 or CD40LG); representative of the tumor necrosis factor receptor superfamily 13B (transmembrane activator and CAML interactor or CD267 or TACI or TNFRSF13B); Cytocytotoxic to cells expressing tumor necrosis factor receptor superfamily member 17 (B cell maturation antigen or CD269 or TNFRSF17), CD276 antigen (B7 homolog 3 or 4Ig B7 H3 or costimulatory molecule or CD276), myeloid cell surface antigen such as CD33 antigen (3 lectin-like Ig binding sialic acid or gp67 or CD33), ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 (cyclic ADP-ribose hydrolase 1 or T10 or 2'-phospho ADP-ribosyl cyclase/2'-phospho cyclic ADP-ribose transferase or ADP-ribosyl cyclase 1 or CD38 or EC 3.2.2.6 or EC 2.4.99.20), lectin domain family 14 member A type (epidermal growth factor receptor 5 or EGFR5 or CLEC14A), hepatocyte growth factor receptor (c-Met proto-oncogene or tyrosine -protein kinase Met or HGF/SF receptor or scattering factor receptor or MET or EC 2.7.10.1), epithelial cell adhesion molecule (adenocarcinoma associated antigen, cell surface glycoprotein Trop 1 or epithelial cell surface antigen or epithelial glycoprotein 314 or KS antigen 1/4 or KSA or tumor-associated calcium signal transducer 1 or CD326 or EPCAM), ganglioside GD3, interleukin-13 receptor alpha 2 subunit (interleukin 13 binding protein or CD213a2 or IL13RA2); kappa myeloma antigen (KMA), lambdamyeloma antigen (LMA), latent membrane protein 1 (p63 protein or LMP1), melanoma-associated antigen, cytotoxic to cells expressing T-lymphocyte activating antigen CD80 (activating antigen B7-1 or counter- CTLA 4 receptor B7.1 or CD80); cytotoxic for cells expressing T-lymphocyte activation antigen CD86 (activating antigen B7-2 or counter-receptor CTLA 4 B7.2 or CD86), inactive protein tyrosine kinase transmembrane receptor ROR1 (1 neurotrophic tyrosine kinase receptor-related protein or ROR1 or EC 2.7.10.1 ), 3 Fas-apoptosis inhibitory molecule (IgM Fc fragment receptor or Fas-induced apoptosis regulator Toso or TOSO or FAIM3 or FCMR), chain C region of T-cell receptor beta 1 (TRBC1), 2 vascular endothelial growth factor receptor (fetal liver kinase 1 or receptor containing a kinase domain or protein tyrosine kinase receptor flk 1 or VEGFR2 or CD309 or KDR or EC 2.7.10.1), alpha-fetoprotein (alpha-1 fetoprotein or alpha-fetoglobulin or AFP), cancer/testis antigen 1 (autoimmunogenic cancer/testis antigen NY ESO 1 or cancer/testis 6.1 or 2 member of the L antigen family or CTAGIA or CTAG1B), T cell surface glycoprotein CD5 (lymphocyte antigen T1/Leu 1 or CD5), FAP prolyl endopeptidase (170 kDa gelatinase , melanoma membrane associated, or dipeptedyl endopeptidase FAP or integral membrane serine protease or fibroblast activation protein alpha or gelatin degradation protease FAP or seprase or FAP or EC 3.4.21.26 or EC 3.4.14.5), neural cell adhesion molecule 1 (antigen recognized monoclonal antibody 5.1H11 or CD56 or NCAM1), member A of type C lectin domain 12 family (inhibitory myeloid lectin-like receptor type C or 2 dendritic cell associated lectin or 1 type C lectin-like molecule or CLEC12A), integrin alpha V (subunit vitronectin receptor alpha or CD51 or ITGAV); cytocytotoxic to cells expressing beta-6 integrin (ITGB6), alpha-2 receptor subunit of the interleukin 13 receptor (interleukin 13 binding protein or CD213a2 or IL13RA2), trophoblast glycoprotein (M6P1 or oncofetal antigen 5T4 or 5T4 oncofetal trophoblast glycoprotein or Wnt- activated inhibitory factor 1 or TPBG), member A of type C lectin domain family 12 (inhibitory myeloid lectin-like receptor type C or 2 dendritic cell associated lectin or 1 type C lectin-like molecule or CLEC12A), 7 member of SLAM family 7 (CD319 or membrane protein FOAP 12 or CD2-like receptor activating cytocytotoxic cells, or novel Ly9 or protein 19A or CD2 subset 1 or CS1 or SLAMF7), 7 member of the SLAM family (CD319 or membrane protein FOAP 12 or CD2-like receptor activating cytocytotoxic cells or novel Ly9 or protein 19A or CD2 subgroup 1 or CS1 or SLAMF7), immunoglobulin, multidrug resistance-associated protein 3 (MRP3), proto-oncogenic tyrosine protein kinase ABL1, prostatic acid phosphatase, OY-TES-1, ACSM2A, alpha-actinin- 4, perilipin-2, alphafetoprotein, lymphoid blast crisis (Lbc) oncogene, aldehyde dehydrogenase 1 family member A1 (ALDH1A1), AML, ANKRD17, NY-BR-1, annexin II, ARHGAP17, ARHGAP30, ARID1B, endoplasmic reticulum resident protein, 5 '-aminoimidazole-4-carboxamide-1-beta-dribonucleotide transfamylase/inosinicase (AICRT/I), ATR, ATXN2, ATXN2L, BAGE1, BCL11A, Bcl-xL, point break cluster region, Survivin, Livin/ML-IAP, HM1. 24, BTB domain containing 2 (BTBD2), C6ORF carbonic anhydrase IX, CLCA2, CRT2, CAMEL, CAN protein, caspase-5, caspase-8, KM-HN1, CCDC88B, cyclin B1, cyclin D1, CCNI, CDC2, CDC25A, CDC27, CDK12, intestinal carboxylesterase, CEP95, CHAF1A, coactosin-like 1, CPSF, CRYBA1, TRAG-3, macrophage colony-stimulating factor, CSNK1A1, melanoma-associated chondroitin sulfate proteoglycan (MCSP), cathepsin H, Kitakyushu lung cancer antigen 1, P450 1B1 or CYP1B1 , DDR1, DEK-oncogene, DEK-CAN,

- 40 043393

Dickkopf-1 (DKK1), DNAJC8, DSCAML1, EEF2, Tu elongation factor, GTP or SNRP116 binding domain, EIF4EBP1, human Mena protein, EP300EL ETV5 or ETV6, Polycomb group enhancer protein homologue 2 (EZH2), F2R, F4.2, FAM53C, fibroblast g, growth factor 5 or FGF5, leukocyte-related protein 1 (FMNL1), fibromodulin (FMOD), FNDC3B, FKHR, GDP-L-fucose, GAS7, GFI1, GIGYF2, GPNMB, O, A1, GPSM3, GRK2 , GRM5, H3F3A, HAUS3, HERC1, HERV-K-MEL, HIVEP2, HMGN, HMHA1, heme oxygenase-1 (HO-1), HNRPL, heparanase, HMSD-v-encoded mHA, HSPA1A, Hsp70, HSPB1, immediate early gene response X-1 (IEX-1), insulin-like growth factor (IGF)-II mRNA-binding protein 3 (IMP-3), IP6K1, IRS2, ITGB8, JUP, RU2AS, KANSL3, KLF10, KLF2, KLK4, KMT2A, K -ras, low-density lipid receptor (LDLR), LDLR-FUT, Mac-2-binding protein, KIAA0205, LPP, LRP1, LRRC41, LSP1, LUZP1, lymphocyte antigen complex 6 locus (LY6K), MACF1, Μαρία, MAPZK11, MAP7D1, matrilin-2, Mcl-1, MDM2, malic enzyme, MEF2D, MEFV, milk fat globule membrane protein BA46 (lactadherin), melanotransferrin, GNT-V or Nacetylglucosaminitransferase V, MIIP, MMP14, matrix metalloproteinase-2, MORC2, melanoma antigen p15, MUC2, MUM, MYC, MYL9, non-standard class I myosin gene, N4BP2, NCBP3, NCOA1, NCOR2, NFATC2, NFYC, NIFK, ninein, NPM, NPM1-ALK1 polypeptide, N-ras, OAS3, Ppolypeptide, OGT, OS -9, Erb3-binding protein 1, PAGE-4, P21-activated serine kinase 2 (PAK2), neo-PAP, PARP12, PAX3, PAX3-FKHR, PCBP2, phosphoglycerate kinase 1 (PKG1), PLEKHM2, promyelocytic leukemia or PML, -RARA, POLR2A, cyclophilin B, PPP1CA, PPP1R3B, peroxiredoxin 5, proteinase 3, parathyroid hormone-related protein (PTHrP), protein tyrosine phosphatase receptor-like kappa, MG50, NY-MEL-1 or RAB38, RAGE, RALGAP alpha, RBM, RCSD1, recoverin, RERE, RGS5, RHAMM/CD168, RPA1, ribosomal protein L10a, ribosomal protein S2, RREB1, RSRP1, RTCB, SART, SCAP, mammaglobin A, secernin 1, SDCB3, SFD2, RQB1, SFD2, RQB1, SFD2, SFD2, SFD2, SFD2, RQB1, SFD2, SFD2, RQB1, SFD2, SFD2, SFD2, SFD2, alpha, RBM, RCSD1, recoverin, RERE, RGS5, RHAMM/CD168, RPA1, ribosomal protein L10a, ribosomal protein S2, RREB1, RSRP1, RTCB, SART, SCAP, mammaglobin A, secernin 1, SDCBP, SETD2, SF3B1, renal ubiquitous protein 1, SIK1, SLRT2, SKI, hairpin binding protein, SLC35A4, prostein, SLC46A1, SNRPD1, SOGA1, SON, SOX10, SOX11, SOX2, SOX-4, sperm protein 17, SPEN, SRRM2, SRSF7, SRSF8, SSX1, SSX2 or HOM-MEL-40, SSX4, STAT1, STEAP, STRAP, ART-1, SVIL, HOM- TES-14/SCP1, CD138, SYNM, SYNPO, SYT, SYT15, SYT-SSX1, SYT-SSX2, SZT2, TAPBP, TBC1D10C, TBC1D9B, hTERT, THNSL2, THOC6, TLK1, TNS3, TOP2A, TOP2B, ATP-dependent interferon -responsive (ADIR), TP53, triosephosphate isomerase or TPI1, tropomyosin-4, TPX2, TRG receptor, T-cell receptor gamma alternative reading frame protein (TARP), TRIM68, prostate-specific transient receptor potential protein-p8 (trp- p8), TSC22D4, TTK protein kinase (TTK), thymidylate synthase (TYMS), UBE2A, ubiquitin-conjugating enzyme Kua variant, COA-1, USB1, NA88A, VPS13D, BING4, WHSC1L1, WHSC2, WNK2, WT1, XBP1, XPO1, ZC3H14 , ZNF106, ZNF219, papilloma virus binding factor (PBF), E3 ubiquitin protein ligase UBR4.

In certain embodiments of the invention, the use of certain expressed receptor/ligand or antibody target or cellular immunotherapy could be eliminated and avoided, including, but not limited to; proto-oncogene tyrosine protein kinase ABL1, citrullinated antigen, ErbB2/HER2, CD16, WT-1, KRAS, glypican 3, CD3, CD20, CD226, CD155, CD123, HPV-16 E6, melan-A/MART-l, TRAIL, receptor-associated DR4, LMP, MTCR, ESO, NY-ESO-1, gp100, 4SCAR-GD2/CD56, mesothelin (CAK1 antigen or pre-pro-megakaryocyte potentiating factor or MSLN); DNA synthesis inhibitor; histamine Hl receptor antagonist (HRH1); inhibitor of prostaglandin G/H synthase 2 (cyclooxygenase 2 or COX2 or prostaglandin endoperoxide synthase 2 or PHS II or prostaglandin H2 synthase 2 or PTGS2 or EC 1.14.99.1), CD19 (B-lymphocyte surface antigen, B4 antigen or differentiation antigen CD19 or T -cell antigen Leu 12 or CD19), cell adhesion molecule 5 (carcinoembryonic antigen or CEA or meconium antigen 100 or CD66e or CEACAM5); interleukin 2 receptor (IL2R) agonist, epidermal growth factor receptor (proto-oncogene with ErbB 1 or receptor protein tyrosine kinase erbB 1 or HER1 or ERBB1 or EGFR or EC 2.7.10.1); DNA ligase (EC 6.5.1.); DNA ligase (EC 6.5.1.), DNA polymerase inhibitor alpha (POLA or EC 2.7.7.7); DNA primase inhibitor (EC 2.7.7.6); ribonucleoside diphosphate reductase inhibitor (ribonucleotide reductase or RRM or EC 1.17.4.1); RNA polymerase II inhibitor (RNAP II or Pol II or EC 2.7.7.6), DNA polymerase inhibitor (EC 2.7.7.7); DNA topoisomerase II inhibitor (EC 5.99.1.3); CD22, meso, DNA primase (EC 2.7.7.6); programmed cell death protein ligand 1 inhibitor 1 (PD L1 or B7 homolog 1 or CD274); RNA polymerase II inhibitor (RNAP II or Pol II or EC 2.7.7.6), histone lysine N-methyltransferase inhibitor EZH2 (ENX 1 or Zeste homolog 2 enhancer or lysine N-methyltransferase 6 or EZH2 or EC 2.1.1.43); programmed cell death protein 1 ligand 1 (PD L1 or B7 homologue 1 or CD274), CXC chemokine receptor type 4 antagonist (FB22 or Fusia or HM89 or LCR1 or leukocyte seven transmembrane domain receptor or lipopolysaccharide-associated protein 3 or stromal derived receptor cells 1 NPYRL or CD184 or CXCR4); granulocyte colony-stimulating factor receptor (CD114 or GCSFR or CSF3R), adenosine deaminase agonist inhibitor

- 41 043393 (adenosine aminohydrolases or ADA or EC 3.5.4.4); 17, a member of the tumor necrosis factor receptor superfamily (B-cell maturation antigen or CD269 or TNFRSF17), cytocytotoxic to cells expressing the inactive transmembrane tyrosine protein kinase receptor ROR1 (neurotrophic tyrosine kinase receptor-related protein 1, or ROR1 or EC 2.7.10.1); CD3 epsilon chain T cell surface glycoprotein (T3/Leu 4 T cell surface antigen epsilon chain or CD3E); dihydrofolate reductase inhibitor (DHFR or EC 1.5.1.3); ephrin inhibitor type A 2 (inhibitor of epithelial cell or tyrosine-protein kinase receptors ECK or EPHA2 or EC 2.7.10.1); glucocorticoid receptor agonist (GR or nuclear receptor subfamily 3, group C, 1 member, or NR3C1); inhibitor of the mast/stem cell growth factor receptor set (c-Kit proto-oncogene or tyrosine-protein kinase set or v-Kit Hardy Zuckerman 4 feline sarcoma viral oncogene homolog, or Piebald Trait protein or p145 c set or CD117, or KIT, or EC 2.7. 10.1); platelet-derived growth factor receptor beta inhibitor (platelet-derived growth factor receptor beta, or CD140 antigen-like family member B, or platelet-derived growth factor receptor 1, or CD140b, or PDGFRB, or EC 2.7. 10.1); tubulin inhibitor; CSK protein tyrosine kinase inhibitor (c-Src kinase or protein tyrosine kinase CYL or CSK or EC 2.7.10.2); inhibitor of tyrosine-protein kinase Fyn (Syn proto-oncogene or c-Fyn proto-oncogene or Src-like kinase or p59 Fyn or FYN or EC 2.7.10.2); tyrosine-protein kinase inhibitor Lck (leukocyte terminal Src kinase or YT16 protein or Lck proto-oncogene or T-cell specific protein tyrosine kinase or lymphocyte-specific protein tyrosine kinase or p56 LCK or LCK or EC 2.7.10.2); tyrosine-protein kinase inhibitor Yes (proto-oncogene c-Yes or p61 Yes or YES1 or EC 2.7.10.2), tumor necrosis factor inhibitor (cachectin or TNF alpha or 2 representative of the tumor necrosis factor ligand superfamily or TNF a or TNF), signal transporter inhibitor and transcription activator 3 (acute phase response factor or APRF or STAT3 binding protein), Bcr-Abl tyrosine kinase inhibitor (EC 2.7.10.2); dihydrofolate reductase (DHFR or EC 1.5.1.3); ephrin receptor type A 2 (epithelial cell kinase receptor or tyrosine-protein kinase ECK or EPHA2 or EC 2.7.10.1); mast/stem cell growth factor receptor Kit (c-Kit proto-oncogene or protein tyrosine kinase set or v-Kit Hardy Zuckerman 4 feline sarcoma viral oncogene homologue or Piebald Trait protein or p145 c set or CD117 or KIT or EC 2.7.10.1); platelet-derived growth factor receptor beta, beta type (platelet-derived growth factor receptor, or CD140 antigen-like family member B, or platelet-derived receptor 1, or CD140b, or PDGFRB, or EC 2.7.10.1) ; tubulin; CSK protein tyrosine kinase inhibitor (c-Src kinase or protein tyrosine kinase CYL or CSK or EC 2.7.10.2); inhibitor of tyrosine-protein kinase Fyn (Syn proto-oncogene or cFyn proto-oncogene or Src-like kinase or p59 Fyn or FYN or EC 2.7.10.2); inhibitor of tyrosine protein kinase Lck (leukocyte terminal Src kinase or protein YT16 or proto-oncogene Lck or T-cell specific protein tyrosine kinase or lymphocyte-specific protein tyrosine kinase or p56 LCK or LCK or EC 2.7.10.2); tyrosine-protein kinase inhibitor Yes (proto-oncogene c-Yes or p61 Yes or YES1 or EC 2.7.10.2); activator of caspase 9 (activator of apoptotic protease Mch 6 or activating apoptotic protease 3 or ICE-like apoptotic protease 6 or CASP9 or EC 3.4.22.62); prostate stem cell antigen (PSCA), melanoma antigen predominantly expressed in tumors (cancer/testis antigen 130 or Ora-interacting protein 4 or OIP4 or predominantly expressed melanoma antigen or PRAME), signal transporter and activator of transcription 3 (responsive factor acute phase or DNA binding protein inhibitor APRF or STAT3), CD44 antigen (CDw44 or epican or extracellular matrix receptor III or GP90, lymphocyte homing/adhesion receptor or HUTCH I, or heparan sulfate, proteoglycan or Hermes antigen, or hyaluronate receptor, or phagocytic glycoprotein 1, CDG 1) receptor tyrosine kinase AXL (anexelekto), GAS6, receptor tyrosine kinases TAM, TYRO-3 (also known as Brt, Dtk, Rse, Sky and Tif), AXL (also known as Ark, Tyro7 and Ufo) and MER (also known as Eyk, Nym and Tyro 12), CTLA4, 8 representative of the tumor necrosis factor receptor superfamily (CD30L receptor or Ki antigen 1 or lymphocyte activation antigen CD30 or CD30 or TNFRSF8), caspase activator 9 (apoptotic protease Mch 6 or apoptotic protease A activating factor 3 or ICE such as apoptotic protease 6 or CASP9 or EC 3.4.22.62); Cytocytotoxicity for cells expressing ganglioside GD2; inhibitor of prostaglandin G/H synthase 1 (cyclooxygenase 1 or COX1 or prostaglandin endoperoxide synthase 1 or prostaglandin H2 synthase 1 or PTGS1 or EC 1.14.99.1); cytokines, interleukins, claudin 6 (scullin or CLDN6), NKG2D, MICA, MICB and ULBP 1-6, NKp30, B7H6 (NCR3LG1), Bag6, B7 family, activator of CD40 ligand (T cell antigen Gp39 or activator protein related TNF or tumor necrosis factor ligand superfamily member 5 or CD154 or CD40LG); Interleukin 12 activator (IL12), interleukin 3 receptor alpha subunit (IL3RAMast/stem cell growth F), receptor activator Kit (proto-oncogene cKit or tyrosine protein kinase kit or Hardy Zuckerman v-Kit, feline sarcoma virus oncogene homologue 4, or Piebald Trait protein or p145 c-Kit or CD117 or KIT or EC 2.7.10.1) antagonist; inhibitor of proto-oncogene receptor tyrosine-protein kinase Ret (12 member of the catherin family or

- 42 043393 proto-oncogene cRet or RET or EC 2.7.10.1); FLT3 type receptor tyrosine kinase antagonist (FMS-like tyrosine kinase 3 or FL cytokine receptor or stem cell tyrosine kinase 1 or fetal liver kinase 2 or CD135 or FLT3 or EC 2.7.10.1); vascular endothelial growth factor receptor 1 antagonist (FMS-like tyrosine kinase 1 or receptor tyrosine kinase FLT or tyrosine protein kinase FRT or vascular permeability factor receptor or VEGFR1 or FLT1 or EC 2.7.10.1); vascular endothelial growth factor receptor 2 antagonist (fetal liver kinase 1 or receptor containing a kinase domain or protein tyrosine kinase receptor flk 1 or VEGFR2 or CD309 or KDR or EC 2.7.10.1); vascular endothelial growth factor receptor antagonist 3 (FMS-like tyrosine kinase 4 or receptor tyrosine kinase FLT4 or VEGFR3 or FLT4 or EC 2.7.10.1), caspase activator 9 (apoptotic protease Mch 6 or apoptotic protease activating factor 3 or ICE-like apoptotic protease 6 or CASP9 or EC 3.4.22.62), cytocytotoxic T-lymphocyte protein 4 antagonist (cytocytotoxic T-lymphocyte-associated antigen 4 or CD152 or CTLA4), myeloid cell surface antigen CD33 (sialic acid-binding lectin-like Ig 3 or gp67 or CD33) , hepatocyte growth factor receptor (c-Met proto-oncogene or tyrosine-protein kinase Met, or HGF/SF receptor, or scatter factor receptor, or MET or EC 2.7.10.1), epithelial cell adhesion molecule (adenocarcinoma-associated antigen or cell surface glycoprotein Trop 1 or epithelial cell surface antigen or epithelial glycoprotein 314 or KS 1/4 antigen or KSA or tumor-associated calcium signal transducer 1 or CD326 or EPCAM), ganglioside GD2, Lewis antigen Y (CD174), latent membrane protein 1 (p63 protein or LMP1), mucin 1 (breast carcinoma-associated antigen DF3 or episialin or H23AG or Krebs Von Den Lungen 6 or PEMT or peanut-reactive urinary mucin or polymorphic epithelial membrane mucin or tumor-associated epithelial membrane antigen or tumor-associated mucin or CD227 or MUC1 ), T cell receptor beta chain C region 1 (TRBC1), vascular endothelial growth factor receptor 2 (fetal liver kinase 1 or receptor having a kinase domain or protein tyrosine kinase receptor flk 1 or VEGFR2 or CD309 or KDR or EC 2.7.10.1), BCMA, PD-1, interleukin-6 receptor, NKR2, CX-072, T-lymphocyte protein 4 (cytocytotoxic T-lymphocyte-associated antigen 4 or CD152 or CTLA4); inhibitor of serine/threonine protein kinase B Raf (p94 or proto-oncogene B Raf or v Raf homologue B1 oncogene of murine sarcoma virus or BRAF or EU 2.7.11.1), mucin 16 (tumor marker associated with ovarian cancer CA125 or ovarian cancer antigen CA125 or MUC) ; Bcr-Abl tyrosine kinase inhibitor (EC 2.7.10.2); CSK protein tyrosine kinase inhibitor (c-Src kinase or protein tyrosine kinase CYL or CSK or EC 2.7.10.2); inhibitor of tyrosine-protein kinase Fyn (Syn proto-oncogene or c-Fyn proto-oncogene or Src-like kinase or p59 Fyn or FYN or EC 2.7.10.2); tyrosine-protein kinase inhibitor Lck (leukocyte terminal Src kinase or YT16 protein or Lck proto-oncogene or T-cell specific protein tyrosine kinase or lymphocyte-specific protein tyrosine kinase or p56 LCK or LCK or EC 2.7.10.2); tyrosine protein kinase inhibitor Yes (protoncogene c-Yes or p61 Yes or YES1 or EC 2.7.10.2), cyclin-dependent kinase inhibitor 1 (p34 protein kinase or protein kinase 1 cell division 1 or homolog of cell division control protein 2 or CDK1 or EC 2.7.11.22 or EC 2.7.11.23); cyclin-dependent kinase 2 inhibitor (p33 protein kinase or cell division protein kinase 1 or CDK2 or EC 2.7.11.22); granulocyte-monocyte colony-stimulating factor receptor alpha subunit agonist (CDw116 or CD116 or CSF2RA), EGFRVIII, SYK tyrosine-protein kinase inhibitor (spleen tyrosine kinase or p72 Syk or SYK or EC 2.7.10.2), alpha-fetoprotein (alpha 1 fetoprotein or alpha-fetoglobulin or AFP), cancer/testis antigen 1 (autoimmunogenic cancer/testis antigen or cancer/testis antigen 6.1 or 2 member of the L antigen family or CTAG1A or CTAG1B); HBV antigen, EGFR family member, herin, tyrosine kinase inhibitor BTK (Bruton's tyrosine kinase or B-cell precursor kinase or agammaglobulinemia tyrosine kinase or BTK or EC 2.7.10.2), CD4, epithelial cell adhesion molecule (adenocarcinoma-associated antigen or cell surface glycoprotein Trop 1 or epithelial cell surface antigen or epithelial glycoprotein 314 or KS 1/4 antigen or KSA or tumor-associated connective calcium signal transducer 1 or CD326 or EPCAM), shed endopeptidase FAP (170 kDa melanoma membrane-associated gelatinase, or dipeptedyl endopeptidase FAP or integral membrane serine protease or fibroblast activation protein alpha or gelatin degradation protease FAP or seprase or FAP or EC 3.4.21.26 or EC 3.4.14.5), neural cell adhesion molecule 1 (antigen recognized by monoclonal antibody 5.1H11 or CD56 or NCAM1); epidermal growth factor receptor (proto-oncogene with ErbB 1 or receptor tyrosine protein kinase erbB 1 or HER1 or ERBB1 or EGFR or EC 2.7.10.1), antagonist of transmembrane receptor tyrosine protein kinase ROR1 (1 protein related to the neurotrophic tyrosine kinase receptor or ROR1 or EC 2.7. 10.1); Wilms tumor protein (WT33 or WT1); interleukin 13 receptor alpha-2 subunit (interleukin 13 binding protein or CD213a2 or IL13RA2), trophoblast glycoprotein (M6P1 or oncofetal antigen 5T4 or oncofetal trophoblast glycoprotein 5T4 or Wnt-activated inhibitory factor 1 or TPBG), 7 family member

- 43 043393 SLAM properties (CD319 or membrane protein FOAP 12 or CD2-like receptor activating cytotoxic cells or new Ly9 or Protein 19 A or CD2 subset 1 or CS1 or SLAMF7), inhibitor of B-cell lymphoma 2 (Bcl 2); inhibitor of DNA (Cytosine 5) methyltransferase 1 (CXXC-type zinc finger protein 9 or DNA methyltransferase HsaI or MSMT or DNMT1 or EC 2.1.1.37), ROR1, CD19&CD40L, avidin (EGFRiiiv), folate receptor, CD30, pmel CD*8 T, CD33, NKR2, epithelial tumor antigen (ETA), tyrosinase, melanoma-associated antigen, abnormal ras products, p53, alpha-fetoprotein (AFP), CA-125, CA15-3, CA27-29, CA19-9, calcitonin , calretinin, CD34, CD99 MIC 2, CD117, chromogranin, cytokeratin (various types: TPA, TPS, Cyfra21-1), desmin, epithelial membrane antigen (EMA), factor VIII, CD31 FL1, glial fibrillary acidic protein (GFAP), fibrocystic disease fluid protein (GCDFP-15), HMB-45, human chorionic gonadotropin (hCG), immunoglobulin, inhibin, keratin (various types), lymphocyte marker (various types), BCR-ABL, Myo D1, muscle-specific actin (MSA), neurofilament, neuron-specific enolase (NSE), placental alkaline phosphatase (PLAP), prostate-specific antigen (PSA), PTPRC (CD45), S100 protein, smooth muscle actin (SMA), synaptophysin, thymidine kinase, thyroglobulin (Tg ), thyroid transcription factor-1 (TTF-1), tumor M2-PK, vimentin, SV40, adenovirus Elb-58kd, IGF2B3, ubiquitous (low level), kallikrein 4, KIF20A, lengsin, Meloe, MUC5AC, immature laminin receptor , TAG-72, HPV E6, HPV E7, BING-4, Calcium-activated chloride channel 2, cyclin B1, 9D7, Ep-CAM, EphA3, telomerase, SAP-1, BAGE family, CAGE family, GAGE family, MAGE family, SAGE family, XAGE family, LAGE-1 family, PRAME, SSX-2, pmel17, tyrosinase, TRP-1/-2, polypeptide P, MC1R, β-catenin, Prostate-specific antigen, BRCA1, BRCA2, CDK4, CML66, fibronectin, MART-2, Ras, TGF-beta receptor II, T-cell receptor (TCR), BLOC1S6, CD10/neprilysin, CD24, CD248, CD5/cluster of differentiation 5, CD63/Tspan-30/tetraspanin-30, CEACAM5/CD66e , CT45A3, CTAG1A, CXORF61, DC, GPA33, HPSE, KLK3, LCP1, LRIG3, LRRC15, megakaryocyte potentiating factor, MOK, MUC4, NDNL2, OCIAD1, РМРSV, PTOV1, RCAS1/EBAG9, RNF43, ROPN1, RPLP1, SARNP, SBEM /MUCL1, TRP1/TYRP1, CA19-9, inactive tyrosine protein kinase transmembrane receptor ROR1 (neurotrophic tyrosine kinase receptor-related protein or ROR1 or EC 2.7.10.1), tyrosine kinase receptor ALK (anaplastic lymphoma kinase or CD246 or ALK or EC 2.7. 10.1), prostate stem cell antigen (PSCA), melanoma antigen predominantly expressed in tumors (cancer/testis antigen 130 or Ora-interacting protein 4 or OIP4 or predominantly expressed melanoma antigen or PRAME), inhibitor of signal transporter and activator of transcription 3 (responsive acute phase factor or DNA-binding protein APRF or STAT3), CD44 antigen (CDw44 or epican or extracellular matrix receptor III or lymphocyte adhesion receptor GP90 or HUTCH I, or heparan sulfate, proteoglycan, or Hermes antigen, or hyaluronate receptor CDCD or phagocytic glycoprotein- 1, CD44), CD40 ligand activator (T cell antigen Gp39 or TNF-related activating protein or tumor necrosis factor ligand superfamily member 5 or CD154 or CD40LG); representative of the tumor necrosis factor receptor superfamily 13B (transmembrane activator and CAML interactor or CD267 or TACI or TNFRSF13B); Cytocytotoxic to cells expressing tumor necrosis factor receptor superfamily member 17 (B cell maturation antigen or CD269 or TNFRSF17), CD276 antigen (B7 homolog 3 or 4Ig B7 H3 or costimulatory molecule or CD276), myeloid cell surface antigen such as CD33 antigen (3 lectin-like Ig binding sialic acid or gp67 or CD33), ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 (cyclic ADPribose hydrolase 1 or T10 or 2' phospho ADP-ribosyl cyclase/transferase 2' phospho cycloADP-ribose or ADP-ribosyl cyclase 1 or CD38 or EC 3.2.2.6 or EC 2.4.99.20), type C member A of lectin domain family 14 (epidermal growth factor receptor 5 or EGFR5 or CLEC14A), hepatocyte growth factor receptor (c-Met proto-oncogene or tyrosine-protein kinase Met or HGF /SF receptor or scatter factor receptor or MET or EC 2.7.10.1), epithelial cell adhesion molecule (adenocarcinoma associated antigen, Trop 1 cell surface glycoprotein or epithelial cell surface antigen or epithelial glycoprotein 314 or KS 1/4 antigen or KSA or tumor-associated calcium signal transducer 1 or CD326 or EPCAM), ganglioside GD3, interleukin-13 receptor alpha 2 subunit (interleukin 13 binding protein or CD213a2 or IL13RA2); kappa myeloma antigen (KMA), lambda myeloma antigen (LMA), latent membrane protein 1 (p63 protein or LMP1), melanoma-associated antigen, cytotoxic to cells expressing T-lymphocyte activating antigen CD80 (activating antigen B7-1 or counter-receptor CTLA 4 B7.1 or CD80); cytotoxic for cells expressing T-lymphocyte activation antigen CD86 (activating antigen B7-2 or counter-receptor CTLA 4 B7.2 or CD86), inactive protein tyrosine kinase transmembrane receptor ROR1 (1 neurotrophic tyrosine kinase receptor-related protein or ROR1 or EC 2.7.10.1 ), 3 Fas-apoptosis inhibitory molecule (IgM Fc fragment receptor or Fas-induced apoptosis regulator Toso or TOSO or FAIM3 or FCMR), chain C region of T-cell receptor beta 1 (TRBC1), 2 vascular endothelial growth factor receptor ( fetal liver kinase 1 or a receptor containing a domain with

- 44 043393 holding kinase, or protein tyrosine kinase receptor flk 1 or VEGFR2 or CD309 or KDR or EC 2.7.10.1), alpha-fetoprotein (alpha-1 fetoprotein or alpha-fetoglobulin or AFP), cancer/testis antigen 1 (autoimmunogenic cancer antigen/ testicular NY ESO 1 or cancer/testicular 6.1 or 2 antigen family member L or CTAG1A or CTAG1B), T-cell surface glycoprotein CD5 (lymphocyte antigen T1/Leu 1 or CD5), FAP prolyl endopeptidase (170 kDa melanoma membrane-associated gelatinase , or dipeptedyl endopeptidase FAP or integral membrane serine protease or fibroblast activation protein alpha or gelatin degradation protease FAP or seprase or FAP or EC 3.4.21.26 or EC 3.4.14.5), neural cell adhesion molecule 1 (antigen recognized by monoclonal antibody 5.1H11 or CD56 or NCAM1), member A of type C lectin domain 12 family (inhibitory myeloid lectin-like receptor type C or 2 dendritic cell-associated lectin or 1 type C lectin-like molecule or CLEC12A), integrin alpha V (vitronectin receptor subunit alpha or CD51 or ITGAV); cytocytotoxic to cells expressing beta-6 integrin (ITGB6), alpha-2 receptor subunit of the interleukin 13 receptor (interleukin 13 binding protein or CD213a2 or IL13RA2), trophoblast glycoprotein (M6P1 or oncofetal antigen 5T4 or 5T4 oncofetal trophoblast glycoprotein or Wnt- activated inhibitory factor 1 or TPBG), member A of type C lectin domain family 12 (inhibitory myeloid lectin-like receptor type C or 2 dendritic cell associated lectin or 1 type C lectin-like molecule or CLEC12A), 7 member of SLAM family 7 (CD319 or membrane protein FOAP 12 or CD2-like cytocytotoxic cell-activating receptor, or novel Ly9 or protein 19A or CD2 subset 1 or CS1 or SLAMF7), 7 a member of the SLAM family (CD319 or membrane protein FOAP 12 or CD2-like receptor activating cytocytotoxic cells, or novel Ly9 or protein 19A or CD2 subgroup 1 or CS1 or SLAMF7), immunoglobulin, multidrug resistance-associated protein 3 (MRP3), proto-oncogenic tyrosine protein kinase ABL1, prostatic acid phosphatase, OY-TES-1, ACSM2A, alpha-actinin- 4, perilipin-2, alpha-fetoprotein, lymphoid blast crisis (Lbc) oncogene, aldehyde dehydrogenase 1 family member A1 (ALDH1A1), AML, ANKRD17, NY-BR-1, annexin II, ARHGAP17, ARHGAP30, ARID1B, endoplasmic reticulum resident protein , 5'-aminoimidazole-4-carboxamide-1-beta-dribonucleotide transfamylase/inosinicase (AICRT/I), ATR, ATXN2, ATXN2L, BAGE1, BCL11A, Bcl-xL, point break cluster region, survivin, livin/ML-IAP, HM1.24, BTB domain containing 2 (BTBD2), C6ORF carbonic anhydrase IX, CLCA2, CRT2, CAMEL, CAN protein, caspase-5, caspase-8, KM-HN1, CCDC88B, cyclin B1, cyclin D1, CCNI, CDC2, CDC25A, CDC27, CDK12, intestinal carboxylesterase, CEP95, CHAF1A, coactosin-like 1, CPSF, CRYBA1, TRAG-3, macrophage colony-stimulating factor, CSNK1A1, melanoma-associated chondroitin sulfate proteoglycan (MCSP), cathepsin H, Kitakyushu lung cancer antigen 1, P450 1B1 or CYP1B1, DDR1, DEK oncogene, DEK-CAN, Dickkopf-1 (DKK1), DNAJC8, DSCAML1, EEF2, Tu elongation factor, GTP binding domain or SNRP116, EIF4EBP1, human Mena protein, EP300EL ETV5 or ETV6, group enhancer protein Polycomb homolog 2 (EZH2), F2R, F4.2, FAM53C, fibroblast g, growth factor 5 or FGF5, leukocyte-related protein 1 (FMNL1), fibromodulin (FMOD), FNDC3B, FKHR, GDP-L-fucose, GAS7, GFI1, GIGYF2, GPNMB, O, A1, GPSM3, GRK2, GRM5, H3F3A, HAUS3, HERC1, HERV-K-MEL, HIVEP2, HMGN, HMHA1, heme oxygenase-1 (HO-1), HNRPL, heparanase, HMSD-v -encoded mHA, HSPA1A, Hsp70, HSPB1, immediate early response gene X-1 (LEX-1), insulin-like growth factor (IGF)-II mRNA-binding protein 3 (IMP-3), LP6K1, IRS2, ITGB8, JUP, RU2AS, KANSL3, KLF10, KLF2, KLK4, KMT2A, K-ras, low-density lipid receptor (LDLR), LDLR-FUT, Mac-2-binding protein, KIAA0205, LPP, LRP1, LRRC41, LSP1, LUZP1, K complex locus Lymphocyte antigen 6 (LY6K), MACF1, Μαρία, MAP3K11, MAP7D1, matrilin-2, Mcl-1, MDM2, malic enzyme, MEF2D, MEFV, milk fat globule membrane protein BA46 (lactadherin), melanotransferrin, GNT-V or Nacetylglucosaminitransferase V, MIIP, MMP14, matrix metalloproteinase-2, MORC2, melanoma antigen p15, MUC2, MUM, MYC, MYL9, class I non-standard myosin gene, N4BP2, NCBP3, NCOA1, NCOR2, NFATC2, NFYC, NIFK, ninein, NPM, NPM1- polypeptide ALK1, N-ras, OAS3, P polypeptide, OGT, OS-9, Erb3-binding protein 1, PAGE-4, P21-activated serine kinase 2 (PAK2), neo-PAP, PARP12, PAX3, PAX3-FKHR, PCBP2 , phosphoglycerate kinase 1 (PKG1), PLEKHM2, promyelocytic leukemia or PML, -RARA, POLR2A, cyclophilin B, PPP1CA, PPP1R3B, peroxiredoxin 5, proteinase 3, parathyroid hormone-related protein (PTHrP), kappa protein tyrosine phosphatase receptor-like, MG50, NY-MEL-1 or RAB38, RAGE, RALGAP alpha, RBM, RCSD1, recoveryin, RERE, RGS5, RHAMM/CD168, RPA1, ribosomal protein L10a, ribosomal protein S2, RREB1, RSRP1, RTCB, SART, SCAP, mammaglobin A, secernin 1, SDCB3, SFD2, RQB1, SFD2, RQB1, SFD2, SFD2, SFD2, SFD2, RQB1, SFD2, SFD2, RQB1, SFD2, SFD2, SFD2, SFD2, alpha, RBM, RCSD1, recoveryin, RERE, RGS5 , RHAMM/CD168, RPA1, ribosomal protein L10a, ribosomal protein S2, RREB1, RSRP1, RTCB, SART, SCAP, mammaglobin A, secernine 1, SDCBP, SETD2, SF3B1, renal ubiquitous protein 1, SIK1, SLRT2, SKI, protein, hairpin binding, SLC35A4, prostein, SLC46A1, SNRPD1, SOGA1, SON, SOX10, SOX11, SOX2, SOX-4, sperm protein 17, SPEN, SRRM2, SRSF7, SRSF8,

- 45 043393

SSX1, SSX2 or HOM-MEL-40, SSX4, STAT1, STEAP, STRAP, ART-1, SVIL, HOM-TES-14/SCP1, CD138, SYNM, SYNPO, SYT, SYT15, SYT-SSX1, SYT-SSX2, SZT2, TAPBP, TBC1D10C, TBC1D9B, hTERT, THNSL2, THOC6, TLK1, TNS3, TOP2A, TOP2B, ATP-dependent interferon-responsive (ADIR), TP53, triosephosphate isomerase or TPI1, tropomyosin-4, TPX2, TRG receptor, protein T cell receptor alternative reading frame gamma (TARP), TRIM68, prostate-specific transient receptor potential protein-p8 (trp-p8), TSC22D4, TTK protein kinase (TTK), thymidylate synthase (TYMS), UBE2A, ubiquitin-conjugating enzyme Kua variant , SOA-1, USB1, NA88A, VPS13D, BING4, WHSC1L1, WHSC2, WNK2, WT1, XBP1, XPO1, ZC3H14, ZNF106, ZNF219, papillomavirus binding factor (PBF), E3 ubiquitin-protein ligase UBR4.

T cell activator domains.

The T cell activator domain of a CAR T or other targeted cell therapy may be 4-1BB, CD3, CD3 zeta, CD3 zeta cytoplasmic signaling domain and utilizes the natural co-stimulatory molecule DAP10 or any other suitable T cell activator domain including , without limitation CD28, 41BB, ICOS, CD3z-CD28-41BB, CD3z-CD28-OX40, CD27 or any combination thereof.

Production of an antibody or receptor to be expressed by a cellular immunotherapy agent.

Production of the expressed receptor/ligand or antibody can be accomplished by any method, including Conditionally Active Biologies (CAB) technology. The antibody may be single chain or double chain. The antibody may be an Fc fusion protein, Fab, F(ab') ₂ , Fab', single chain variable fragment, di-scFv, single domain antibody, trifunctional antibody, chemically linked or bi-specific T cell recruiter.

Cellular immunotherapy pretreatment.

Pretreatment of cellular immunotherapy in vitro or ex vivo can be carried out and is not exclusive to interleukin-1, interleukin-2, interleukin-7, interleukin-15, allogeneic PBMC, anti-CD3, anti-CD28, anti-CD3 and 28, peptide HA 512-520, IL2 and anti-CD3 and CD28, PBMC activation, PMA/ionomycin, PHA, Con A, LPS, PWM, phytolacca mitogen, comitogenic monoclonal antibodies (mAbs) CD2/CD2R, superantigenic staphylococcal enterotoxin B (SEB) and Candida albicans specific antigen, SLAM, CD80 or CD86 cross-linked to CD28, dexamethasone or other steroids, or any combination of the above pretreatments.

In some embodiments of the invention, pretreatment of cellular immunotherapy in vitro or ex vivo should exclude treatment with dexamethasone or other steroids, interleukin-1, interleukin-2, interleukin-7, interleukin-15, allogeneic PBMC, anti-CD3, anti-CO28, anti- CD3 and 28, peptide HA 512-520, IL2 and anti-CD3 and CD28, PBMC activation, PMA/ionomycin, PHA, Con A, LPS, PWM, phytolacca mitogen, comitogenic monoclonal antibodies (mAb) CD2/CD2R, superantigenic staphylococcal enterotoxin B (SEB) and Candida albicans specific antigen, SLAM, CD80 or CD86, cross-linked with CD28, dexamethasone or other steroid, or any combination of the above pretreatments.

The diseases to be treated are not exclusive to all types of cancer, autoimmune diseases and infectious diseases.

In certain embodiments of the invention, a patient will be identified and/or selected who has one or more of cancer, autoimmune and infectious diseases. The following list and tables provide a list of diseases that can be used to identify and/or select a patient:

Hemophagocytic lymphohistiocytosis, multiple myeloma, allergen-specific immunotherapy, autosomal dominant haploinsufficiency, anterior interosseous nerve syndrome of the forearm, Churg-Strauss syndrome, systemic vasculitis, chronic graft-versus-host disease, opsoclonus-myoclonus syndrome, necrotizing autoimmune myopathy (NAM), pulmonary sar comatoid carcinomas lung, Waldenström's macroglobulinemia (WM), fertility, Behçet's disease, alopecia areata (AA), acute chronic liver failure, melanoma, organized bronchiolitis syndrome, encephalitis, minimal change disease, or a patient receiving paradoxical response therapy for cancer treatment, or sublingual immunotherapy (SLIT) or subcutaneous immunotherapy (SCIT), or having:

disease (source of disease) infection Acinetobacter (Acinetobacter baumannii), Actinomycosis (Actinomyces israelii, Actinomyces gerencseriae and Propionibacterium propionicus) African sleeping sickness or African trypanosomiasis (Trypanosoma brucei), AIDS (acquired immunodeficiency virus, immunodeficiency syndrome, purulent immunodeficiency) Anaplasmosis (Anaplasm spp. a ), angiostrongylus (Angiostrongylus), anisakiasis (Anisakis), anthrax (Bacillus anthracis), Arcanobacterium haemolyticum infection (Arcanobacterium haemolyticum), Argentine hemorrhagic fever (Junin vims), ascariasis (Ascaris lumbricoides), aspergillosis (Aspergillus spp.), astrovirus infection ( family Astroviridae), babesiosis (Babesia spp.), Bacillus cereus infection (Bacillus cereus), bacterial

- 46 043393 pneumonia (multiple bacteria), bacterial vaginosis (list of microbiota of bacterial vaginosis), bacteroides infection (Bacteroides spp.), balantidiasis (Balantidium coli), bartonellosis (Bartonella), baylisascaris (Baylisascaris spp.), BK virus infection (BK virus) , black piedra (Piedraia hortae), blastocystis (Blastocystis spp.), blastomycosis (Blastomyces dermatitidis), Bolivian hemorrhagic fever (Machupo virus), botulism (botulism and infant botulism) (Clostridium botulinum; Note: botulism is not an infection of Clostridium botulinum, but is caused by consumption of botulinum toxin), Brazilian hemorrhagic fever (Sabia virus), brucellosis (Brucella spp.), bubonic plague (bacterial family Enterobacteriaceae), Burkholderia infection, usually Burkholderia cepacia and other Burkholderia species, Buruli ulcer (Mycobacterium ulcerans), calicivirus infection (Norovirus and Sapovirus) (family Caliciviridae), campylobacteriosis (Campylobacter species), candidiasis (moniliasis; thrush (usually Candida albicans and other Candida species), Capillariasis (intestinal disease due to Capillaria philippinensis, liver disease due to Capillaria hepatica and pulmonary disease due to Capillaria aerophila), Carrion's disease (Bartonella bacilliformis), cat scratch disease ( Bartonella henselae), cellulitis (usually group A Streptococcus and Staphylococcus), Chagas disease (American trypanosomiasis) (Trypanosoma cruzi), chancroid (Haemophilus ducreyi), chickenpox (Varicella zoster virus (VZV)), Chikungunya (Alphavirus), chlamydia (Chlamydia trachomatis), Chlamydophila pneumoniae (Taiwan Acute Respiratory Agent or TWAR) infection (Chlamydophila pneumoniae), cholera (Vibrio cholerae), chromoblastomycosis (usually Fonsecaea pedrosoi), chytridiomycosis (Batrachochytrium dendrabatidis), clonorchiasis (Clonorchis sinensis), Clostridium difficile colitis ( Clostridium difficile), coccidioides immitis and Coccidioides posadasii, Colorado tick fever (CTF) (Colorado tick fever virus (CTFV)), colds (acute viral nasopharyngitis; Acute coryza) (usually rhinoviruses and coronaviruses), Creutzfeldt-Jakob disease (CJD) (PRNP), Crimean-Congo hemorrhagic fever (CCHF) (Crimea-Congo hemorrhagic fever virus), cryptococcosis (Cryptococcus neoformans), cryptosporidiosis (Cryptosporidium spp.), larva migrans syndrome, cutaneous form (CLM) (usually Ancylostoma braziliense; many other parasites), cyclosporiasis (Cyclospora cayetanensis), cysticercosis (Taenia solium), cytomegalovirus infection (cytomegalovirus), Dengue fever (Dengue viruses (DEN-1, DEN-2 , DEN-3 and DEN-4) - flaviviruses), Desmodesmus infection (green algae Desmodesmus armatus), dientamoeba fragilis, diphtheria (Corynebacterium diphria), diphyllobothrium, dracunculiasis (Dracunculus medinensis), Ebola hemorrhagic fever (Ebolavirus (EBOV)), Echinococcosis (Echinococcus spp.), ehrlichiosis (Ehrlichia spp.), enterobiasis (oxyurosis) (Enterobius vermicularis), Enterococcus infection (Enterococcus spp.), enterovirus infection (enterovirus spp.), epidemic typhus (Rickettsia prowazekii), erythema infectiosum ( fifth disease) (parvovirus B19), sudden exanthema (Sixth disease) (human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7)), fascioliasis (Fasciola hepatica and Fasciola gigantica), fasciolopsis (Fasciolopsis buski), fatal familial insomnia (FFI) (PRNP), filariasis (Filarioidea superfamily), Clostridium perfringens food poisoning (Clostridium perfringens), free-living amoebic infection (multiple), Fusobacterium infection (Fusobacterium spp.), gas gangrene (Clostridial myonecrosis) (usually Clostridium perfringens; other Clostridium species), geotrichosis (Geotrichum Candidum), Gerstmann-Strüssler-Scheinker syndrome (GSS) (PRNP), giardiasis (Giardia lamblia), glanders (Burkholderia mallei), gnathostomiasis (Gnathostoma spinigerum and Gnathostoma hispidum), gonorrhea (Neisseria gonorrhoeae) , granuloma inguinalis (donovanosis) (Klebsiella granulomatis), group A streptococcal infection (Streptococcus pyogenes), group B streptococcal infection (Streptococcus agalactiae), Haemophilus influenza infection (Haemophilus influenzae) Hand, foot and mouth disease (HFMD) (enteroviruses, mainly Coxsackie A virus and enterovirus 71 (EV71 hantavirus pulmonary syndrome (HPS) (Sin Nombre virus), Heartland virus disease (Heartland virus), Helicobacter pylori infection (Helicobacter pylori), hemolytic uremic syndrome (HUS), Escherichia coli O157: H7, O111 and O104: H4, hemorrhagic fever with renal syndrome (HFRS) (family Bunyaviridae), hepatitis A (hepatitis A virus), hepatitis B (hepatitis B virus), hepatitis C (hepatitis C virus), hepatitis D (hepatitis D virus) , hepatitis E (hepatitis E virus), herpes simplex virus (herpes simplex virus 1 and 2 (HSV-1 and HSV-2)), histoplasmosis (Histoplasma capsulatum), hookworm infection (Ancylostoma duodenale and Necator americanus), human bavirus infection (bocavirus human (HBoV) infection, human Ehrlichia ewingii infection (Ehrlichia ewingii), human granulocytic anaplasmosis (HGA) (Anaplasma phagocytophilum), human metapneumovirus infection, human metapneumovirus (hMPV), human monocytic ehrlichiosis (Ehrlichia chaffeensis), human papillomavirus (HPV) infection ) (human papillomavirus (HPV)), human parainfluenza virus infection (human parainfluenza viruses (HPIV)), hymenolepiasis (Hymenolepis papa and Hymenolepis diminuta), infectious mononucleosis Epstein-Barr virus (Mono) (Epstein-Barr virus (EBV)), influenza (influenza) (family Orthomyxoviridae) isosporiasis (Isospora belli), Kawasaki disease (unknown; evidence supports that it is infectious), keratitis (multiple), Kingella kingae infection (Kingella kingae), Kuru (PRNP), Lassa fever (Lassa virus), Legionellosis (Legionella pneumophila), Legionellosis (Pontiac fever) ( Legionella pneumophila), leishmaniasis (Leishmania spp.), leprosy (Mycobacterium leprae and Mycobacterium lepromatosis), leptospirosis (Leptospira spp.), listeriosis

- 47 043393 (Listeria monocytogenes), Lyme disease (Lyme borreliosis) (Borrelia burgdorferi, Borrelia garinii and Borrelia afzelii), lymphatic filariasis (Elephantiasis) (Wuchereria bancrofti and Brugia malayi), lymphocytic choriomeningitis (lymphocytic choriomeningitis virus (LCMV) )), malaria ( Plasmodium species), Marburg hemorrhagic fever (MHF) (Marburg virus), measles, Middle East respiratory syndrome (MERS) (Middle East respiratory syndrome coronavirus), melioidosis (Whitmore disease) (Burkholderia pseudomallei), meningitis (several), meningococcal disease (meningococcus) , metagonimiasis (usually Metagonimus yokagawai), microsporidiosis (Microsporidia phylum), molluscum contagiosum (MC) (molluscum contagiosum virus (MCV)), monkeypox (monkeypox virus), mumps (mumps virus), murine typhus (endemic typhus) (Rickettsia typhi), mycoplasma pneumoniae (Mycoplasma pneumoniae), mycetoma (disambiguation) (numerous species of bacteria (Actinomycetoma) and fungi (Eumycetoma)), myiasis (parasitic larvae of the dipterous fly), neonatal conjunctivitis (Ophthalmia neonatorum) (most often Chlamydia trachomatis and Neisseria gonorrhoeae ), norovirus (children and infants) ((new) variant Creutzfeldt-Jakob disease (vCJD, nvCJD), PRNP), nocardia (usually Nocardia asteroides and other Nocardia species), onchocerciasis (river blindness) (Onchocerca volvulus), opisthorchiasis (Opisthorchis viverrini and Siberian fluke), paracoccidiosis (South American blastomycosis) (Paracoccidioides brasiliensis), paragonimiasis (usually Paragonimus westermani and other Paragonimus species), pasteurellosis (Pasteurella spp.), head lice (Pediculus humanus capitis), body lice (body lice) ) (Pediculus humanus corporis), pediculosis pubis (pubic lice) (Phthirus pubis), pelvic inflammatory disease (PID) (multiple), whooping cough (whooping cough) (Bordetella pertussis), plague (Yersinia pestis), pneumococcal infection (Streptococcus pneumoniae), Pneumocystis jirovecii (Pneumocystis jirovecii), pneumonia (several), poliomyelitis (poliovirus), Prevotella infection (Prevotella species), primary amoebic meningoencephalitis (PAM) (usually Naegleria fowleri), progressive multifocal leukoencephalopathy (JC virus), psittacosis ( Chlamydophila psittaci), Q fever (Coxiella burnetii), rabies (rabies virus), relapsing fever (Borrelia hermsii, Borrelia recurrentis, and other Borrelia species), respiratory syncytial virus infection (respiratory syncytial virus (RSV)), rhinosporidiosis ( Rhinosporidium seeberi), rhinovirus infection (rhinovirus), rickettsial infection (Rickettsia spp.), smallpox rickettsial disease (Rickettsia akari), Rift Valley fever (RVF) (Rift Valley fever virus), Rocky Mountain spotted fever (RMSF) (Rickettsia rickettsii), rotavirus infection (rotavirus), measles rubella (Rubella virus), salmonellosis (Salmonella spp.), SARS (SARS coronavirus), scabies (Sarcoptes scabiei), schistosomiasis (Schistosoma spp.), sepsis (several), shigellosis (bacterial dysentery ) (Shigella spp.), herpes zoster (Varicella zoster virus (VZV)), smallpox (Variola) (Variola major or Variola minor), sporotrichosis (Sporothrix schenckii), staphylococcal food poisoning (Staphylococcus spp.), staph infection ( Staphylococcus spp.), strongyloidiasis (Strongyloides stercoralis), sclerosing panencephalitis (measles virus), syphilis (Treponema pallidum), teniasis (Taenia spp.), tetanus (lockjaw) (Clostridium tetani), tinea beard and mustache (barber's itch) (usually Trichophyton spp. ), ringworm (ringworm of the scalp), Trichophyton tonurans), ringworm of the smooth skin (ringworm of the body) (usually Trichophyton species), tinea groin (ringworm of the groin) (usually Epidermophyton floccosum, Trichophyton rubrum and Trichophyton mentagrophytes), ringworm of the hands (ringworm ringworm (Trichophyton rubrum), ringworm (usually Hortaea werneckii), dermatophytosis (athlete's foot) (usually Trichophyton spp.), dermatophytic onychomycosis (onychomycosis) (usually Trichophyton spp.), pityriasis versicolor (tinea versicolor) (Malassezia spp.), toxocariasis (larva migrans syndrome, ocular form (OLM)) (Toxocara canis or Toxocara cati), toxocariasis (larva migrans syndrome, visceral form (VLM)) (Toxocara canis or Toxocara cati), trachoma (Chlamydia trachomatis), toxoplasmosis (Toxoplasma gondii) , trichinosis (Trichinella spiralis), trichomoniasis (Trichomonas vaginalis), trichuriasis (whipworm infection) (Trichuris trichiura), tuberculosis (usually Mycobacterium tuberculosis), tularemia (Francisella tularensis), typhoid fever (Salmonella enterica subsp. enterica, serovar typhi), Typhoid (Rickettsia), Ureaplasma urealyticum infection (Ureaplasma urealyticum), valley fever (Coccidioides immitis or Coccidioides posadasii), Venezuelan equine encephalitis (Venezuelan equine encephalitis virus), Venezuelan hemorrhagic fever (Guanarito virus), Vibri infection o vulnificus (Vibrio vulnificus), Vibrio parahaemolyticus enteritis (Vibrio parahaemolyticus), viral pneumonia (multiple viruses), West Nile fever (West Nile virus), white piedra (Tinea blanca) (Trichosporon beigelii infection), Yersinia pseudotuberculosis infection (Yersinia pseudotuberculosis), yersineosis (Yersinia enterocolitica), yellow fever (yellow fever virus), Yersinia yellow, Yersinia, yellow intestine (Yersinia), Yersinis) fever (yellow fever virus), zygomycosis (order Mucorales (mucoromycosis) and order Entomophthorales (entomophthoramycosis)), immunodeficiency virus human [HIV], HIV infection with infectious and parasitic diseases, HIV infection with mycobacterial infection, HIV infection with cytomegalovirus disease, HIV infection with other viral infections, HIV infection with candidiasis, HIV infection with other mycoses, HIV infection with Pneumocystis pneumonia, HIV infection with malignant neoplasms, HIV infection with Kaposi's sarcoma, HIV infection with Burkitt's lymphoma, HIV infection with another type of non-Hodgkin's lymphoma, HIV infection with other malignancies

- 48 043393 related neoplasms of lymphoid, hematopoietic and related tissues, HIV infection with multiple malignant neoplasms, HIV infection with other malignant neoplasms, HIV infection with an unspecified malignant neoplasm, HIV infection with encephalopathy, HIV infection with lymphoid interstitial pneumonitis, HIV infection with wasting syndrome, HIV infection with multiple conditions classified elsewhere, HIV infection with other conditions, HIV infection, acute HIV infection syndrome, HIV infection with (persistent) generalized lymphadenopathy, HIV infection with hematological and immunological abnormalities, not elsewhere classified, HIV infection with other conditions, HIV infection unspecified, malignant neoplasm of the lip, malignant neoplasm of the tonsils, malignant neoplasm of the tongue, malignant neoplasm of the gingiva, malignant neoplasm of the mouth, malignant neoplasm of the parotid gland, malignant neoplasm of the salivary glands, malignant neoplasm of the pharynx , malignant neoplasm of the esophagus, malignant neoplasm of the stomach, malignant neoplasm of the small intestine, malignant neoplasm of the colon, malignant neoplasm of the rectosigmoid junction, malignant neoplasm of the rectum, malignant neoplasm of the anus, malignant neoplasm of the liver, malignant neoplasm of the gall bladder, malignant neoplasm of the bile duct, malignant neoplasm of the pancreas glands, malignant neoplasm of the intestinal tract, malignant neoplasm of the spleen, malignant neoplasm of the nasal cavity and middle ear, malignant neoplasm of the paranasal sinuses, malignant neoplasm of the larynx, malignant neoplasm of the trachea, malignant neoplasm of the bronchi and lungs, malignant neoplasm of the thymus, malignant neoplasm of the heart, mediastinum and pleura, malignant neoplasm of areas in the respiratory system and intrathoracic organs, malignant neoplasm of bones and articular cartilage of the extremities, malignant neoplasm of the bones of the skull and face, malignant neoplasm of the spine, malignant neoplasm of the ribs, sternum and clavicle, malignant neoplasm of the pelvic bones, sacrum and coccyx, malignant melanoma of the skin, malignant melanoma of the lip, malignant melanoma of the eyelids, including the canthus, malignant melanoma of the ear and external ear canal, malignant melanoma of the face, malignant melanoma of the anal skin, malignant melanoma of the skin of the breast, malignant melanoma of the extremities, including the shoulder, Merkel cell carcinoma, basal cell carcinoma skin of the lip, squamous cell carcinoma of the skin of the lip, other and unspecified malignant neoplasms of the skin/eyelids, including canthus, malignant neoplasms of the skin/ear and external ear canal, other and unspecified malignant neoplasms of the skin/and unspecified parts of the face, basal cell carcinoma of the skin of other and unspecified parts of the face , squamous cell carcinoma of the skin and unspecified areas of the face, basal cell carcinoma of the skin of the head and neck, squamous cell carcinoma of the skin of the head and neck, basal cell carcinoma of the skin of the trunk, basal cell carcinoma of the anal skin, basal cell carcinoma of the skin of the breast, squamous cell carcinoma of the skin of the trunk, squamous cell carcinoma of the anal skin, squamous cell skin carcinoma of the breast, squamous cell carcinoma of the skin of another part of the body, other and unspecified malignancies of the skin/extremities, including the shoulder, basal cell carcinoma of the skin/limb, including the shoulder, squamous cell carcinoma of the skin/limb, including the shoulder, basal cell carcinoma of the skin/limb, including the thigh, squamous cell carcinoma of the skin of the extremities, including the thigh, mesothelioma, Kaposi's sarcoma, malignant neoplasm of the peripheral nerves and autonomic nervous system, malignant neoplasm of the retroperitoneum and peritoneum, malignant neoplasm of other connective and soft tissues, malignant neoplasm of connective and soft tissue of the chest, malignant neoplasm of soft tissues and connective tissue of the abdominal cavity, malignant neoplasm of connective and soft tissue of the pelvis, malignant neoplasm of connective and soft tissue of an unspecified part of the trunk, malignant neoplasm of overlapping areas of connective and soft tissue, unspecified malignant neoplasm of connective and soft tissue, stromal tumor of the gastrointestinal tract, malignant neoplasm breast, malignant neoplasm of the vulva, malignant neoplasm of the vagina, malignant neoplasm of the cervix, malignant neoplasm of the uterine body, malignant neoplasm of the unspecified part of the uterus, malignant neoplasm of the ovaries, malignant neoplasm of other and unspecified female genital organs, malignant neoplasm of the placenta, malignant neoplasm of the penis, malignant neoplasm of the prostate, malignant neoplasm of the testis, malignant neoplasm of other and unspecified male genital organs, malignant neoplasm of the kidney, malignant neoplasm of the renal pelvis, malignant neoplasm of the ureter, malignant neoplasm of the bladder, malignant neoplasm of other and unspecified urinary organs, malignant neoplasm of the eye and adnexa , malignant neoplasm of the meninges, malignant

- 49 043393 neoplasm of the brain, malignant neoplasm of the spinal cord, cranial nerves, malignant neoplasm of the optic nerve, malignant neoplasm of other and unspecified cranial nerves, unspecified malignant neoplasm of the central nervous system, malignant neoplasm of the thyroid gland, malignant neoplasm of the adrenal glands, malignant neoplasm of the endoglands and related structures, malignant neuroendocrine tumors, malignant carcinoid tumors, secondary neuroendocrine tumors, malignant neoplasm of the head, face and neck, malignant neoplasm of the chest, malignant neoplasm of the pelvis, malignant neoplasm of the extremities, malignant neoplasm of the lower extremities, secondary and unspecified malignant neoplasms of the lymph nodes, secondary malignant neoplasm of the respiratory and digestive organs, secondary malignant neoplasm of the kidneys and renal pelvis, secondary malignant neoplasm of the bladder and other and unspecified urinary organs, secondary malignant neoplasm of the skin, secondary malignant neoplasm of the skin, secondary malignant neoplasm of the skin, secondary malignant neoplasm of the brain and meninges , secondary malignant neoplasm of unspecified parts of the nervous system, secondary malignant neoplasm of bone and bone marrow, secondary malignant neoplasm of the ovary, secondary malignant neoplasm of the adrenal gland, Hodgkin's lymphoma, follicular lymphoma, small B-cell lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma , lymphoblastic (diffuse) lymphoma, Burkitt's lymphoma, other non-follicular lymphomas, unspecified non-follicular (diffuse) lymphoma, unspecified mature T/NK-cell lymphomas, Sésar's disease, unclassified peripheral T-cell lymphoma, anaplastic large cell lymphoma, ALK-positive, anaplastic large cell lymphoma, unspecified ALK-negative, cutaneous T-cell lymphoma, other mature T/NK-cell lymphomas, unspecified mature T/NK-cell lymphomas, other and unspecified types of non-Hodgkin's lymphoma, malignant immunoproliferative dys and certain other B-cell lymphomas, multiple myeloma and plasma malignancy, lymphocytic leukemia, acute lymphoblastic leukemia [ALL], B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, cellular leukemia, T-cell lymphoma/adult leukemia (HTLV-1 associated), prolymphocytic T-cell leukemia, mature B-cell leukemia Burkitt type, other lymphocytic leukemias, unspecified lymphocytic leukemia, myeloid leukemia, acute myeloblastic leukemia, BCR/ABL-positive leukemia, atypical chronic myeloid leukemia, BCR/ABL-negative, myeloid sarcoma, acute promyelocytic ny leukemia, acute myelomonocytic leukemia, acute myeloid leukemia with 11q23 abnormality, other myeloid leukemia, other unspecified myeloid leukemia, monocytic leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, other monocytic leukemia, unspecified monocytic leukemia , other leukemias of specified cell types, acute erythroid leukemia, acute megakaryoblastic leukemia, mast cell leukemia, acute panmyelosis, with myofibrosis, unclassified myelodysplastic disease, other established leukemias, leukemia of unspecified cell type, Chronic leukemia of unspecified cell type, unspecified leukemia, other and unspecified malignancies of lymphoid, hematopoietic tissue, carcinoma in situ of the oral cavity, esophagus and stomach, carcinoma in situ of the colon, carcinoma in situ of the rectosigmoid junction, carcinoma in situ of the rectum, carcinoma in situ of the anus and anal canal, carcinoma in situ of other and unspecified parts of the intestine, carcinoma in situ of the unspecified part of the intestine, carcinoma in situ of others parts of the intestine, carcinoma in situ of the liver, gall bladder and bile ducts, carcinoma in situ of other parts of the specified digestive organs, unspecified carcinoma in situ of the digestive organs, carcinoma in situ of the middle ear and respiratory system, carcinoma in situ of the larynx, carcinoma in situ of the trachea, carcinoma in situ of the bronchi and lungs, carcinoma in situ of other parts of the respiratory system, melanoma in situ, melanoma in situ of the lip, melanoma in situ of the eyelid including the canthus, melanoma in situ of the ear and external ear canal, melanoma in situ of unspecified part of the face, melanoma in situ skin of the head and neck, melanoma in situ of the trunk, melanoma in situ of the anal skin, melanoma in situ of the breast (skin) (soft tissue), melanoma in situ of the upper extremity, including the shoulder, melanoma in situ of the lower extremity, including the thigh, melanoma in situ other sites, carcinoma in situ of the skin, carcinoma in situ of the skin of the lips, carcinoma in situ of the skin of the eyelids, including the canthus, carcinoma in situ of the skin of the ear and external ear canal, carcinoma in situ of the skin of other and unspecified parts of the face, carcinoma in situ of the scalp and neck, carcinoma in situ of the skin of the trunk, carcinoma in situ of the skin of the upper extremity, including the shoulder, carcinoma in situ of the skin of the lower extremity, including the thigh, carcinoma in situ of the skin of other areas, carcinoma in situ of the breast, lobular carcinoma in situ of the breast, intraductal carcinoma in situ of the breast, other specified type carcinoma in situ of the breast, unspecified type carcinoma in situ of the breast, carcinoma in situ of the cervix, carcinoma in situ of other parts of the cervix, unspecified carcinoma in situ of the cervix, carcinoma in situ of others and unspecified genital organs, carcinoma in situ of the endometrium, carcinoma in situ of the external female genitalia, carcinoma in situ of the vagina, carcinoma in situ of other and unspecified female genital organs, carcinoma in situ of the genitalia

- 50 043393 members, carcinoma in situ of the prostate, carcinoma in situ of unspecified male genital organs, carcinoma in situ of the scrotum, carcinoma in situ of other male genital organs, carcinoma in situ of the bladder, carcinoma in situ of other and unspecified urinary organs, carcinoma in situ eyes, carcinoma in situ of the thyroid gland and other endocrine glands, benign neoplasm of the mouth and pharynx, benign neoplasm of the major salivary glands, benign neoplasm of the colon, rectum, anus and anal canal, benign neoplasm of ill-defined areas of the digestive system, benign neoplasm of the esophagus, benign neoplasm of the stomach, benign neoplasm of the duodenum, benign neoplasm of other and unspecified parts of the small intestine, benign neoplasm of the liver, benign neoplasm of the extrahepatic bile ducts, benign neoplasm of the pancreas, benign neoplasm of the endocrine pancreas, benign neoplasm of the endocrine pancreas, benign neoplasm of ill-defined sites in the digestive system, benign neoplasm of the middle ear and respiratory system, unspecified benign neoplasm of the respiratory system, benign neoplasm of other and unspecified intrathoracic organs, benign neoplasm of the thymus, benign neoplasm of the heart, benign neoplasm of the mediastinum, benign neoplasm of other specified intrathoracic organs, benign neoplasm of an unspecified intrathoracic organ , benign neoplasm of bone and articular cartilage, benign neoplasm of short bones of the upper extremity, benign neoplasm of long bones of the lower extremity, benign neoplasm of short bones of the lower extremity, benign neoplasm of the bones of the skull and face, benign neoplasm of the lower jaw, benign neoplasm of the spinal column, benign neoplasm of the ribs, sternum and clavicle, benign neoplasm of the pelvis, sacrum and coccyx, unspecified benign neoplasm of bones and articular cartilage, benign lipomatous neoplasm, benign lipomatous neoplasm of the skin, subcutaneous in the head, face and neck, benign lipomatous neoplasm of the intrathoracic organs, benign lipomatous neoplasm of the intra-abdominal organs , benign lipomatous neoplasm of the spermatic cord, benign lipomatous neoplasm of other areas, benign lipomatous neoplasm of the kidneys, benign lipomatous neoplasm of other genitourinary organs, hemangioma, hemangioma of an unspecified area, hemangioma of the skin and subcutaneous tissue, hemangioma of intracranial structures, hemangioma of intra-abdominal structures, hemangioma of other areas, lymphangioma any area, benign neoplasm of mesothelial tissue, benign neoplasm of soft tissues of the retroperitoneum and peritoneum, other benign neoplasms of connective and other soft tissues, melanocytic nevi, melanocytic nevi of the lip, melanocytic nevi of the eyelids, including the canthus, melanocytic nevi of the unspecified eyelid, including the canthus, melanocytic nevi of the ear and external auditory canal, melanocytic nevi of other and unspecified parts of the face, melanocytic nevi of the scalp and neck, melanocytic nevi of the trunk, melanocytic nevi of the upper limb, including the shoulder, melanocytic nevi of the lower limb, including the thigh, unspecified melanocytic nevi, other benign skin neoplasms eyelids, including canthus, other benign neoplasms of the skin/ear and external ear canal, other benign neoplasms of the skin/left ear and external auditory canal, other benign neoplasms of the skin of other and unspecified parts of the face, other benign neoplasms of the skin of other parts of the face, other benign neoplasms of the skin head and neck, other benign neoplasm of the skin of the trunk, other benign neoplasm of the skin/upper extremities, including the shoulder, other benign neoplasm of the skin of the lower extremities, including the thighs, other unspecified benign neoplasm of the skin, benign neoplasm of the breast, benign neoplasm of the unspecified breast, uterine leiomyoma , other benign neoplasm of the uterus, benign neoplasm of the ovary, benign neoplasm of other and unspecified female genital organs, benign neoplasm of the male genital organs, benign neoplasm of the urinary organs, benign neoplasm of the kidney, benign neoplasm of the renal pelvis, benign neoplasm of the ureter, benign neoplasm of the bladder, benign neoplasm urethra, benign neoplasm of other specified urinary organs, unspecified benign neoplasm of the urinary organ, benign neoplasm of the eye and adjacent organs, benign neoplasm of the conjunctiva, benign neoplasm of the cornea, benign neoplasm of the retina, benign neoplasm of the choroid, benign neoplasm of the ciliary body, benign neoplasm of the lacrimal glands and ducts , benign neoplasm of an unspecified part of the orbit, benign neoplasm of an unspecified part of the eye, benign neoplasm of the brain

- 51 043393 membranes, benign neoplasm of the brain and central nervous system, benign neoplasm of the thyroid gland, benign neoplasm of other and unspecified endocrine glands, benign neoplasm of other and unspecified areas, benign neoplasm of lymph nodes, benign neoplasm of peripheral nerves and autonomic nervous system, benign neoplasm of other specified sites, benign neuroendocrine tumors, other benign neuroendocrine tumors, neoplasm of undefined behavior of the oral cavity and digestive organs, neoplasm of undefined behavior of the major salivary glands, neoplasm of undefined behavior of the pharynx, neoplasm of undefined behavior of areas of the oral cavity, neoplasm of undefined behavior of the stomach, neoplasm of undefined behavior small intestine, neoplasm of uncertain behavior of the appendix, neoplasm of uncertain behavior of the colon, neoplasm of uncertain behavior of the rectum, neoplasm of uncertain behavior of the liver, GB and bile ducts, neoplasm of uncertain behavior of other digestive organs, neoplasm of uncertain behavior of the digestive organs, neoplasm of the middle ear and intrathoracic organs, neoplasm of unspecified behavior of the larynx, neoplasm of unspecified behavior of the trachea, bronchi and lungs, neoplasm of unspecified behavior of the pleura, neoplasm of unspecified behavior of the mediastinum, neoplasm of unspecified behavior of the thymus, neoplasm of unspecified behavior of other respiratory organs, unspecified neoplasm of unspecified behavior of the respiratory organs, neoplasm of unspecified behavior of the female genital organs, neoplasm of unspecified behavior of the uterus, neoplasm of unspecified behavior of the ovary, neoplasm of unspecified behavior of the ovary, neoplasm of unspecified behavior of the placenta, neoplasm of unspecified behavior of the male genital organs, neoplasm of unspecified behavior of the urinary organs, neoplasm of unspecified behavior of the kidneys, unspecified neoplasm of unspecified behavior of the kidneys, neoplasm of unspecified behavior of the renal pelvis, neoplasm of unspecified behavior of the ureter, neoplasm of unspecified behavior of the bladder, neoplasm of unspecified behavior of other urinary organs, neoplasm of unspecified behavior of an unspecified urinary organ, neoplasm of unspecified behavior of the meninges, neoplasm of unspecified behavior of the meninges, neoplasm of unspecified behavior of the meninges of the spinal cord, neoplasm of unspecified behavior of unspecified meninges membranes, neoplasm of undetermined behavior of the brain, neoplasm of undetermined behavior of the brain, neoplasm of undetermined behavior of the brain, infratentorial, neoplasm of undetermined behavior of the brain, unspecified, neoplasm of undetermined behavior of the cranial nerves, neoplasm of undetermined behavior of the spinal cord, neoplasm of undetermined behavior of the central nervous system, neoplasm of uncertain behavior of the endocrine glands, neoplasm of uncertain behavior of the thyroid gland, neoplasm of uncertain behavior of the adrenal glands, neoplasm of uncertain behavior of the adrenal glands, neoplasm of uncertain behavior of the parathyroid gland, neoplasm of uncertain behavior of the pituitary gland, neoplasm of uncertain behavior of the craniopharyngeal duct, neoplasm of uncertain behavior of the pineal gland, neoplasm of uncertain behavior of the carotid gland sinus, neoplasm of uncertain behavior of the body of the aorta and other paraganglia, neoplasm of uncertain behavior of the endocrine gland, polycythemia vera, myelodysplastic syndromes, refractory anemia without ring sideroblasts, refractory anemia with ring sideroblasts, refractory anemia with excess blasts [RAEB], myelodysplastic syndrome unspecified, other new education of uncertain behavior of lymphoid, hematopoietic tissue, histiocytic and mast cell tumors of uncertain behavior, chronic myeloproliferative disease, monoclonal gammopathy, essential hypertension, osteomyelofibrosis, other neoplasms of uncertain behavior of lymphoid, hematopoietic tissue, neoplasm of uncertain behavior of lymphoid, hematopoietic and unspecified tissue, neoplasm of uncertain behavior other and unspecified areas, neoplasm of unspecified bone/articular cartilage, neoplasm of unspecified connective/soft tissue, neoplasm of unspecified peripheral nerves and autonomic nervous system, neoplasm of unspecified retroperitoneum, neoplasm of unspecified peritoneum, neoplasm of unspecified skin, neoplasm of unspecified behavior breast, neoplasm of undetermined behavior of the digestive system, neoplasm of undetermined behavior of the respiratory system, neoplasm of undetermined behavior of bone, soft tissue and skin, neoplasm of undetermined behavior of the mammary gland, neoplasm of undetermined behavior of the bladder, neoplasm of undetermined behavior of other genitourinary organs, neoplasm of undetermined behavior of the kidney, neoplasm of uncertain behavior of another MP organ, neoplasm of uncertain behavior of the brain, neoplasm of uncertain behavior

- 52 043393 endocrine glands and other parts of the nervous system, neoplasm of unspecified behavior of the retina and choroid, neoplasm of unspecified behavior of an unspecified area, iron deficiency anemia, anemia caused by vitamin B12 deficiency, anemia caused by folate deficiency, anemia caused by protein deficiency, other megaloblastic anemias not elsewhere classified, anemia due to scurvy, other specified nutritional anemias, unspecified nutritional anemia, anemia due to enzyme disorders, anemia, thalassemia, hereditary persistence of fetal hemoglobin [HPFH], hemoglobin E beta thalassemia, other thalassemias, thalassemia unspecified, sickle cell disorders, other inherited hemolytic anemias, acquired hemolytic anemia, acquired true red cell aplasia [erythroblastopenia], unspecified acquired true red cell aplasia, other aplastic anemias and other bone marrow failure syndromes, drug-induced aplastic anemia, aplastic anemia caused by other external agents ami , idiopathic aplastic anemia, other aplastic anemia and other bone marrow failure syndromes, unspecified aplastic anemia, acute posthemorrhagic anemia, anemia, disseminated intravascular coagulation, hereditary factor VIII deficiency, hereditary factor IX deficiency, other coagulation defects, acquired coagulation factor deficiency, primary thrombophilia, other thrombophilias, purpura and other hemorrhagic conditions, secondary thrombocytopenia, unspecified thrombocytopenia, other specified hemorrhagic conditions, unspecified hemorrhagic condition, neutropenia, congenital agranulocytosis, agranulocytosis secondary to cancer chemotherapy, other drug-induced agranulocytosis, neutropenia due to infection, cyclic neutropenia, other neutropenia, other leukocyte disorders, genetic abnormalities of leukocytes, eosinophilia, other specified cell disorders, decreased number of leukocytes, lymphocytosis (symptomatic), spleen disease, methemoglobinemia, congenital methemoglobinemia, other methemoglobinemia, unspecified methemoglobinemia, other and unspecified blood and blood disorders creative organs, other familial erythrocyte erythrocytes, secondary diseases caused by other erythrocytes, blood and hematopoietic organs, myelofibrosis, heparin-induced thrombocytopenia (HIT), other specified diseases of the blood and hematopoietic organs, other diseases associated with lymphoreticular and reticulohistiocytic tissue, intraoperative and post-procedural complications of the spleen, immunodeficiency with a predominance of antibody defects, hereditary hypogammaglobulinemia, non-familial hypogammaglobulinemia, selective deficiency of immunoglobulin A [IgA], selective deficiency of subclasses of immunoglobulin G [IgG], selective deficiency of immunoglobulin M [IgM], immunodeficiency with increased immunoglobulin M [IgM] , antibody deficiency with almost normal immunoglobulin or with hyperimmunoglobulin, transient hypogammaglobulinemia of infancy, other immunodeficiencies with predominantly antibody defects, unspecified immunodeficiency with predominantly antibody defects, combined immunodeficiencies, severe combined immunodeficiency with reticular dysgenesis, severe combined immunodeficiency with low T- and B counts -cells, severe immunodeficiency with low or normal B cell counts, adenosine deaminase deficiency [ADA], Nezelof syndrome, purine nucleoside phosphorylase [PNP] deficiency, MHC class I deficiency, MHC class II deficiency, other combined immunodeficiencies, unspecified combined immunodeficiency, immunodeficiency associated with other underlying defects, Wiskott-Aldrich syndrome, DiGeorge syndrome, immunodeficiency with dwarfism due to short limbs, immunodeficiency after reaction to Epstein-Barr virus, hyperimmunoglobulin E [IgE] syndrome, immunodeficiency associated with other underlying defects, immunodeficiency associated with an unspecified underlying defect, common variable immunodeficiency, other immunodeficiencies, lymphocyte function antigen-1 [LFA-1] defect, defects in the complement system, other specified immunodeficiencies, sarcoidosis, other disorders involving the immune mechanism, NEC, polyclonal hypergammaglobulinemia, cryoglobulinemia, unspecified hypergammaglobulinemia, immune reconstitution syndrome, mast cell activation syndrome and related disorders, unspecified mast cell activation syndrome, monoclonal mast cell activation syndrome, idiopathic mast cell activation syndrome, secondary mast cell activation disorder, other activation disorders mast cell, other immune-related disorders, NEC, graft-versus-host disease, acute graft-versus-host disease, chronic graft-versus-host disease, acute chronic graft-versus-host disease, unspecified graft-versus-host disease, autoimmune lymphoproliferative syndrome [ALPS], other immune-related disorder, NEC, unspecified immune-related disorder, autoimmune thyroiditis, type 1 diabetes mellitus, other diabetes mellitus with other specified complications, primary adrenocortical deficiency, autoimmune polyglandabular deficiency, dementia due to human immunodeficiency virus disease [HIV] ] (B22.0), multiple sclerosis, Guillain-Barré syndrome, myasthenia gravis without (acute) exacerbation, myasthenia gravis with (acute) exacerbation, cytotoxic myoneural disorders, congenital or acquired myasthenia, unspecified

- 53 043393 Lambert-Eaton syndrome, Lambert-Eaton syndrome in diseases classified elsewhere, other specified myoneural disorders, unspecified myoneural disorders, unspecified acute and subacute iridocyclitis, Crohn's disease, ulcerative (chronic) pancolitis, inflammatory polyps of the colon , left-sided colitis, other ulcerative colitis without/with complications, chronic persistent hepatitis, chronic lobular hepatitis, chronic active hepatitis, other chronic hepatitis, unspecified chronic hepatitis, primary biliary cirrhosis, autoimmune hepatitis, celiac disease, pemphigus, bullous pemphigoid, cicatricial pemphigoid, chronic bullous disease of childhood, unspecified acquired epidermosis bullosa, other acquired epidermosis bullosa, other pemphigoid, psoriasis vulgaris, other psoriatic arthropathy, generalized alopecia (capitis), alopecia generalis, ophiasis, other alopecia areata, unspecified alopecia areata, vitiligo, Felty's syndrome , rheumatoid lung disease with rheumatoid arthritis, rheumatoid vasculitis with rheumatoid arthritis, unspecified site, rheumatoid vasculitis with rheumatoid arthritis, rheumatoid heart disease with rheumatoid arthritis, rheumatoid myopathy with rheumatoid arthritis, rheumatoid polyneuropathy with rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis with/without rheumatoid arthritis factor, adult Still's disease, rheumatoid bursitis, rheumatoid nodule, inflammatory polyarthropathy, other specified rheumatoid arthritis, juvenile rheumatoid arthritis, juvenile ankylosing spondylitis, juvenile arthritis, Wegener's granulomatosis without renal involvement, Wegener's granulomatosis with renal involvement, juvenile dermatopolymyositis, polymyositis, dermatopol imositis , giant cell arteritis with polymyalgia rheumatica, systemic lupus erythematosus, endocarditis with systemic lupus erythematosus, pericarditis with systemic lupus erythematosus, pulmonary damage with systemic lupus erythematosus, glomerular disease with systemic lupus erythematosus, tubulointerstitial neuropathy with systemic lupus erythematosus, progressive systemic sclerosis, CR syndrome (E)ST, systemic sclerosis, dry eye syndrome, polymyalgia rheumatica, systemic connective tissue disease, ankylosing spondylitis, laboratory evidence of human immunodeficiency virus [HIV].

In certain embodiments of the invention, treatment of certain patients who have one or more cancer or autoimmune or infectious diseases, in the list and tables below, could be excluded and avoided.

Hemophagocytic lymphohistiocytosis, multiple myeloma, allergen-specific immunotherapy, autosomal dominant haploinsufficiency, anterior interosseous nerve syndrome of the forearm, Churg-Strauss syndrome, systemic vasculitis, chronic graft-versus-host disease, opsoclonus-myoclonus syndrome, necrotizing autoimmune myopathy (NAM), pulmonary sar comatoid carcinomas, Waldenström's macroglobulinemia (WM), fertility, Behçet's disease, alopecia areata (AA), acute chronic liver failure, melanoma, organized bronchiolitis syndrome, encephalitis, minimal change disease, or a patient receiving tumor suppression therapy or sublingual immunotherapy (SLIT) ) or subcutaneous immunotherapy (SCIT), or having:

disease (source of disease) infection Acinetobacter (Acinetobacter baumannii), Actinomycosis (Actinomyces israelii, Actinomyces gerencseriae and Propionibacterium propionicus) African sleeping sickness or African trypanosomiasis (Trypanosoma brucei), AIDS (acquired immunodeficiency virus, immunodeficiency syndrome, purulent immunodeficiency) Anaplasmosis (Anaplasm spp. a ), angiostro -sagiliasis (angiostrongylus), anisakiosis (Anisakis), Siberian ulcer (Bacillus anthracis), infection of Arcanobacterium haemolyticum (Arcanobacterium haemolyticum), Argentinean hemorrhagic virtue KU (Junin Virus), ascaris (Ascaris Lumbricoides), aspergilliosis (types of aspergillus), astrovirus infection ( family Astroviridae), babesiosis (Babesia spp.), Bacillus cereus infection (Bacillus cereus), bacterial pneumonia (multiple bacteria), bacterial vaginosis (list of microbiota of bacterial vaginosis), bacteroides infection (Bacteroides spp.), balantidium coli, bartonellosis (Bartonella ), baylisascariasis (Baylisascaris spp.), BK virus infection (BK virus), black piedra (Piedraia hortae), blastocystis (Blastocystis spp.), blastomycosis (Blastomyces dermatitidis), Bolivian hemorrhagic fever (Machupo virus), botulism (botulism and infant botulism) (Clostridium botulinum; Note: Botulism is not an infection of Clostridium botulinum but is caused by consumption of botulinum toxin), Brazilian hemorrhagic fever (Sabia virus), brucellosis (Brucella spp.), bubonic plague (bacterial family Enterobacteriaceae), Burkholderia infection, usually Burkholderia cepacia and other Burkholderia species, ulcers Buruli (Mycobacterium ulcerans), calicivirus infection (Norovirus and Sapovirus) (family Caliciviridae), campylobacteriosis (Campylobacter species), candidiasis (moniliasis; thrush) (usually Candida albicans and other Candida species), Capillariasis (intestinal disease due to Capillaria philippinensis, liver disease due to Capillaria hepatica and pulmonary disease due to Capillaria aerophila), Carrion disease (Bartonella bacilliformis), cat scratch disease (Bartonella henselae), cellulitis (usually group A Streptococcus and Staphylococcus), Chagas disease (American trypanosomiasis) (Trypanosoma cruzi), chancroid (Haemophilus ducreyi), chickenpox (Varicella zoster virus (VZV)), Chikungunya (Alphavirus), chlamydia (Chlamydia trachomatis), Chla infection

- 54 043393 mydophila pneumoniae (Taiwan Acute Respiratory Agent or TWAR) (Chlamydophila pneumoniae), cholera (Vibrio cholerae), chromoblastomycosis (usually Fonsecaea pedrosoi), chytridiomycosis (Batrachochytrium dendrabatidis), clonorchiasis (Clonorchis sinensis), colitis caused by Clostridium difficile (Clostrid ium difficile), coccidioridomycosis (Coccidioides immitis and Coccidioides posadasii), Colorado tick fever (CTF) (Colorado tick fever virus (CTFV)), colds (acute viral nasopharyngitis; Acute coryza) (usually rhinoviruses and coronaviruses), Creutzfeldt-Jakob disease (CJD) ) (PRNP), Crimean-Congo hemorrhagic fever (CCHF) (Crimea-Congo hemorrhagic fever virus), cryptococcosis (Cryptococcus neoformans), cryptosporidiosis (Cryptosporidium spp.), larva migrans syndrome, cutaneous form (CLM) (usually Ancylostoma braziliense; many others parasites), cyclosporiasis (Cyclospora cayetanensis), cysticercosis (Taenia solium), cytomegalovirus infection (cytomegalovirus), Dengue fever (Dengue viruses (DEN-1, DEN-2, DEN-3 and DEN-4) - flaviviruses), Desmodesmus infection ( green algae Desmodesmus armatus), dentamebiasis (dentamoeba fragilis), diphtheria (Corynebacterium diphria), diphylobotriosis (Diphylobothrium), Dracunculus Medinsis), hemorrhoids) Ebolavirus ragine fever (EBOV)), echinococcosis (types of echinococcus), erlichiosis (types of Ehrlichia) , enterobiasis (oxyurosis) (Enterobius vermicularis), Enterococcus infection (Enterococcus species), enterovirus infection (enterovirus species), epidemic typhus (Rickettsia prowazekii), erythema infectious (fifth disease) (parvovirus B19), sudden exanthema (Sixth disease) (herpes virus human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7), fascioliasis (Fasciola hepatica and Fasciola gigantica), fasciolopsis (Fasciolopsis buski), fatal familial insomnia (FFI) (PRNP), filariasis (Filarioidea superfamily), food Clostridium perfringens poisoning (Clostridium perfringens), free-living amoebic infection (multiple), Fusobacterium infection (Fusobacterium spp.), gas gangrene (Clostridial myonecrosis) (usually Clostridium perfringens; other Clostridium species), geotrichosis (Geotrichum Candidum), Gerstmann-Strüssler-Scheinker syndrome (GSS) (PRNP), giardiasis (Giardia lamblia), glanders (Burkholderia mallei), gnathostomiasis (Gnathostoma spinigerum and Gnathostoma hispidum), gonorrhea (Neisseria gonorrhoeae) , granuloma inguinalis (donovanosis) (Klebsiella granulomatis), group A streptococcal infection (Streptococcus pyogenes), group B streptococcal infection (Streptococcus agalactiae), Haemophilus influenza infection (Haemophilus influenzae) Hand, foot and mouth disease (HFMD) (enteroviruses, mainly Coxsackie A virus and enterovirus 71 (EV71 hantavirus pulmonary syndrome (HPS) (Sin Nombre virus), Heartland virus disease (Heartland virus), Helicobacter pylori infection (Helicobacter pylori), hemolytic uremic syndrome (HUS), Escherichia coli O157: H7, O111 and O104: H4, hemorrhagic fever with renal syndrome (HFRS) (family Bunyaviridae), hepatitis A (hepatitis A virus), hepatitis B (hepatitis B virus), hepatitis C (hepatitis C virus), hepatitis D (hepatitis D virus) , hepatitis E (hepatitis E virus), herpes simplex virus (herpes simplex virus 1 and 2 (HSV-1 and HSV-2)), histoplasmosis (Histoplasma capsulatum), hookworm infection (Ancylostoma duodenale and Necator americanus), human bavirus infection (bocavirus human (HBoV) infection, human Ehrlichia ewingii infection (Ehrlichia ewingii), human granulocytic anaplasmosis (HGA) (Anaplasma phagocytophilum), human metapneumovirus infection, human metapneumovirus (hMPV), human monocytic ehrlichiosis (Ehrlichia chaffeensis), human papillomavirus (HPV) infection ) (human papillomavirus (HPV)), human parainfluenza virus infection (human parainfluenza viruses (HPIV)), hymenolepiasis (Hymenolepis papa and Hymenolepis diminuta), infectious mononucleosis Epstein-Barr virus (Mono) (Epstein-Barr virus (EBV)), influenza (influenza) (family Orthomyxoviridae) isosporiasis (Isospora belli), Kawasaki disease (unknown; evidence supports that it is infectious), keratitis (multiple), Kingella kingae infection (Kingella kingae), Kypy (PRNP), Lassa fever (Lassa virus), Legionellosis (Legionella pneumophila), Legionellosis (Pontiac fever) ( Legionella pneumophila), leishmaniasis (Leishmania spp.), leprosy (Mycobacterium leprae and Mycobacterium lepromatosis), leptospirosis (Leptospira spp.), listeriosis (Listeria monocytogenes), Lyme disease (Lyme borreliosis) (Borrelia burgdorferi, Borrelia garinii and Borrelia afzelii), lymphatic filariasis ( Elephantiasis) (Wuchereria bancrofti and Brugia malayi), lymphocytic choriomeningitis (lymphocytic choriomeningitis virus (LCMV)), malaria (Plasmodium spp.), Marburg hemorrhagic fever (MHF) (Marburg virus), measles, Middle East respiratory syndrome (MERS) (Middle East respiratory syndrome coronavirus syndrome), melioidosis (Whitmore's disease) (Burkholderia pseudomallei), meningitis (several), meningococcal disease (meningococcus), metagonimiasis (usually Metagonimus yokagawai), microsporidiosis (Microsporidia phylum), molluscum contagiosum (MCV) (molluscum contagiosum virus (MCV)) , monkeypox (monkeypox virus), mumps (mumps virus), murine typhus (endemic typhus) (Rickettsia typhi), mycoplasma pneumoniae (Mycoplasma pneumoniae), mycetoma (disambiguation) (numerous species of bacteria (Actinomycetoma) and fungi (Eumycetoma)) , myiasis (parasitic dipteran fly larvae), neonatal conjunctivitis (Ophthalmia neonatorum) (most commonly Chlamydia trachomatis and Neisseria gonorrhoeae), norovirus (children and infants) ((new) variant Creutzfeldt-Jakob disease (vCJD, nvCJD), PRNP), nocardiosis (usually Nocardia asteroides and other Nocardia species), onchocerciasis (river blindness) (Onchocerca volvulus), opisthorchiasis (Opisthorchis viverrini and Siberian fluke), paracoccidiosis (South American blastomycosis) (Paracoccidioides brasiliensis), paragonimiasis (usually Paragonimus westermani and other Paragoni species

- 55 043393 mus), pasteurellosis (Pasteurella spp.), head lice (Pediculus humanus capitis), body lice (Pediculus humanus corporis), pediculosis pubis (pubic lice) (Phthirus pubis), pelvic inflammatory disease (PID) (many), whooping cough (Bordetella pertussis), plague (Yersinia pestis), pneumococcal disease (Streptococcus pneumoniae), Pneumocystis jirovecii (Pneumocystis jirovecii), pneumonia (multiple), poliomyelitis (poliovirus), infection Prevotella (Prevotella species), primary amoebic meningoencephalitis (PAM) (usually Naegleria fowleri), progressive multifocal leukoencephalopathy (JC virus), psittacosis (Chlamydophila psittaci), Q fever (Coxiella burnetii), rabies (rabies virus), relapsing fever ( Borrelia hermsii, Borrelia recurrentis, and other Borrelia species), respiratory syncytial virus infection (respiratory syncytial virus (RSV)), rhinosporidiosis (Rhinosporidium seeberi), rhinovirus infection (rhinovirus), rickettsial infection (Rickettsia spp.), smallpox rickettsiosis (Rickettsia akari), Rift Valley fever (RVF) (Rift Valley fever virus), Rocky Mountain spotted fever (RMSF) (Rickettsia rickettsii), rotavirus (rotavirus), measles rubella (Rubella virus), salmonellosis (Salmonella spp.), SARS (syndrome) SARS (SARS coronavirus), scabies (Sarcoptes scabiei), schistosomiasis (Schistosoma spp.), sepsis (several), shigellosis (bacterial dysentery) (Shigella spp.), herpes zoster (Varicella zoster virus (VZV)), smallpox (Variola) (Variola major or Variola minor), sporotrichosis (Sporothrix schenckii), staphylococcal food poisoning (Staphylococcus spp.), staphylococcal infection (Staphylococcus spp.), strongyloidiasis (Strongyloides stercoralis), sclerosing panencephalitis (measles virus), syphilis (Treponema pallidum ), teniasis (Taenia spp.), tetanus (lockjaw) (Clostridium tetani), tinea beard and mustache (barber's itch) (usually Trichophyton spp.), ringworm (tinea scalp), Trichophyton tonurans), tinea cruris (body ringworm) (usually Trichophyton species), ringworm (usually Epidermophyton floccosum, Trichophyton rubrum and Trichophyton mentagrophytes), ringworm of the hands (Trichophyton rubrum), ringworm (usually Hortaea werneckii), dermatophytosis (athlete's foot) (usually Trichophyton spp.), dermatophytic onychomycosis (onychomycosis) (usually Trichophyton spp.), pityriasis versicolor (lichen versicolor) (Malassezia spp.), toxocariasis (larva migrans syndrome, ocular form (OLM)) (Toxocara canis or Toxocara cati), toxocariasis ( larva migrans syndrome, visceral form (VLM)) (Toxocara canis or Toxocara cati), trachoma (Chlamydia trachomatis), toxoplasmosis (Toxoplasma gondii), trichinosis (Trichinella spiralis), trichomoniasis (Trichomonas vaginalis), trichuriasis (whipworm infection) (Trichuris trichiura ), tuberculosis (usually Mycobacterium tuberculosis), tularemia (Francisella tularensis), typhoid fever (Salmonella enterica subsp. enterica, serovar typhi), Typhoid (Rickettsia), Ureaplasma urealyticum infection (Ureaplasma urealyticum), valley fever (Coccidioides immitis or Coccidioides posadasii), Venezuelan equine encephalitis (Venezuelan equine encephalitis virus), Venezuelan hemorrhagic fever (Guanarito virus), Vibri infection o vulnificus (Vibrio vulnificus), Vibrio parahaemolyticus enteritis (Vibrio parahaemolyticus), viral pneumonia (multiple viruses), West Nile fever (West Nile virus), white piedra (Tinea blanca) (Trichosporon beigelii infection), Yersinia pseudotuberculosis infection (Yersinia pseudotuberculosis), yersineosis (Yersinia enterocolitica), yellow fever (yellow fever virus), Yersinia yellow, Yersinia, yellow intestine (Yersinia), Yersinis) fever (yellow fever virus), zygomycosis (order Mucorales (mucoromycosis) and order Entomophthorales (entomophthoramycosis)), immunodeficiency virus human [HIV], HIV infection with infectious and parasitic diseases, HIV infection with mycobacterial infection, HIV infection with cytomegalovirus disease, HIV infection with other viral infections, HIV infection with candidiasis, HIV infection with other mycoses, HIV infection with Pneumocystis pneumonia, HIV infection with malignant neoplasms, HIV infection with Kaposi's sarcoma, HIV infection with Burkitt's lymphoma, HIV infection with another type of non-Hodgkin's lymphoma, HIV infection with other malignant neoplasms of lymphoid, hematopoietic and related tissues, HIV- infection with multiple malignancies, HIV infection with other malignancies, HIV infection with unspecified malignancy, HIV infection with encephalopathy, HIV infection with lymphoid interstitial pneumonitis, HIV infection with wasting syndrome, HIV infection with multiple diseases classified elsewhere else, HIV infection with other conditions, HIV infection, acute HIV infection syndrome, HIV infection with (persistent) generalized lymphadenopathy, HIV infection with hematological and immunological abnormalities not elsewhere classified, HIV infection with other conditions, HIV- unspecified infection, malignant neoplasm of the lip, malignant neoplasm of the tonsils, malignant neoplasm of the tongue, malignant neoplasm of the gums, malignant neoplasm of the mouth, malignant neoplasm of the parotid gland, malignant neoplasm of the salivary glands, malignant neoplasm of the pharynx, malignant neoplasm of the esophagus, malignant neoplasm of the stomach, malignant neoplasm of the small intestine, malignant neoplasm of the colon, malignant neoplasm of the rectosigmoid junction, malignant neoplasm of the rectum, malignant neoplasm of the anus, malignant neoplasm of the liver,

- 56 043393 malignant neoplasm of the gallbladder, malignant neoplasm of the biliary tract, malignant neoplasm of the pancreas, malignant neoplasm of the intestinal tract, malignant neoplasm of the spleen, malignant neoplasm of the nasal cavity and middle ear, malignant neoplasm of the paranasal sinuses, malignant neoplasm of the larynx, malignant neoplasm of the trachea, malignant neoplasm bronchi and lungs, malignant neoplasm of the thymus, malignant neoplasm of the heart, mediastinum and pleura, malignant neoplasm of areas in the respiratory system and intrathoracic organs, malignant neoplasm of bones and articular cartilage of the extremities, malignant neoplasm of the bones of the skull and face, malignant neoplasm of the spine, malignant neoplasm of the ribs, sternum and clavicle, malignant neoplasm of the pelvic bones, sacrum and coccyx, malignant melanoma of the skin, malignant melanoma of the lip, malignant melanoma of the eyelids, including the canthus, malignant melanoma of the ear and external ear canal, malignant melanoma of the face, malignant melanoma of the anal skin, malignant melanoma of the skin of the breast, malignant melanoma of the extremities, including the shoulder, Merkel cell carcinoma, basal cell carcinoma of the skin of the lip, squamous cell carcinoma of the skin of the lip, other and unspecified malignancies of the skin/eyelids, including the canthus, malignancies of the skin/ear and external ear canal, other and unspecified malignancies neoplasms of the skin/and unspecified parts of the face, basal cell carcinoma of the skin of other and unspecified parts of the face, squamous cell carcinoma of the skin and unspecified areas of the face, basal cell carcinoma of the skin of the head and neck, squamous cell carcinoma of the head and neck skin, basal cell carcinoma of the skin of the trunk, basal cell carcinoma of the anal skin, basal cell skin carcinoma of the breast, squamous cell carcinoma of the skin of the trunk, squamous cell carcinoma of the anal skin, squamous cell carcinoma of the skin of the breast, squamous cell carcinoma of the skin of other part of the trunk, other and unspecified malignancies of the skin/extremities, including the shoulder, basal cell carcinoma of the skin/extremities, including the shoulder, squamous cell carcinoma of the skin/extremity, including the shoulder, basal cell carcinoma of the skin of the extremities, including the thigh, squamous cell carcinoma of the skin of the extremities, including the thigh, mesothelioma, Kaposi's sarcoma, malignancy of the peripheral nerves and autonomic nervous system, malignancy of the retroperitoneum and peritoneum, malignancy of other connective and soft tissue, malignant neoplasm of connective and soft tissue of the chest, malignant neoplasm of soft tissue and connective tissue of the abdomen, malignant neoplasm of connective and soft tissue of the pelvis, malignant neoplasm of connective and soft tissue of an unspecified part of the trunk, malignant neoplasm of overlapping areas of connective and soft tissue, unspecified malignant neoplasm of connective and soft tissue, stromal tumor of the gastrointestinal tract, malignant neoplasm of the breast, malignant neoplasm of the vulva, malignant neoplasm of the vagina, malignant neoplasm of the cervix, malignant neoplasm of the body of the uterus, malignant neoplasm of unspecified part of the uterus, malignant neoplasm of the ovaries, malignant neoplasm of others and unspecified female genital organs, malignant neoplasm of the placenta, malignant neoplasm of the penis, malignant neoplasm of the prostate, malignant neoplasm of the testis, malignant neoplasm of other and unspecified male genital organs, malignant neoplasm of the kidney, malignant neoplasm of the renal pelvis, malignant neoplasm of the ureter, malignant neoplasm of the bladder , malignant neoplasm of other and unspecified urinary organs, malignant neoplasm of the eye and adnexa, malignant neoplasm of the meninges, malignant neoplasm of the brain, malignant neoplasm of the spinal cord, cranial nerves, malignant neoplasm of the optic nerve, malignant neoplasm of other and unspecified cranial nerves, unspecified malignant neoplasm of the central nervous system, malignant neoplasm of the thyroid gland, malignant neoplasm of the adrenal gland, malignant neoplasm of the endoglands and related structures, malignant neuroendocrine tumors, malignant carcinoid tumors, secondary neuroendocrine tumors, malignant neoplasm of the head, face and neck, malignant neoplasm of the chest, malignant neoplasm pelvis, malignant neoplasm of the extremities, malignant neoplasm of the lower extremities, secondary and unspecified malignant neoplasms of the lymph nodes, secondary malignant neoplasms of the respiratory and digestive organs, secondary malignant neoplasms of the kidneys and renal pelvis, secondary malignant neoplasms of the bladder and other and unspecified urinary organs, secondary malignant neoplasms skin, secondary malignant neoplasm of the skin, secondary malignant neoplasm of the skin, secondary malignant neoplasm of the brain and meninges, secondary malignant neoplasm of unspecified parts of the nervous system, secondary malignant neoplasm of the bone and marrow, secondary malignancy

- 57 043393 new ovarian neoplasm, secondary adrenal malignancy, Hodgkin's lymphoma, follicular lymphoma, small cell B-cell lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, lymphoblastic (diffuse) lymphoma, Burkitt's lymphoma, other non-follicular lymphoma, unspecified nonfollicular (diffuse) lymphoma, unspecified mature T/NK-cell lymphoma, Sesar disease, unclassified peripheral T-cell lymphoma, anaplastic large cell lymphoma, ALK-positive, anaplastic large cell lymphoma, unspecified ALK-negative, cutaneous T-cell lymphoma, other mature T/NK cell lymphomas, unspecified mature T/NK cell lymphomas, other and unspecified types of non-Hodgkin's lymphoma, malignant immunoproliferative dys and certain other B-cell lymphomas, multiple myeloma and plasma malignancy, lymphocytic leukemia, acute lymphoblastic leukemia [ALL] , chronic lymphocytic leukemia B-cell type, cellular prolymphocytic leukemia B-cell type, cellular leukemia, adult T-cell lymphoma/leukemia (associated with HTLV-1), prolymphocytic leukemia T-cell type, mature B-cell leukemia Burkitt type, others lymphocytic leukemia, unspecified lymphocytic leukemia, myeloid leukemia, acute myeloid leukemia, BCR/ABL-positive leukemia, atypical chronic myeloid leukemia, BCR/ABL-negative, myeloid sarcoma, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute myeloid leukemia goats with 11q23 abnormality, other myeloid leukemia , other unspecified myeloid leukemia, monocytic leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, other monocytic leukemia, unspecified monocytic leukemia, other leukemias of specified cell types, acute erythroid leukemia, acute megakaryoblastic leukemia, mast cell leukemia, acute pan myelosis, with myofibrosis, unclassified myelodysplastic disease , other established leukemias, leukemia of unspecified cell type, Chronic leukemia of unspecified cell type, unspecified leukemia, other and unspecified malignancies of lymphoid, hematopoietic tissue, carcinoma in situ of the oral cavity, esophagus and stomach, carcinoma in situ of the colon, carcinoma in situ of the rectosigmoid junction , carcinoma in situ of the rectum, carcinoma in situ of the anus and anal canal, carcinoma in situ of other and unspecified parts of the intestine, carcinoma in situ of the unspecified part of the intestine, carcinoma in situ of other parts of the intestine, carcinoma in situ of the liver, gall bladder and bile ducts, carcinoma in situ of other parts of the specified digestive organs, unspecified carcinoma in situ of the digestive organs, carcinoma in situ of the middle ear and respiratory system, carcinoma in situ of the larynx, carcinoma in situ of the trachea, carcinoma in situ of the bronchi and lungs, carcinoma in situ of other parts of the respiratory system, melanoma in situ, melanoma in situ of the lip, melanoma in situ of the eyelid, including the canthus, melanoma in situ of the ear and external ear canal, melanoma in situ of the unspecified part of the face, melanoma in situ of the scalp and neck, melanoma in situ of the trunk, melanoma in situ of the anal skin , melanoma in situ of the breast (skin) (soft tissue), melanoma in situ of the upper extremity, including the shoulder, melanoma in situ of the lower extremity, including the thigh, melanoma in situ of other sites, carcinoma in situ of the skin, carcinoma in situ of the skin of the lips, carcinoma in situ skin of the eyelids, including the canthus, carcinoma in situ of the skin of the ear and external ear canal, carcinoma in situ of the skin of other and unspecified parts of the face, carcinoma in situ of the skin of the head and neck, carcinoma in situ of the skin of the trunk, carcinoma in situ of the skin of the upper extremity , including shoulder, carcinoma in situ of the skin of the lower extremity, including the thigh, carcinoma in situ of the skin of other sites, carcinoma in situ of the breast, lobular carcinoma in situ of the breast, intraductal carcinoma in situ of the breast, other specified type of carcinoma in situ of the breast, unspecified carcinoma in situ of the breast, carcinoma in situ of the cervix, carcinoma in situ of other parts of the cervix, unspecified carcinoma in situ of the cervix, carcinoma in situ of other and unspecified genital organs, carcinoma in situ of the endometrium, carcinoma in situ of the external female genitalia , carcinoma in situ of the vagina, carcinoma in situ of other and unspecified female genital organs, carcinoma in situ of the penis, carcinoma in situ of the prostate, carcinoma in situ of unspecified male genital organs, carcinoma in situ of the scrotum, carcinoma in situ of other male genital organs, carcinoma in situ of the bladder, carcinoma in situ of other and unspecified urinary organs, carcinoma in situ of the eye, carcinoma in situ of the thyroid and other endocrine glands, benign neoplasm of the mouth and pharynx, benign neoplasm of the major salivary glands, benign neoplasm of the colon, rectum, posterior passage and anal canal, benign neoplasm of unspecified parts of the digestive system, benign neoplasm of the esophagus, benign neoplasm of the stomach, benign neoplasm of the duodenum, benign neoplasm of other and unspecified parts of the small intestine, benign neoplasm of the liver, benign neoplasm of the extrahepatic bile ducts, benign neoplasm of the pancreas, benign neoplasm of the endocrine pancreas, benign neoplasm of the endocrine pancreas, benign neoplasm of ill-defined sites in the digestive system, benign neoplasm of the middle ear and respiratory system, unspecified benign neoplasm of the respiratory system, benign neoplasm of other and unspecified intrathoracic organs, benign neoplasm of the thymus, ext.

- 58 043393 benign neoplasm of the heart, benign neoplasm of the mediastinum, benign neoplasm of other specified intrathoracic organs, benign neoplasm of an unspecified intrathoracic organ, benign neoplasm of bone and articular cartilage, benign neoplasm of the short bones of the upper extremity, benign neoplasm of the long bones of the lower extremity, benign neoplasm of the short bones of the lower extremity extremities, benign neoplasm of the skull and face, benign neoplasm of the lower jaw, benign neoplasm of the spinal column, benign neoplasm of the ribs, sternum and clavicle, benign neoplasm of the pelvis, sacrum and coccyx, unspecified benign neoplasm of bones and articular cartilage, benign lipomatous neoplasm, benign lipomatous skin neoplasm, subcutaneous in the head, face and neck, benign lipomatous neoplasm of the intrathoracic organs, benign lipomatous neoplasm of the intra-abdominal organs, benign lipomatous neoplasm of the spermatic cord, benign lipomatous neoplasm of other areas, benign lipomatous neoplasm of the kidneys, benign lipomatous neoplasm of other genitourinary organs, hemangioma, hemangioma of an unspecified area, hemangioma of the skin and subcutaneous tissue, hemangioma of intracranial structures, hemangioma of intra-abdominal structures, hemangioma of other areas, lymphangioma of any area, benign neoplasm of mesothelial tissue, benign neoplasm of soft tissues of the retroperitoneum and peritoneum, other benign neoplasms of connective and other soft tissues, melanocytic nevi, melanocytic nevi of the lip, melanocytic nevi of the eyelids, including the canthus, melanocytic nevi of the unspecified eyelid, including the canthus, melanocytic nevi of the ear and external auditory canal, melanocytic nevi of other and unspecified parts of the face, melanocytic nevi of the scalp and neck, melanocytic nevi of the trunk, melanocytic nevi of the upper extremity, including the shoulder, melanocytic nevi of the lower extremity, including the thigh, unspecified melanocytic nevi, other benign neoplasm of the skin of the eyelids, including the canthus, other benign neoplasm of the skin/ear and external ear canal, other benign neoplasm of the skin/left ear and external auditory canal , other benign neoplasms of the skin of other and unspecified parts of the face, other benign neoplasms of the skin of other parts of the face, other benign neoplasms of the skin of the head and neck, other benign neoplasms of the skin of the torso, other benign neoplasms of the skin/upper extremities, including the shoulder, other benign neoplasms of the skin of the lower extremities including hip, other unspecified benign neoplasm of skin, benign neoplasm of breast, benign neoplasm of unspecified breast, uterine leiomyoma, other benign neoplasm of uterus, benign neoplasm of ovary, benign neoplasm of other and unspecified female genital organs, benign neoplasm of male genital organs, benign neoplasm urinary organs, benign neoplasm of the kidney, benign neoplasm of the renal pelvis, benign neoplasm of the ureter, benign neoplasm of the bladder, benign neoplasm of the urethra, benign neoplasm of other specified urinary organs, unspecified benign neoplasm of the urinary organ, benign neoplasm of the eye and adjacent organs, benign neoplasm of the conjunctiva, benign neoplasm of the cornea, benign neoplasm of the retina, benign neoplasm of the choroid, benign neoplasm of the ciliary body, benign neoplasm of the lacrimal glands and ducts, benign neoplasm of the unspecified area of the orbit, benign neoplasm of the unspecified part of the eye, benign neoplasm of the meninges, benign neoplasm of the brain and central nervous system, benign neoplasm of the thyroid gland, benign neoplasm of other and unspecified endocrine glands, benign neoplasm of other and unspecified sites, benign neoplasm of lymph nodes, benign neoplasm of peripheral nerves and autonomic nervous system, benign neoplasm of other specified sites, benign neuroendocrine tumors, other benign neuroendocrine tumors, neoplasm of indeterminate behavior of the oral cavity and digestive organs, neoplasm of indeterminate behavior of the large salivary glands, neoplasm of indeterminate behavior of the pharynx, neoplasm of indeterminate behavior of the oral cavity, neoplasm of indeterminate behavior of the stomach, neoplasm of indeterminate behavior of the small intestine, neoplasm of indeterminate behavior of the appendix, neoplasm of indeterminate behavior of the large intestine, neoplasm of uncertain behavior of the rectum, neoplasm of uncertain behavior of the liver, GB and bile ducts, neoplasm of uncertain behavior of other digestive organs, neoplasm of uncertain behavior of the digestive organs, neoplasm of the middle ear and intrathoracic organs, neoplasm of uncertain behavior of the larynx, neoplasm of uncertain behavior of the trachea, bronchi and lungs, But

- 59 043393 neoplasm of uncertain behavior of the pleura, neoplasm of uncertain behavior of the mediastinum, neoplasm of uncertain behavior of the thymus, neoplasm of uncertain behavior of other respiratory organs, unspecified neoplasm of uncertain behavior of the respiratory organs, neoplasm of uncertain behavior of the female genital organs, neoplasm of uncertain behavior of the uterus, neoplasm of uncertain behavior of the ovary, neoplasm neoplasm of unspecified behavior of the ovary, neoplasm of unspecified behavior of the placenta, neoplasm of unspecified behavior of the male genital organs, neoplasm of unspecified behavior of the urinary organs, neoplasm of unspecified behavior of the kidneys, unspecified neoplasm of unspecified behavior of the kidneys, neoplasm of unspecified behavior of the renal pelvis, neoplasm of unspecified behavior of the ureter, neoplasm of unspecified behavior of the bladder, neoplasm of unspecified behavior of other urinary organs, neoplasm of unspecified behavior of an unspecified urinary organ, neoplasm of unspecified behavior of the meninges, neoplasm of unspecified behavior of the meninges, neoplasm of unspecified behavior of the meninges of the spinal cord, neoplasm of unspecified behavior of unspecified meninges, neoplasm of unspecified behavior of the brain, neoplasm of unspecified behavior brain, neoplasm of uncertain behavior of the brain, infratentorial, neoplasm of uncertain behavior of the brain, unspecified, neoplasm of uncertain behavior of the cranial nerves, neoplasm of uncertain behavior of the spinal cord, neoplasm of uncertain behavior of the central nervous system, neoplasm of uncertain behavior of the endocrine glands, neoplasm of uncertain behavior of the thyroid gland, neoplasm of undefined behavior of the adrenal glands, neoplasm of undefined behavior of the adrenal glands, neoplasm of undefined behavior of the parathyroid gland, neoplasm of undefined behavior of the pituitary gland, neoplasm of undefined behavior of the craniopharyngeal duct, neoplasm of undefined behavior of the pineal gland, neoplasm of undefined behavior of the carotid sinus, neoplasm of undefined behavior of the body of the aorta and other paraganglia, neoplasm of uncertain behavior of the endocrine gland, polycythemia vera, myelodysplastic syndromes, refractory anemia without ring sideroblasts, refractory anemia with ring sideroblasts, refractory anemia with excess blasts [RAEB], myelodysplastic syndrome unspecified, other neoplasm of uncertain behavior of lymphoid, hematopoietic tissue, histio quotable and fat- cellular tumors of unspecified behavior, chronic myeloproliferative disease, monoclonal gammopathy, essential hypertension, osteomyelofibrosis, other neoplasms of unspecified behavior of lymphoid, hematopoietic tissue, neoplasm of unspecified behavior of lymphoid, hematopoietic and unspecified tissue, neoplasm of unspecified behavior of other and unspecified areas, neoplasm of unspecified behavior of bones/joints cartilage, neoplasm of undetermined connective/soft tissue behavior, neoplasm of undetermined behavior of peripheral nerves and autonomic nervous system, neoplasm of undetermined behavior of the retroperitoneum, neoplasm of undetermined behavior of the peritoneum, neoplasm of undetermined behavior of the skin, neoplasm of undetermined behavior of the mammary gland, neoplasm of undetermined behavior of the digestive system, neoplasm of undetermined behavior behavior of the respiratory system, neoplasm of uncertain behavior of bone, soft tissue and skin, neoplasm of uncertain behavior of the breast, neoplasm of uncertain behavior of the bladder, neoplasm of uncertain behavior of other genitourinary organs, neoplasm of uncertain behavior of the kidney, neoplasm of uncertain behavior of another MP organ, neoplasm of uncertain behavior of the brain brain, neoplasm of unspecified behavior of the endocrine glands and other parts of the nervous system, neoplasm of unspecified behavior of the retina and choroid, neoplasm of unspecified behavior of the unspecified area, iron deficiency anemia, anemia caused by vitamin B12 deficiency, anemia caused by folate deficiency, anemia caused by protein deficiency, other megaloblastic anemias not elsewhere classified, anemia due to scurvy, other specified nutritional anemias, unspecified nutritional anemia, anemia due to enzyme disorders, anemia, thalassemia, hereditary persistence of fetal hemoglobin [HPFH], hemoglobin E beta thalassemia, others thalassemia, unspecified thalassemia, sickle cell disorders, other inherited hemolytic anemias, acquired hemolytic anemia, acquired true red cell aplasia [erythroblastopenia], unspecified acquired true red cell aplasia, other aplastic anemias and other bone marrow failure syndromes, drug-induced aplastic anemia, aplastic anemia, caused by others external agents, idiopathic aplastic anemia, other aplastic anemia and other bone marrow failure syndromes, unspecified aplastic anemia, acute posthemorrhagic anemia, anemia, disseminated intravascular coagulation, hereditary factor VIII deficiency, hereditary factor IX deficiency, other coagulation defects, acquired coagulation factor deficiency

- 60 043393 blood, primary thrombophilia, other thrombophilias, purpura and other hemorrhagic conditions, secondary thrombocytopenia, unspecified thrombocytopenia, other specified hemorrhagic conditions, unspecified hemorrhagic condition, neutropenia, congenital agranulocytosis, agranulocytosis secondary to cancer chemotherapy, other drug-induced agranulocytosis, neutropenia caused by infection, cyclic neutropenia, other neutropenia, other leukocyte disorders, genetic abnormalities of leukocytes, eosinophilia, other specified cell disorders, decreased white blood cell count, lymphocytosis (symptomatic), spleen disease, methemoglobinemia, congenital methemoglobinemia, other methemoglobinemia, unspecified methemoglobinemia, others and unspecified diseases of the blood and hematopoietic organs, other familial erythrocyte erythrocytes, secondary diseases caused by other erythrocytes, blood and hematopoietic organs, myelofibrosis, heparin-induced thrombocytopenia (HIT), other specified diseases of the blood and hematopoietic organs, other diseases associated with lympho- reticular and reticulohistiocytic tissue, intraoperative and post-procedural complications of the spleen, immunodeficiency with a predominance of antibody defects, hereditary hypogammaglobulinemia, non-familial hypogammaglobulinemia, selective deficiency of immunoglobulin A [IgA], selective deficiency of subclasses of immunoglobulin G [IgG], selective deficiency of immunoglobulin M [IgM], immunodeficiency with elevated immunoglobulin M [IgM], antibody deficiency with almost normal immunoglobulin or with hyperimmunoglobulin, transient hypogammaglobulinemia of infancy, other immunodeficiencies with predominantly antibody defects, unspecified immunodeficiency with predominantly antibody defects, combined immunodeficiencies, severe combined immunodeficiency with reticular dysgenesis, severe combined immunodeficiency with low T and B cell counts, severe immunodeficiency with low or normal B cell counts, adenosine deaminase deficiency [ADA], Nezelof syndrome, purine nucleoside phosphorylase [PNP] deficiency, major histocompatibility complex class I deficiency, major complex deficiency histocompatibility class II, other combined immunodeficiencies, unspecified combined immunodeficiency, immunodeficiency associated with other major defects, Wiskott-Aldrich syndrome, DiGeorge syndrome, immunodeficiency with dwarfism due to short limbs, immunodeficiency after reaction to Epstein-Barr virus, hyperimmunoglobulin E syndrome [ IgE], immunodeficiency associated with other underlying defects, immunodeficiency associated with unspecified underlying defect, common variable immunodeficiency, other immunodeficiencies, defect of lymphocyte function antigen-1 [LFA-1], defects in the complement system, other specified immunodeficiencies, sarcoidosis, other disorders including immune mechanism, NEC, polyclonal hypergammaglobulinemia, cryoglobulinemia, unspecified hypergammaglobulinemia, immune reconstitution syndrome, mast cell activation syndrome and related disorders, unspecified mast cell activation syndrome, monoclonal mast cell activation syndrome, idiopathic mast cell activation syndrome, secondary activation mast cell, other mast cell activation disorders, other immune related disorders, NEC, graft-versus-host disease, acute graft-versus-host disease, chronic graft-versus-host disease, acute chronic graft-versus-host disease, unspecified graft-versus-host disease, autoimmune lymphoproliferative syndrome [ALPS], other disorders associated with an immune mechanism, NEC, unspecified disorder associated with an immune mechanism, autoimmune thyroiditis, type 1 diabetes mellitus, other diabetes mellitus with other specified complications, primary adrenocortical insufficiency, autoimmune polyglandabular insufficiency, dementia with human immunodeficiency virus disease [HIV] (B22.0), multiple sclerosis, Guillain-Barré syndrome, myasthenia gravis without (acute) exacerbation, myasthenia gravis with (acute) exacerbation, cytotoxic myoneural disorders, congenital or acquired myasthenia, unspecified Lambert's syndrome- Eaton, Lambert-Eaton syndrome in diseases classified elsewhere, other specified myoneural disorders, unspecified myoneural disorders, unspecified acute and subacute iridocyclitis, Crohn's disease, ulcerative (chronic) pancolitis, inflammatory polyps of the colon, left-sided colitis, other ulcerative colitis without/with complications, chronic persistent hepatitis, chronic lobular hepatitis, chronic active hepatitis, other chronic hepatitis, unspecified chronic hepatitis, primary biliary cirrhosis, autoimmune hepatitis, celiac disease, pemphigus, bullous pemphigoid, cicatricial pemphigoid, chronic bullous disease in childhood, unspecified acquired epidermos bullosa, other acquired epidermos bullosa, other pemphigoid, psoriasis vulgaris, other psoriatic arthropathy, generalized alopecia (capitis), alopecia generalis, ophiasis, other alopecia areata, unspecified alopecia areata, vitiligo, Felty's syndrome, rheumatoid lung disease with rheumatoid arthritis , rheumatoid vasculitis with rheumatoid arthritis of unspecified site, rheumatoid vasculitis with rheumatoid arthritis, rheumatoid heart disease with rheumatoid arthritis, rheumatoid myopathy with rheumatoid arthritis, rheumatoid polyneuropathy with rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis with/without rheumatoid factor, Still's disease in adults, rheumatoid bursitis, rheumatoid nodule, inflammatory

- 61 043393 liarthropathy, other specified rheumatoid arthritis, juvenile rheumatoid arthritis, juvenile ankylosing spondylitis, juvenile arthritis, Wegener's granulomatosis without renal involvement, Wegener's granulomatosis with renal involvement, juvenile dermatopolymyositis, polymyositis, dermatopolymyositis, giant cell arteritis with rheumatic polymyositis gia, systemic lupus erythematosus, endocarditis in systemic lupus erythematosus, pericarditis in systemic lupus erythematosus, pulmonary disease in systemic lupus erythematosus, glomerular disease in systemic lupus erythematosus, tubulointerstitial neuropathy in systemic lupus erythematosus, progressive systemic sclerosis, CR(E)ST syndrome, systemic sclerosis, dry eye syndrome , polymyalgia rheumatica, systemic connective tissue disease, ankylosing spondylitis, laboratory evidence of human immunodeficiency virus [HIV].

Route of administration.

In certain embodiments of the invention, cellular immunotherapy may be administered to a patient by the following, but not limited to, routes: nasal submucosal, lingual, bronchoscopy, intravenous, intratumoral, intraarterial, intramuscular, intraocular, intrastriatal, subcutaneous, intradermal, dermal patch, skin patch, patch , into the cerebrospinal fluid, intraperitoneal, into the portal vein, into the spleen, into the brain, into the lymphatic intraperitoneal, into the portal vein, into the spleen, into the brain, into the lymphatic system, intra-pleural retro-orbital, intralymphatic, intradermal, systemic routes, among others. Cellular immunotherapy can be administered by systemic injection or injection site, as previously defined.

In some embodiments of the present invention, application for the use of cellular immunotherapy directly to an organ or tumor not only refers to collagen matrices, extracellular matrix compositions, biopolymer microstreams made from fibrin or other extracellular matrix material, patches containing extracellular matrix and biodegradable materials, fibrin patches, alginate or agarose patches, scaffolds consisting of extracellular matrix materials and biodegradable physiologically inert material, which may not only refer to components such as dextrans, coating stem cells with organ-specific antigens or binding molecules, residual extracellular matrices, also known as scaffolds or decellularized organs from ex vivo split organ donors or cadaveric organs, and contact lenses among others.

Catheter-based delivery systems that can be used to deliver cellular immunotherapy include not exclusively standard balloon angioplasty infusion catheters, percutaneous coronary artery delivery catheters, stop-flow infusion through balloon catheters with guidewire stent delivery systems, Swan Ganz catheters, Hickman catheters, Foley catheters, central venous catheters, pigtail catheters, SmartPort® systems, magnetically guided catheters with a metal tip, such as the Gentle Touch™ magnetic navigation system developed by Stereotaxis Inc. or Mitralign, the Accucinch System®, and catheters that are inserted directly into an organ, such as HELIX™, MyoCath™, NOGA R-guided Myostar™, Stiletto™ or the intravascular ultrasound (IVUS) TransAccess Delivery™ system, or catheters that deliver via arterial pathways such as OpenSail™, Concerto™, microsyringe infusion catheter from Mercator and Maverick™ or via implantable devices such as left ventricular assist device (LVAD), biventricular assist devices (BiVAD), Optimizer™, delivery catheters cells such as those described in US 2009/0299269.

When administering antibody therapeutic agents that inhibit the binding of cellular immunotherapy to secondary lymphoid organ tissue, it is preferable to administer them systemically, multiple times, about three weeks before administering the cellular immunotherapy. When administering small molecule therapeutic agents that inhibit the binding of cellular immunotherapy to secondary lymphoid organ tissue, it is preferable to administer them systemically, repeatedly over 1 to 4 weeks. For dexamethasone-containing agents, it is preferable to administer them systemically about 12-72 hours before administering the cellular immunotherapy, and most preferably, administering the NTLA-containing dexamethasone systemically about 36-48 hours before administering the cellular immunotherapy.

Example 1.

T-cell immunotherapy binds to the germinal center and marginal zone regions of the spleen and secondary lymphoid organs, and binding is reduced by administration of NTLA dexamethasone.

Mice were treated intravenously with NK cells isolated from syngeneic mice (using commercially available kits), the KIL NK cell line (from ATCC), CD4+/CD8+ T cell mixtures isolated from syngeneic mice (using commercially available kits), or with other ACTs , labeled with vital dyes such as DiR and STO. Mice were injected intravenously into the tail vein at levels ranging from about 1 x 10 5 cells/kg to about 1 x 10 ⁷ cells/kg. After 1 to 48 h, mice were sacrificed by

- 62 043393 exsanguination, and then residual blood cells were washed out with 5U heparin/ml PBS through the retrograde inflow into the thoracic jugular vein. The spleens were removed, wet weighed, and then fixed in 10% formaldehyde. The spleens were then sectioned using proprietary techniques that do not record or increase splenic temperature and then incubated with FITC-PNA to co-label germinal centers or FITC-anti-CD21 (10 μg) to co-label marginal zones at 4°C for 24 h, washed, placed on glass slides, and immunofluorescence images were obtained. Metamorphic software was used to quantify the immunofluorescence signal. T cell, NK cell, and KIL binding fluorescence colocalized with FITC-PNA and FITC-anti-CD21 fluorescence, indicating sequestration of cells in the marginal zones and germinal centers of secondary lymphoid organs.

Male C57B1/6 mice weighing approximately 25 g were treated orally on day -2 with placebo or HED 12 mg/kg dexamethasone. Naïve T cells were isolated on day 1 from the spleens of donor C57Bl/6 mice using EasySep™ Mouse T Cell Isolation Kits from Miltenyi. The resulting CD4+/CD8+ T cells were incubated overnight at 37°C in 5% CO ₂ . On Day 0, a fresh solution of CMPTX dye was prepared to a concentration of 5 μM. T cells isolated on day -1 were incubated with CMPTX dye solution for 40 minutes at 37°C in 5% CO2. Mice treated orally on day -2 were injected into each tail vein with 5M labeled T cells in a volume of 80 μl. Three hours later, mice were sacrificed by exsanguination, and the spleens were weighed and then cut into thick sections to visualize T-cell binding sites. Spleen sections were incubated overnight at 4 degrees with FITCPNA to label germinal centers and anti-CD21/CD35 to label marginal zones. The next day, sections were washed, fixed with 4% PFA/PBS 5% sucrose, and images were collected using an EVOS fluorescence microscope.

Labeled T cells were visualized binding in clusters at the germinal centers and marginal zones of the splenic zone. Compared to placebo-treated mice, spleens from dexamethasone-pretreated mice were significantly smaller, and overall T-cell binding, as measured by fluorescence intensity, was dramatically reduced.

Male C57B1/6 mice weighing approximately 25 g were treated orally on day -2 with placebo or HED 12 mg/kg dexamethasone. Splenic NK cells were isolated on Day -1 from the spleens of C57Bl/6 donor mice using the MojoSort™ Mouse NK Cell Isolation Kit from BioLegend. The resulting NK cells were incubated overnight at 37°C in 5% CO ₂ . On Day 0, a fresh solution of CMPTX dye was prepared to a concentration of 5 μM. NK cells isolated on Day -1 were incubated with CMPTX dye solution for 40 minutes at 37°C in 5% CO2. Mice treated orally on Day -2 were injected into each tail vein with 3M labeled NK cells in a volume of 80 μl. Three hours later, mice were sacrificed by exsanguination, and the spleens were weighed and then cut into thick sections to visualize areas of NK cell binding. Sections were washed, fixed with 4% PFA/PBS 5% sucrose and imaged using an EVOS fluorescence microscope.

Labeled NK cells were visualized in clusters along the marginal zones of the spleen. Compared to placebo-treated mice, spleens from dexamethasone-pretreated mice were significantly smaller, and overall NK cell binding, as measured by fluorescence intensity, was dramatically reduced.

Example 2: Immunosuppressive reduction of sites in secondary lymphoid organs in which cellular immunotherapy binds and sequesters.

For mice, male mice were intraperitoneally injected with dexamethasone sodium phosphate on day 0 at a dose of 114.6 mg/kg dexamethasone base (HED 9.32 mg/kg) and sacrificed 96 h after dexamethasone injection. Acute high dose dexamethasone is also referred to herein as Dex, AugmenStem™, PlenaStem™, or AVM0703. Mice were sacrificed by exsanguination, and then residual blood cells were washed out with 5U heparin/ml PBS via retrograde inflow into the thoracic jugular vein. The spleens were removed, wet weighed, and then fixed in 10% formaldehyde. The spleens were then sectioned using proprietary methods and then incubated with FITC-PNA at 4°C for 24 h, washed, mounted on glass slides, and immunofluorescence images obtained. Metamorphic software was used to quantify the immunofluorescence signal. Sample images and results normalized by spleen area are shown in FIG. 1. Control mice have significant FITC-PNA immunofluorescence, while dexamethasone sodium phosphate-treated mice have almost no immunofluorescence signal. FITC-PNA marks germinal centers, the site where cellular immunotherapy binds in secondary lymphoid organs, which is not exclusive to the spleen and lymph nodes. This example demonstrates that cellular immunotherapy fails to bind and sequester to secondary lymphoid organs following treatment with an immunosuppressant at effective doses to eliminate germinal centers. When cellular immunotherapy fails to bind to secondary lymphoid organs, it remains at the injection site or in the bloodstream for extended periods of time, during which it can detect and kill a cancer cell, autoimmune cell, or pathogenic target. In addition, the duration of engraftment of cellular immunotherapy increases.

In fig. Figure 2 shows the dose response of acute exposure to high dose dexamethasone (in HED) on the number of germinal centers in the spleen of mice. Reduction of germinal centers is evident at HED 6 mg/kg, and is slightly reduced at HED doses of 9 and 12 mg/kg.

In rats, Dex HED 3.23, 6.45, and 12.9 mg/kg (rat doses 20, 40, and 80 mg/kg) was administered (intravenous or oral) to determine GC and marginal zone inhibition at 48 h. In the rat, a dose of 12.9 mg/kg HED Dex maximally inhibited both GC and the number and area of marginal zones, as shown in Fig. 3 and fig. 4. Five sections were cut from the formalin-fixed spleens, trimmed and embedded in paraffin, cut and stained with hematoxylin and eosin (H&E). Measurements of periarteriolar lymphoid membrane (PAL) diameter and marginal zone (MZ) width in areas of the white pulp that had the largest diameter PAL were measured using an ocular micrometer. Immunohistochemical staining of BCL-6 in rat spleen was assessed to determine GC area using automated image analysis methods.

Example 3. Immunosuppressive lymphodepletion in mice, rats and humans 36-48 hours after acute administration of dexamethasone, with preservation of the properties of neutrophils, erythrocytes, platelets and stem cells.

As shown in FIG. 5, intravenous or oral administration of dexamethasone at a dose of 20 (3.2 HED), 40 (6.5 HED) or 80 (12.9 HED) mg/kg to male Lewis rats weighing 250-300 grams significantly reduced the number of lymphocytes at all compared doses compared to placebo 48 hours after administration. In contrast, as shown in FIG. 6, neutrophils were not reduced by acute high-dose dexamethasone. Neutrophil counts actually increased at all doses of dexamethasone, likely due to a demargination effect. Dexamethasone treatment had no effect on red blood cells, platelets, Hct, and HgB.

Oral acute administration of dexamethasone to male C57B1 mice at HED 3 mg/kg (n=4), HED 6 mg/kg (n=6), 9 mg/kg (n=4) or 12 mg/kg (n=4) compared with placebo (n=7) led to a decrease in CD3+ T lymphocytes by 65% and CD4+ T lymphocytes by 75% (Fig. 7), led to a decrease in CD8+ T lymphocytes by 56% and Tregs by 78% (Fig. 8) , a decrease in natural killer (NK) cells by 87% and Blymphocytes by 83% (Fig. 9), a decrease in the absolute number of lymphocytes by 84%, but at the same time leaving unchanged neutrophils (Fig. 10), red blood cells (Fig. 11) and platelets (Fig. 11). Blood was collected for SHS and flow cytometry 48 hours after dexamethasone administration by oral gavage.

Acute oral administration of 3 mg/kg dexamethasone base equivalent (all given doses in these examples are given in dexamethasone base equivalent) was administered to four patients, three with knee osteoarthritis and one with an aortic aneurysm. Blood was collected before drug treatment and 48 hours after treatment for SBC analysis and flow cytometry to determine populations of lymphocytes and other blood cells. Serum was analyzed for cytokine levels. For one patient, no preliminary SHS was performed, and thus normalized flow cytometry data are shown for only 3 patients. By non-normalized flow cytometry data, only 2 of 4 patients responded to dexamethasone with lymphodepletion (Figs. 12, 13 and 14), while 2 of 4 patients showed a lymphocytosis response in CD3 and CD4 lymphocytes, and 1 of 4 patients showed a response lymphocytosis in CD8, B lymphocytes and NK cells to this dose of dexamethasone. 3 of 4 patients showed elevated IL-2 levels and 4 of 4 showed elevated IL-15 levels 48 hours after an acute oral dose of dexamethasone base (3 mg/kg) (Fig. 15). IL-6, a cytokine known to be a major driver of the potentially fatal cytokine release syndrome (CRS), was not elevated in any patients. Based on the response to lymphocytosis seen in 2 of 4 non-cancer patients at 3 mg/kg, preferred doses for lymphodepletion prior to ACT would be 3 mg/kg or higher depending on the increased sensitivity of tumor-bearing mice to dexamethasone, where the lethal level is lowest dose was 43 mg/kg HED in mice with tumors compared to 114 mg/kg HED in healthy mice (P. Scorza Barcellona, Arch. Toxiccl, Supp!. 7, 90-93 (1984)).

Bone marrow was collected 48 h after dexamethasone administration, and the number of mesenchymal stem cells (MSC) was determined using a colony-forming fibroblast assay (CFU-F). Oral administration of dexamethasone base 3 mg/kg increased the iliac crest of VM MSCs by almost twofold (Fig. 16). The trilineage differentiation capacity of BM MSCs was also determined in an equine study. HED at 6 mg/kg doubled the number of sternal BM MSC stem cells 48 hours after intravenous infusion into horses for one hour, but did not alter the ability of MSCs to trilineage differentiate toward osteocytes, chondrocytes, or adipocytes.

Example 4: Comparison of an acute dose of 12 mg/kg dexamethasone base HED with a standard Cy (cyclophosphamide)-Flu (fludarabine) preconditioning regimen.

Dexamethasone base was administered orally via gavage to adult male mice at a dose of 12 mg/kg HED on Day -2. Another group of mice was administered Cy IP at a dose of 166 mg/kg (HED 500 mg/ ^m2 ) on days -5 and day -4 and fludarabine 10 mg/kg (HED 30 mg/ ^m2 ) on days -5, -4, -3, -2. The third group of mice Su

- 64 043393 was administered intraperitoneally at a dose of 166 mg/kg (HED 500 mg/m ² ) on day -5 and fludarabine 10 mg/kg (HED 30 mg/m ² ) on days -5, then 12 mg/kg HED dexamethasone base administered orally on day -2. The results of SHS and flow cytometry are shown in Fig. 17-22, and the body weight is shown in Fig. 23. Dexamethasone-based 12 mg/kg HED given 12-72 hours before blood collection results in a comparable lymphodepletion profile compared to standard 2-day Cy with 4-day Flu, as do combinations of one Cy on day -5 and one Flu on day -5 with 12 mg/kg dexamethasone FLED on day -2. A single dose of Su and a single dose of Flu can be administered on day -6, day-4 or day-3 with the same effect. The lymphodepletion profile of dexamethasone alone may be preferable because absolute lymphocytes are not depleted as dramatically as with CyFlu, and the degree of lymphodepletion may be related to neuroedema when ACT is administered after CyFlu.

Standard repeated CyFlu preconditioning significantly reduced body weight as an overall measure of toxicity, while dexamethasone-based HED at 12 mg/kg had no effect on body weight, and the combination of one dose of Cy and one dose of Flu on Day -5 with dexamethasone at At a dose of 12 mg/kg, HED affects body weight significantly less than the standard CyFlu regimen.

Other standard preconditioning agents that can be administered as a single dose(s) on Day -1 or Day -2 or Day -3 or Day -4 or Day -5 and combined with dexamethasone in the range of about 3 to about 12 mg /kg per day -2 include: Su 120 mg/kg and Flu 75 mg/ ^m2 ; 30 mg/ ^m2 influenza and 50 mg/kg Su and 200 cGy TBI; Su 1500 mg/ ^m2 and bendamustine 120 mg/ ^m2 ; Su from about 300 mg/ ^m2 to about 2300 mg/ ^m2 ; Influenza from about 10 mg/ ^m2 to about 900 mg/ ^m2 ; Su 600 mg/ ^m2 and Flu 30 mg/ ^m2 ; Busulfan and Melphalan and Flu; Busulfan (dose adjusted depending on weight) and thiotepa (10 mg/kg) and fludarabine (160 mg/ ^m2 ); Flu 30 mg/ ^m2 and Su 300 mg/ ^m2 and Mensa 300 mg/ ^m2 ; Flu 30 mg/ ^m2 and Su 60 mg/ ^m2 and Alemtuzumab 0.2 mg/kg.

Example 5. Immunocompetent mouse model of multiple myeloma.

The mouse multiple myeloma cell line MOPC315, available from ATCC, is a tail vein inoculated into immunocompetent Balbc mice at 2x106 cells. After about 21 days, symptoms begin to appear, which include paralysis of the hind limbs. Between 21 and 67 days after inoculation, the disease affects more than 90% of inoculated mice.

Mice were preconditioned with standard CyFlu (Cy 300 to 2100 mg/m ² for 2 to 5 days around days -6, -5, -4, -3, -2 or -1 before ACT and Flu 10 to 30 mg / ^m2 for 2 to 5 days around days -6, -5, -4, -3, -2 or -1 to ACT); other mice were pretreated with FIED base dexamethasone at a dose of 3-12 mg/kg administered orally or over 15-60 minutes intravenous infusion; other mice were pretreated with a single dose of Cy (300 to 2100 mg/ ^m2 for days -6 to -2) and Flu (10 to 30 mg/ ^m2 for days -6 to -2) plus HED base dexamethasone 3 to 12 mg/kg administered orally or over 15 to 60 minutes of intravenous infusion 12 to 72 hours before allogeneic HSCT or natural killer (NK) cell administration, which is considered Day 0 for preconditioning planning purposes.

Mice can also be preconditioned with: an agent containing hydrocortisone administered intravenously or orally every about 12 hours at a dose of about 75 to about 300 mg/kg at an interval of about 12 to about 72 hours before administration of cellular immunotherapy. The cortisone-containing agent was administered intravenously or orally every about 12 hours at a dose of about 93 to about 375 mg/kg for about 12 to about 72 hours before administration of the cellular immunotherapy. The prednisolone-containing agent was administered intravenously or orally every about 24 hours at a dose of about 19 to about 75 mg/kg for about 12 to about 60 hours before administration of the cellular immunotherapy. The methylprednisolone-containing agent was administered intravenously or orally every about 24 hours at a dose of about 15 to about 60 mg/kg from about 12 to about 60 hours before the administration of cellular immunotherapy. The triamcinolone-containing agent was administered intravenously or orally every about 24 hours at a dose of about 15 to about 60 mg/kg from about 12 to about 60 hours before the administration of cellular immunotherapy. The paramethasone-containing agent was administered as a single acute dose or cumulative doses of about 7.5 to about 30 mg/kg administered over about 12 to 72 hours prior to cellular immunotherapy. The betamethasone-containing agent was administered as a single acute dose or cumulative doses of about 2.5 to 10 mg/kg administered over about 12 to 72 hours prior to cellular immunotherapy.

Balb/cJ (H-2d) and B10.D2 (H-2d) mice were purchased from The Jackson Laboratory (Bar Harbor, ME, USA). Mice were used from 10 to 14 weeks of age. For allogeneic HSCT, spleen and bone marrow (femur and tibia) from donor B10.D2 mice were collected and homogenized in RPMI 1640 medium containing 10% FBS and 1% penicillin/streptomycin (5-complete medium). Red blood cells were lysed using sterile-filtered RBC lysis buffer (eBioscience, San Diego, USA), and the cells were washed, resuspended in phosphate-buffered saline (PBS) containing 3% FBS, and filtered through a 70 mM nylon membrane. The CD8a Positive Selection Kit in Mice (Stem Cell, Grenoble, France) is used to deplete CD8 T cells according to the manufacturer's EASYSEP depletion protocol. Finally, the cells were suspended in 200 ml PBS for intravenous injection. Balbc mice were transplanted by intravenous injection into the tail vein with 1x10 ⁷ bone marrow cells and

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7χ10 ⁷ splenocytes from B10.D2 donor mice between 10 and 30 days after MOPC315 inoculation. 94% of mice will demonstrate complete clearance of MOPC315 cells after alloHSCT. The group that received dexamethasone preconditioning would have similar removal of MOPC315 cells after alloHSCT compared to standard CyFlu, but less toxicity as body weight was reduced by 20% with CyFlu preconditioning but not reduced with Dex preconditioning. The single dose combination of CyFlu plus Dex is also effective and has less toxicity than standard CyFlu re-preconditioning. The Dexa preconditioning group will have the same or better antitumor effect, improved progression-free survival, reduced disease progression, increased duration of response, improved overall survival, reduced minimal residual disease compared to mice that were pretreated with CyFlu for 2 up to 5 days.

For the administration of allogeneic NK cells, fully functional NK cells were isolated from donor B10.D2 mice using commercially available kits, such as the kit from Miltenyi. Alternatively, murine NK cells can be purchased from ATCC (KIL cells). The NK cell isolation kit was designed to isolate intact NK cells from single-cell suspensions of mouse spleen. HeNK cells, i.e. T cells, dendritic cells, B cells, granulocytes, macrophages and erythroid cells are magnetically labeled using a mixture of biotin-conjugated antibodies and anti-biotin microbeads. Isolation of highly pure unlabeled NK cells is achieved by depletion of non-target cells. The kit has been optimized to provide exceptional purity in C57BL/6J mice. 1 x 10 ⁷ isolated NK cells were transplanted by intravenous injection into the tail vein 10-30 days after MOPC315 inoculation. NK cell eradication of MOPC315 cells is as effective using Dex preconditioning as using standard CyFlu preconditioning, with much less toxicity. The single dose combination of CyFlu plus Dex is also effective and has less toxicity than standard CyFlu re-preconditioning. The Dex preconditioning group will have the same or better antitumor effect, improved progression-free survival, reduced disease progression, increased duration of response, improved overall survival, reduced minimal residual disease compared to mice that were pretreated with CyFlu for 2 up to 5 days.

Example 6: A patient with a condition selected from the group that includes the following.

Hemophagocytic lymphohistiocytosis, multiple myeloma, allergen-specific immunotherapy, autosomal dominant haploinsufficiency, anterior interosseous nerve syndrome of the forearm, Churg-Strauss syndrome, systemic vasculitis, chronic graft-versus-host disease, opsoclonus-myoclonus syndrome, necrotizing autoimmune myopathy (NAM), pulmonary arcomatoid carcinomas, Waldenström's macroglobulinemia (WM), fertility, Behçet's disease, alopecia areata (AA), acute chronic liver failure, melanoma, organized bronchiolitis syndrome, encephalitis, minimal change disease, or a patient receiving therapy for transient worsening of clinical manifestations of tumor or sublingual immunotherapy ( SLIT) or subcutaneous immunotherapy (SCIT), or having:

disease (source of disease) infection Acinetobacter (Acinetobacter baumannii), Actinomycosis (Actinomyces israelii, Actinomyces gerencseriae and Propionibacterium propionicus) African sleeping sickness or African trypanosomiasis (Trypanosoma brucei), AIDS (acquired immunodeficiency virus, immunodeficiency syndrome, purulent immunodeficiency) Anaplasmosis (Anaplasm spp. a ), angiostrongylus (Angiostrongylus), anisakiasis (Anisakis), anthrax (Bacillus anthracis), Arcanobacterium haemolyticum infection (Arcanobacterium haemolyticum), Argentine hemorrhagic fever (Junin vims), ascariasis (Ascaris lumbricoides), aspergillosis (Aspergillus spp.), astrovirus infection ( family Astroviridae), babesiosis (Babesia spp.), Bacillus cereus infection (Bacillus cereus), bacterial pneumonia (multiple bacteria), bacterial vaginosis (list of microbiota of bacterial vaginosis), bacteroides infection (Bacteroides spp.), balantidium coli, bartonellosis (Bartonella ), baylisascariasis (Baylisascaris spp.), BK virus infection (BK virus), black piedra (Piedraia hortae), blastocystis (Blastocystis spp.), blastomycosis (Blastomyces dermatitidis), Bolivian hemorrhagic fever (Machupo virus), botulism (botulism and infant botulism) (Clostridium botulinum; Note: Botulism is not an infection of Clostridium botulinum but is caused by consumption of botulinum toxin), Brazilian hemorrhagic fever (Sabia virus), brucellosis (Brucella spp.), bubonic plague (bacterial family Enterobacteriaceae), Burkholderia infection, usually Burkholderia cepacia and other Burkholderia species, ulcers Buruli (Mycobacterium ulcerans), calicivirus infection (Norovirus and Sapovirus) (family Caliciviridae), campylobacteriosis (Campylobacter species), candidiasis (moniliasis; thrush) (usually Candida albicans and other Candida species), Capillariasis (intestinal disease due to Capillaria philippinensis, liver disease due to Capillaria hepatica and pulmonary disease due to Capillaria aerophila), Carrion disease (Bartonella bacilliformis), feline disease

- 66 043393 rapine (Bartonella henselae), cellulitis (usually group A Streptococcus and Staphylococcus), Chagas disease (American trypanosomiasis) (Trypanosoma cruzi), chancroid (Haemophilus ducreyi), chickenpox (Varicella zoster virus (VZV)), Chikungunya (Alphavirus ), chlamydia (Chlamydia trachomatis), Chlamydophila pneumoniae (Taiwan Acute Respiratory Agent or TWAR) infection (Chlamydophila pneumoniae), cholera (Vibrio cholerae), chromoblastomycosis (usually Fonsecaea pedrosoi), chytridiomycosis (Batrachochytrium dendrabatidis), clonorchiasis (Clonorchis sinensis), colitis caused by Clostridium difficile (Clostridium difficile), coccidioridomycosis (Coccidioides immitis and Coccidioides posadasii), Colorado tick fever (CTF) (Colorado tick fever virus (CTFV)), colds (acute viral nasopharyngitis; Acute coryza) (usually rhinoviruses and coronaviruses), Creutzfeldt-Jakob disease (CJD) (PRNP), Crimean-Congo hemorrhagic fever (CCHF) (Crimea-Congo hemorrhagic fever virus), cryptococcosis (Cryptococcus neoformans), cryptosporidiosis (Cryptosporidium spp.), larva migrans syndrome, cutaneous form (CLM) ( usually Ancylostoma braziliense; many other parasites), cyclosporiasis (Cyclospora cayetanensis), cysticercosis (Taenia solium), cytomegalovirus infection (cytomegalovirus), Dengue fever (Dengue viruses (DEN-1, DEN-2, DEN-3 and DEN-4) - flaviviruses), infection Desmodesmus (green algae Desmodesmus armatus), Dientamoeba fragilis, Diphtheria (Corynebacterium diphria), Diphyllobothrium, Dracunculiasis (Dracunculus medinensis), Ebola hemorrhagic fever (Ebolavirus (EBOV)), Echinococcosis (Echinococcus spp.), Ehrlichiosis (sp. s Ehrlichia), enterobiasis (oxyurosis) (Enterobius vermicularis), Enterococcus infection (Enterococcus species), enterovirus infection (enterovirus species), epidemic typhus (Rickettsia prowazekii), infectious erythema (fifth disease) (parvovirus B19), sudden exanthema (Sixth disease) (human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7)), fascioliasis (Fasciola hepatica and Fasciola gigantica), fasciolopsis (Fasciolopsis buski), fatal familial insomnia (FFI) (PRNP), filariasis (Filarioidea superfamily) , Clostridium perfringens (Clostridium perfringens) food poisoning, free-living amoebic infection (multiple), Fusobacterium infection (Fusobacterium spp.), gas gangrene (Clostridial myonecrosis) (usually Clostridium perfringens; other Clostridium species), geotrichosis (Geotrichum Candidum), Gerstmann-Strüssler-Scheinker syndrome (GSS) (PRNP), giardiasis (Giardia lamblia), glanders (Burkholderia mallei), gnathostomiasis (Gnathostoma spinigerum and Gnathostoma hispidum), gonorrhea (Neisseria gonorrhoeae) , granuloma inguinalis (donovanosis) (Klebsiella granulomatis), group A streptococcal infection (Streptococcus pyogenes), group B streptococcal infection (Streptococcus agalactiae), Haemophilus influenza infection (Haemophilus influenzae) Hand, foot and mouth disease (HFMD) (enteroviruses, mainly Coxsackie A virus and enterovirus 71 (EV71 hantavirus pulmonary syndrome (HPS) (Sin Nombre virus), Heartland virus disease (Heartland virus), Helicobacter pylori infection (Helicobacter pylori), hemolytic uremic syndrome (HUS), Escherichia coli O157: H7, O111 and O104: H4, hemorrhagic fever with renal syndrome (HFRS) (family Bunyaviridae), hepatitis A (hepatitis A virus), hepatitis B (hepatitis B virus), hepatitis C (hepatitis C virus), hepatitis D (hepatitis D virus) , hepatitis E (hepatitis E virus), herpes simplex virus (herpes simplex virus 1 and 2 (HSV-1 and HSV-2)), histoplasmosis (Histoplasma capsulatum), hookworm infection (Ancylostoma duodenale and Necator americanus), human bavirus infection (bocavirus human (HBoV) infection, human Ehrlichia ewingii infection (Ehrlichia ewingii), human granulocytic anaplasmosis (HGA) (Anaplasma phagocytophilum), human metapneumovirus infection, human metapneumovirus (hMPV), human monocytic ehrlichiosis (Ehrlichia chaffeensis), human papillomavirus (HPV) infection ) (human papillomavirus (HPV)), human parainfluenza virus infection (human parainfluenza viruses (HPIV)), hymenolepiasis (Hymenolepis papa and Hymenolepis diminuta), infectious mononucleosis Epstein-Barr virus (Mono) (Epstein-Barr virus (EBV)), influenza (influenza) (family Orthomyxoviridae) isosporiasis (Isospora belli), Kawasaki disease (unknown; evidence supports that it is infectious), keratitis (multiple), Kingella kingae infection (Kingella kingae), Kypy (PRNP), Lassa fever (Lassa virus), Legionellosis (Legionella pneumophila), Legionellosis (Pontiac fever) ( Legionella pneumophila), leishmaniasis (Leishmania spp.), leprosy (Mycobacterium leprae and Mycobacterium lepromatosis), leptospirosis (Leptospira spp.), listeriosis (Listeria monocytogenes), Lyme disease (Lyme borreliosis) (Borrelia burgdorferi, Borrelia garinii and Borrelia afzelii), lymphatic filariasis ( Elephantiasis) (Wuchereria bancrofti and Brugia malayi), lymphocytic choriomeningitis (lymphocytic choriomeningitis virus (LCMV)), malaria (Plasmodium spp.), Marburg hemorrhagic fever (MHF) (Marburg virus), measles, Middle East respiratory syndrome (MERS) (Middle East respiratory syndrome coronavirus syndrome), melioidosis (Whitmore's disease) (Burkholderia pseudomallei), meningitis (several), meningococcal disease (meningococcus), metagonimiasis (usually Metagonimus yokagawai), microsporidiosis (Microsporidia phylum), molluscum contagiosum (MCV) (molluscum contagiosum virus (MCV)) , monkeypox (monkeypox virus), mumps (mumps virus), murine typhus (endemic typhus) (Rickettsia typhi), mycoplasma pneumoniae (Mycoplasma pneumoniae), mycetoma (disambiguation) (numerous species of bacteria (Actinomycetoma) and fungi (Eumycetoma)) , myiasis (parasitic fly larvae), neonatal conjunctivitis (Ophthalmia neonatorum) (most commonly Chlamydia trachomatis and Neisseria gonorrhoeae), norovirus (children and infants) ((new) variant Creutzfeldt-Jakob disease (vCJD, nvCJD), PRNP), nocardiosis (usually

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Nocardia asteroides and other Nocardia species), onchocerciasis (river blindness) (Onchocerca volvulus), opisthorchiasis (Opisthorchis viverrini and Siberian fluke), paracoccidiosis (South American blastomycosis) (Paracoccidioides brasiliensis), paragonimiasis (usually Paragonimus westermani and other Paragonimus species), pasteurellosis ( Pasteurella spp.), head lice (Pediculus humanus capitis), body lice (Pediculus humanus corporis), pediculosis pubis (Phirus pubis), pelvic inflammatory disease (PID) (multiple), whooping cough (whooping cough) (Bordetella pertussis), plague (Yersinia pestis), pneumococcal infection (Streptococcus pneumoniae), Pneumocystis jirovecii, pneumonia (several), poliomyelitis (poliovirus), Prevotella infection (Prevotella species), primary amoebic meningoencephalitis (PAM) (usually Naegleria fowleri), progressive multifocal leukoencephalopathy (JC virus), psittacosis (Chlamydophila psittaci), Q fever (Coxiella burnetii), rabies (rabies virus), relapsing fever (Borrelia hermsii, Borrelia recurrentis, and others Borrelia spp.), respiratory syncytial virus infection (respiratory syncytial virus (RSV)), rhinosporidiosis (Rhinosporidium seeberi), rhinovirus infection (rhinovirus), rickettsial infection (Rickettsia spp.), rickettsia pox (Rickettsia akari), Rift Valley fever (RVF) ) (Rift Valley fever virus), Rocky Mountain spotted fever (RMSF) (Rickettsia rickettsii), rotavirus infection (rotavirus), measles rubella (Rubella virus), salmonellosis (Salmonella spp.), SARS (SARS coronavirus), scabies (Sarcoptes scabiei), schistosomiasis (Schistosoma spp.), sepsis (several), shigellosis (bacterial dysentery) (Shigella spp.), herpes zoster (Varicella zoster virus (VZV)), smallpox (Variola) (Variola major or Variola minor), sporotrichosis (Sporothrix schenckii), staphylococcal food poisoning (Staphylococcus spp.), staphylococcal infection (Staphylococcus spp.), strongyloidiasis (Strongyloides stercoralis), sclerosing panencephalitis (measles virus), syphilis (Treponema pallidum), teniasis (Taenia spp.), tetanus (lockjaw) (Clostridium tetani), ringworm of the beard and mustache (barber's itch) (usually Trichophyton spp.), ringworm (ringworm of the scalp), Trichophyton tonurans), ringworm of the smooth skin (ringworm of the body) (usually Trichophyton spp.), tinea groin (groin ringworm) (commonly Epidermophyton floccosum, Trichophyton rubrum and Trichophyton mentagrophytes), ringworm of the hands (ringworm of the hand) (Trichophyton rubrum), ringworm (usually Hortaea werneckii), dermatophytosis (athlete's foot) (usually Trichophyton spp.), dermatophyte onychomycosis (onychomycosis) (usually Trichophyton spp.), pityriasis versicolor (lichen versicolor) (Malassezia spp.), toxocariasis (larva migrans syndrome, ocular form (OLM)) (Toxocara canis or Toxocara cati), toxocariasis (larva migrans syndrome, visceral form (VLM) )) (Toxocara canis or Toxocara cati), trachoma (Chlamydia trachomatis), toxoplasmosis (Toxoplasma gondii), trichinosis (Trichinella spiralis), trichomoniasis (Trichomonas vaginalis), trichuriasis (whipworm infection) (Trichuris trichiura), tuberculosis (usually Mycobacterium tuberculosis) , tularemia (Francisella tularensis), typhoid fever (Salmonella enterica subsp. enterica, serovar typhi), Typhoid (Rickettsia), Ureaplasma urealyticum infection (Ureaplasma urealyticum), valley fever (Coccidioides immitis or Coccidioides posadasii), Venezuelan equine encephalitis (Venezuelan equine encephalitis virus), Venezuelan hemorrhagic fever (Guanarito virus), Vibri infection o vulnificus (Vibrio vulnificus), Vibrio parahaemolyticus enteritis (Vibrio parahaemolyticus), viral pneumonia (multiple viruses), West Nile fever (West Nile virus), white piedra (Tinea blanca) (Trichosporon beigelii infection), Yersinia pseudotuberculosis infection (Yersinia pseudotuberculosis), yersineosis (Yersinia enterocolitica), yellow fever (yellow fever virus), Yersinia yellow, Yersinia, yellow intestine (Yersinia), Yersinis) fever (yellow fever virus), zygomycosis (order Mucorales (mucoromycosis) and order Entomophthorales (entomophthoramycosis)), immunodeficiency virus human [HIV], HIV infection with infectious and parasitic diseases, HIV infection with mycobacterial infection, HIV infection with cytomegalovirus disease, HIV infection with other viral infections, HIV infection with candidiasis, HIV infection with other mycoses, HIV infection with Pneumocystis pneumonia, HIV infection with malignant neoplasms, HIV infection with Kaposi's sarcoma, HIV infection with Burkitt's lymphoma, HIV infection with another type of non-Hodgkin's lymphoma, HIV infection with other malignant neoplasms of lymphoid, hematopoietic and related tissues, HIV- infection with multiple malignancies, HIV infection with other malignancies, HIV infection with unspecified malignancy, HIV infection with encephalopathy, HIV infection with lymphoid interstitial pneumonitis, HIV infection with wasting syndrome, HIV infection with multiple diseases classified elsewhere else, HIV infection with other conditions, HIV infection, acute HIV infection syndrome, HIV infection with (persistent) generalized lymphadenopathy, HIV infection with hematological and immunological abnormalities not elsewhere classified, HIV infection with other conditions, HIV- unspecified infection, malignant neoplasm of the lip, malignant neoplasm of the tonsils, malignant neoplasm of the tongue, malignant neoplasm of the gums, malignant neoplasm of the mouth, malignant neoplasm of the parotid gland, malignant neoplasm of the salivary glands, malignant neoplasm of the pharynx, malignant neoplasm of the esophagus, malignant neoplasm of the stomach,

- 68 043393 malignant neoplasm of the small intestine, malignant neoplasm of the colon, malignant neoplasm of the rectosigmoid junction, malignant neoplasm of the rectum, malignant neoplasm of the anus, malignant neoplasm of the liver, malignant neoplasm of the gallbladder, malignant neoplasm of the biliary tract, malignant neoplasm of the pancreas, malignant neoplasm of the intestinal tract , malignant neoplasm of the spleen, malignant neoplasm of the nasal cavity and middle ear, malignant neoplasm of the paranasal sinuses, malignant neoplasm of the larynx, malignant neoplasm of the trachea, malignant neoplasm of the bronchi and lungs, malignant neoplasm of the thymus, malignant neoplasm of the heart, mediastinum and pleura, malignant neoplasm of areas in the respiratory system and intrathoracic organs, malignant neoplasm of bones and articular cartilage of the extremities, malignant neoplasm of the bones of the skull and face, malignant neoplasm of the spine, malignant neoplasm of the ribs, sternum and clavicle, malignant neoplasm of the pelvic bones, sacrum and coccyx, malignant melanoma of the skin, malignant melanoma of the lip, malignant melanoma eyelids, including canthus, malignant melanoma of the ear and external ear canal, malignant melanoma of the face, malignant melanoma of the anal skin, malignant melanoma of the skin of the breast, malignant melanoma of the extremities, including the shoulder, Merkel cell carcinoma, basal cell carcinoma of the skin of the lip, squamous cell carcinoma of the skin lips, other and unspecified malignant neoplasms of the skin/eyelids, including canthus, malignant neoplasms of the skin/ear and external ear canal, other and unspecified malignant neoplasms of the skin/and unspecified parts of the face, basal cell carcinoma of the skin of other and unspecified parts of the face, squamous cell carcinoma of the skin and unspecified areas of the face, basal cell carcinoma of the skin of the head and neck, squamous cell carcinoma of the skin of the head and neck, basal cell carcinoma of the skin of the trunk, basal cell carcinoma of the anal skin, basal cell carcinoma of the skin of the breast, squamous cell carcinoma of the skin of the trunk, squamous cell carcinoma of the anal skin, squamous cell carcinoma of the skin of the breast, squamous cell carcinoma of the skin of another part of the trunk, other and unspecified malignancies of the skin/extremities, including the shoulder, basal cell carcinoma of the skin/extremity, including the shoulder, squamous cell carcinoma of the skin/extremity, including the shoulder, basal cell carcinoma of the skin of the extremities, including the thigh, squamous cell carcinoma of the skin of the extremities, including hip, mesothelioma, Kaposi's sarcoma, malignant neoplasm of peripheral nerves and autonomic nervous system, malignant neoplasm of retroperitoneal space and peritoneum, malignant neoplasm of other connective and soft tissues, malignant neoplasm of connective and soft tissue of the chest, malignant neoplasm of soft tissues and connective tissue of the abdominal cavity, malignant neoplasm of connective and soft tissue of the pelvis, malignant neoplasm of connective and soft tissue of the unspecified part of the trunk, malignant neoplasm of overlapping areas of connective and soft tissue, unspecified malignant neoplasm of connective and soft tissue, stromal tumor of the gastrointestinal tract, malignant neoplasm of the breast, malignant neoplasm of the vulva , malignant neoplasm of the vagina, malignant neoplasm of the cervix, malignant neoplasm of the uterine body, malignant neoplasm of the unspecified part of the uterus, malignant neoplasm of the ovaries, malignant neoplasm of other and unspecified female genital organs, malignant neoplasm of the placenta, malignant neoplasm of the penis, malignant neoplasm of the prostate, malignant neoplasm testicular, malignant neoplasm of other and unspecified male genital organs, malignant neoplasm of the kidney, malignant neoplasm of the renal pelvis, malignant neoplasm of the ureter, malignant neoplasm of the bladder, malignant neoplasm of other and unspecified urinary organs, malignant neoplasm of the eye and adnexa, malignant neoplasm of the meninges, malignant neoplasm of the brain, malignant neoplasm of the spinal cord, cranial nerves, malignant neoplasm of the optic nerve, malignant neoplasm of other and unspecified cranial nerves, unspecified malignant neoplasm of the central nervous system, malignant neoplasm of the thyroid gland, malignant neoplasm of the adrenal glands, malignant neoplasm of the endoglands and related structures , malignant neuroendocrine tumors, malignant carcinoid tumors, secondary neuroendocrine tumors, malignant neoplasm of the head, face and neck, malignant neoplasm of the chest, malignant neoplasm of the pelvis, malignant neoplasm of the extremities, malignant neoplasm of the lower extremities, secondary and unspecified malignant neoplasms of the lymph nodes, secondary malignant neoplasm respiratory and digestive organs, secondary malignant neoplasm of the kidneys and renal pelvis, secondary malignant neoplasm of the bladder and other and unspecified urinary organs, secondary malignant neoplasm of the skin, secondary malignant neoplasm of the skin, secondary

- 69 043393 new malignant neoplasm of the skin, secondary malignant neoplasm of the brain and meninges, secondary malignant neoplasm of unspecified parts of the nervous system, secondary malignant neoplasm of the bone and bone marrow, secondary malignant neoplasm of the ovary, secondary malignant neoplasm of the adrenal gland, Hodgkin's lymphoma, follicular lymphoma, small cell B-cell lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, lymphoblastic (diffuse) lymphoma, Burkitt's lymphoma, other non-follicular lymphomas, unspecified non-follicular (diffuse) lymphoma, unspecified mature T/NK-cell lymphomas, Cesar disease, unclassified peripheral T-cell lymphoma, anaplastic large cell lymphoma, ALK-positive, anaplastic large cell lymphoma, unspecified ALK-negative, cutaneous T-cell lymphoma, other mature T/NK cell lymphomas, unspecified mature T/NK cell lymphomas, other and unspecified types of non-Hodgkin's lymphoma, malignant immunoproliferative dis and some other B-cell lymphoma, multiple myeloma and plasma malignancy, lymphocytic leukemia, acute lymphoblastic leukemia [ALL], chronic lymphocytic leukemia B-cell type, cellular prolymphocytic leukemia B-cell type, cellular leukemia, Adult T-cell lymphoma/leukemia (HTLV-1 associated), prolymphocytic T-cell leukemia, mature B-cell leukemia Burkitt type, other lymphocytic leukemias, unspecified lymphocytic leukemia, myeloid leukemia, acute myeloid leukemia, BCR/ABL-positive leukemia, atypical chronic myeloid leukemia, BCR/ABL negative, myeloid sarcoma, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute myeloid leukemia with 11q23 abnormality, other myeloid leukemia, other unspecified myeloid leukemia, monocytic leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, other monocytic leukemia , unspecified monocytic leukemia, other leukemias of specified cell types, acute erythroid leukemia, acute megakaryoblastic leukemia, mast cell leukemia, acute panmyelosis, with myofibrosis, unclassified myelodysplastic disease, other specified leukemias, leukemia of unspecified cell type, Chronic leukemia of unspecified cell type, unspecified leukemia goats, other and unspecified malignancies of lymphoid, hematopoietic tissue, carcinoma in situ of the oral cavity, esophagus and stomach, carcinoma in situ of the colon, carcinoma in situ of the rectosigmoid junction, carcinoma in situ of the rectum, carcinoma in situ of the anus and anal canal, carcinoma in situ of others and unspecified parts of the intestine, carcinoma in situ of an unspecified part of the intestine, carcinoma in situ of other parts of the intestine, carcinoma in situ of the liver, gallbladder and bile ducts, carcinoma in situ of other parts of the specified digestive organs, unspecified carcinoma in situ of the digestive organs, carcinoma in situ of the middle ear and respiratory system, carcinoma in situ of the larynx, carcinoma in situ of the trachea, carcinoma in situ of the bronchi and lungs, carcinoma in situ of other parts of the respiratory system, melanoma in situ, melanoma in situ of the lip, melanoma in situ of the eyelid, including the canthus, melanoma in situ ear and external ear canal, melanoma in situ of unspecified part of the face, melanoma in situ of the scalp and neck, melanoma in situ of the trunk, melanoma in situ of the anal skin, melanoma in situ of the breast (skin) (soft tissue), melanoma in situ of the upper extremity , including the shoulder, melanoma in situ of the lower extremity, including the thigh, melanoma in situ of other sites, carcinoma in situ of the skin, carcinoma in situ of the skin of the lips, carcinoma in situ of the skin of the eyelids, including the canthus, carcinoma in situ of the skin of the ear and external ear canal, carcinoma carcinoma in situ of the skin of other and unspecified parts of the face, carcinoma in situ of the skin of the head and neck, carcinoma in situ of the skin of the trunk, carcinoma in situ of the skin of the upper extremity, including the shoulder, carcinoma in situ of the skin of the lower extremity, including the thigh, carcinoma in situ of the skin of others carcinoma in situ of the breast, lobular carcinoma in situ of the breast, intraductal carcinoma in situ of the breast, other specified type of carcinoma in situ of the breast, unspecified type of carcinoma in situ of the breast, carcinoma in situ of the cervix, carcinoma in situ of other parts cervix, unspecified carcinoma in situ cervix, carcinoma in situ of other and unspecified genital organs, carcinoma in situ of the endometrium, carcinoma in situ of the external female genitalia, carcinoma in situ of the vagina, carcinoma in situ of other and unspecified female genital organs, carcinoma in situ penis, carcinoma in situ of the prostate, carcinoma in situ of unspecified male genital organs, carcinoma in situ of the scrotum, carcinoma in situ of other male genital organs, carcinoma in situ of the bladder, carcinoma in situ of other and unspecified urinary organs, carcinoma in situ of the eye, carcinoma in situ of the thyroid gland and other endocrine glands, benign neoplasm of the mouth and pharynx, benign neoplasm of the major salivary glands, benign neoplasm of the colon, rectum, anus and anal canal, benign neoplasm of ill-specified areas of the digestive system, benign neoplasm of the esophagus, benign neoplasm stomach, benign neoplasm of the duodenum, benign neoplasm of other and unspecified parts of the small intestine, benign neoplasm of the liver, benign neoplasm of the extrahepatic bile ducts, benign neoplasm of the pancreas, benign neoplasm of the endocrine pancreas, benign neoplasm of the endocrine pancreas, benign neoplasm of ill-defined areas in the pi

- 70 043393 digestive system, benign neoplasm of the middle ear and respiratory system, unspecified benign neoplasm of the respiratory system, benign neoplasm of other and unspecified intrathoracic organs, benign neoplasm of the thymus, benign neoplasm of the heart, benign neoplasm of the mediastinum, benign neoplasm of other specified intrathoracic organs, benign neoplasm of the unspecified intrathoracic organ, benign neoplasm of bone and articular cartilage, benign neoplasm of short bones of the upper extremity, benign neoplasm of long bones of the lower extremity, benign neoplasm of short bones of the lower extremity, benign neoplasm of the bones of the skull and face, benign neoplasm of the lower jaw, benign neoplasm of the spinal column, benign neoplasm ribs, sternum and clavicle, benign neoplasm of the pelvis, sacrum and coccyx, unspecified benign neoplasm of bones and articular cartilage, benign lipomatous neoplasm, benign lipomatous neoplasm of the skin, subcutaneous in the head, face and neck, benign lipomatous neoplasm of the intrathoracic organs, benign lipomatous neoplasm intra-abdominal organs, benign lipomatous neoplasm of the spermatic cord, benign lipomatous neoplasm of other areas, benign lipomatous neoplasm of the kidneys, benign lipomatous neoplasm of other genitourinary organs, hemangioma, hemangioma of an unspecified area, hemangioma of the skin and subcutaneous tissue, hemangioma of intracranial structures, hemangioma of intra-abdominal structures, hemangioma of other areas , lymphangioma of any area, benign neoplasm of mesothelial tissue, benign neoplasm of soft tissues of the retroperitoneum and peritoneum, other benign neoplasms of connective and other soft tissues, melanocytic nevi, melanocytic nevi of the lip, melanocytic nevi of the eyelids, including the canthus, melanocytic nevi of the unspecified eyelid, including canthus, melanocytic nevi of the ear and external auditory canal, melanocytic nevi of other and unspecified parts of the face, melanocytic nevi of the scalp and neck, melanocytic nevi of the trunk, melanocytic nevi of the upper limb, including the shoulder, melanocytic nevi of the lower limb, including the thigh, unspecified melanocytic nevi, other benign neoplasm of the skin of the eyelids, including the canthus, other benign neoplasms of the skin/ear and external ear canal, other benign neoplasms of the skin/left ear and external auditory canal, other benign neoplasms of the skin of other and unspecified parts of the face, other benign neoplasms of the skin of other parts of the face, other benign neoplasm of the skin of the head and neck, other benign neoplasm of the skin of the trunk, other benign neoplasm of the skin/upper extremities, including the shoulder, other benign neoplasm of the skin of the lower extremities, including the thighs, other unspecified benign neoplasm of the skin, benign neoplasm of the breast, benign neoplasm of the unspecified breast, uterine leiomyoma, other benign neoplasm of the uterus, benign neoplasm of the ovary, benign neoplasm of other and unspecified female genital organs, benign neoplasm of the male genital organs, benign neoplasm of the urinary organs, benign neoplasm of the kidney, benign neoplasm of the renal pelvis, benign neoplasm of the ureter, benign neoplasm of the bladder, benign neoplasm of the urethra, benign neoplasm of other specified urinary organs, unspecified benign neoplasm of the urinary organ, benign neoplasm of the eye and adjacent organs, benign neoplasm of the conjunctiva, benign neoplasm of the cornea, benign neoplasm of the retina, benign neoplasm of the choroid, benign neoplasm of the ciliary body, benign neoplasm of the lacrimal glands and ducts, benign neoplasm of an unspecified area of the orbit, benign neoplasm of an unspecified part of the eye, benign neoplasm of the meninges, benign neoplasm of the brain and central nervous system, benign neoplasm of the thyroid gland, benign neoplasm of other and unspecified endocrine glands, benign neoplasm of other and unspecified areas, benign neoplasm of lymph nodes, benign neoplasm of peripheral nerves and autonomic nervous system, benign neoplasm of other specified sites, benign neuroendocrine tumors, other benign neuroendocrine tumors, neoplasm of undefined behavior of the oral cavity and digestive organs, neoplasm of undefined behavior of the large salivary glands, neoplasm of undefined behavior of the pharynx, neoplasm of undefined behavior of the oral cavity, neoplasm of undefined behavior of the stomach, neoplasm of undefined behavior of the small intestine, neoplasm of undefined behavior of the appendix, neoplasm of undefined behavior of the colon, neoplasm of undefined behavior of the rectum, neoplasm of undefined behavior of the liver, GB and bile ducts, neoplasm of neopre

- 71 043393 divided behavior of other digestive organs, neoplasm of indefinite behavior of the digestive organs, neoplasm of the middle ear and intrathoracic organs, neoplasm of indefinite behavior of the larynx, neoplasm of indefinite behavior of the trachea, bronchi and lungs, neoplasm of indefinite behavior of the pleura, neoplasm of indefinite behavior of the mediastinum, neoplasm of indefinite behavior of the thymus , neoplasm of unspecified behavior of other respiratory organs, unspecified neoplasm of unspecified behavior of the respiratory organs, neoplasm of unspecified behavior of the female genital organs, neoplasm of unspecified behavior of the uterus, neoplasm of unspecified behavior of the ovary, neoplasm of unspecified behavior of the ovary, neoplasm of unspecified behavior of the placenta, neoplasm of unspecified behavior of the male genital organs, neoplasm neoplasm of unspecified behavior of the urinary organs, neoplasm of unspecified behavior of the kidneys, unspecified neoplasm of unspecified behavior of the kidneys, neoplasm of unspecified behavior of the renal pelvis, neoplasm of unspecified behavior of the ureter, neoplasm of unspecified behavior of the bladder, neoplasm of unspecified behavior of other urinary organs, neoplasm of unspecified behavior of an unspecified urinary organ, neoplasm of unspecified behavior meninges, neoplasm of unspecified behavior of the meninges, neoplasm of unspecified behavior of the meninges of the spinal cord, neoplasm of unspecified behavior of unspecified meninges, neoplasm of unspecified behavior of the brain, neoplasm of unspecified behavior of the brain, neoplasm of unspecified behavior of the brain, infratentorial, neoplasm of unspecified behavior of the brain, unspecified, neoplasm of unspecified behavior of cranial nerves, neoplasm of unspecified behavior of the spinal cord, neoplasm of undefined behavior of the central nervous system, neoplasm of unspecified behavior of the endocrine glands, neoplasm of unspecified behavior of the thyroid gland, neoplasm of undefined behavior of the adrenal glands, neoplasm of undefined behavior of the adrenal glands, neoplasm of unspecified behavior of the parathyroid gland, neoplasm indeterminate pituitary gland, indeterminate neoplasm of the craniopharyngeal duct, indeterminate neoplasm of the pineal gland, indeterminate neoplasm of the carotid sinus, indeterminate neoplasm of the body of the aorta and other paraganglia, indeterminate neoplasm of the endocrine gland, polycythemia vera, myelodysplastic syndromes, refractory anemia without ring sideroblasts , refractory anemia with ringed sideroblasts, refractory anemia with excess blasts [RAEB], myelodysplastic syndrome unspecified, other neoplasm of unspecified behavior of lymphoid, hematopoietic tissue, histiocytic and mast cell tumors of unspecified behavior, chronic myeloproliferative disease, monoclonal gammopathy, essential hypertension, osteomy elofibrosis, other neoplasms of unspecified behavior of lymphoid, hematopoietic tissue, neoplasm of unspecified behavior of lymphoid, hematopoietic and unspecified tissue, neoplasm of unspecified behavior of other and unspecified areas, neoplasm of unspecified behavior of bones/articular cartilage, neoplasm of unspecified behavior of connective/soft tissues, neoplasm of unspecified behavior of peripheral nerves and autonomic nervous system, neoplasm of uncertain behavior of the retroperitoneal space, neoplasm of uncertain behavior of the peritoneum, neoplasm of uncertain behavior of the skin, neoplasm of uncertain behavior of the mammary gland, neoplasm of uncertain behavior of the digestive system, neoplasm of uncertain behavior of the respiratory system, neoplasm of uncertain behavior of the bone, soft tissues and skin, neoplasm of uncertain behavior breast, neoplasm of indeterminate behavior of the bladder, neoplasm of indefinite behavior of other genitourinary organs, neoplasm of indeterminate behavior of the kidney, neoplasm of indeterminate behavior of another bladder organ, neoplasm of indeterminate behavior of the brain, neoplasm of indeterminate behavior of the endocrine glands and other parts of the nervous system, neoplasm of indeterminate behavior retina and choroid, neoplasm of unspecified behavior of unspecified site, iron deficiency anemia, vitamin B12 deficiency anemia, folate deficiency anemia, protein deficiency anemia, other megaloblastic anemia not elsewhere classified, scurvy anemia, other specified nutritional anemias, unspecified nutritional anemia, anemia due to enzyme disorders, anemia, thalassemia, hereditary persistence of fetal hemoglobin [HPFH], hemoglobin E beta thalassemia, other thalassemias, unspecified thalassemia, sickle cell disorders, other hereditary hemolytic anemias, acquired hemolytic anemia, acquired true red cell aplasia [erythroblastopenia], unspecified acquired true red cell aplasia, other aplastic anemias and other bone marrow failure syndromes, drug-induced aplastic anemia, aplastic anemia caused by other external agents, idiopathic aplastic anemia, other aplastic anemias and other bone marrow failure syndromes

- 72 043393 brain, unspecified aplastic anemia, acute posthemorrhagic anemia, anemia, disseminated intravascular coagulation, hereditary factor VIII deficiency, hereditary factor IX deficiency, other blood coagulation defects, acquired coagulation factor deficiency, primary thrombophilia, other thrombophilias, purpura and others hemorrhagic conditions, secondary thrombocytopenia, unspecified thrombocytopenia, other specified hemorrhagic conditions, unspecified hemorrhagic condition, neutropenia, congenital agranulocytosis, agranulocytosis secondary to cancer chemotherapy, other drug-induced agranulocytosis, neutropenia caused by infection, cyclic neutropenia, other neutropenia, other white blood cell disorders, genetic abnormalities of leukocytes, eosinophilia, other specified cell disorders, decrease in the number of leukocytes, lymphocytosis (symptomatic), disease of the spleen, methemoglobinemia, congenital methemoglobinemia, other methemoglobinemia, unspecified methemoglobinemia, other and unspecified diseases of the blood and hematopoietic organs, other familial red blood cell disorders s, secondary diseases caused by other red blood cells, blood and hematopoietic organs, myelofibrosis, heparin-induced thrombocytopenia (HIT), other specified diseases of the blood and hematopoietic organs, other diseases associated with lymphoreticular and reticulohistiocytic tissue, intraoperative and post-procedural complications of the spleen, immunodeficiency with a predominance of defects antibodies, hereditary hypogammaglobulinemia, nonfamilial hypogammaglobulinemia, selective immunoglobulin A deficiency [IgA], selective deficiency of immunoglobulin G subclasses [IgG], selective immunoglobulin M deficiency [IgM], immunodeficiency with elevated immunoglobulin M [IgM], antibody deficiency with almost normal immunoglobulin or with hyperimmunoglobulin, transient hypogammaglobulinemia of infancy, other immunodeficiencies with predominantly antibody defects, unspecified immunodeficiency with predominantly antibody defects, combined immunodeficiencies, severe combined immunodeficiency with reticular dysgenesis, severe combined immunodeficiency with low numbers of T and B cells, severe immunodeficiency with low or normal B cell count, adenosine deaminase deficiency [ADA], Nezelof syndrome, purine nucleoside phosphorylase [PNP] deficiency, MHC class I deficiency, MHC class II deficiency, other combined immunodeficiencies, unspecified combined immunodeficiency, immunodeficiency related with other major defects, Wiskott-Aldrich syndrome, DiGeorge syndrome, immunodeficiency with dwarfism due to short limbs, immunodeficiency after reaction to Epstein-Barr virus, hyperimmunoglobulin E [IgE] syndrome, immunodeficiency associated with other major defects, immunodeficiency associated with unspecified underlying defect, common variable immunodeficiency, other immunodeficiencies, lymphocyte function antigen-1 [LFA-1] defect, defects in the complement system, other specified immunodeficiencies, sarcoidosis, other disorders involving immune mechanism, NEC, polyclonal hypergammaglobulinemia, cryoglobulinemia, unspecified hypergammaglobulinemia , immune reconstitution syndrome, mast cell activation syndrome and related disorders, unspecified mast cell activation syndrome, monoclonal mast cell activation syndrome, idiopathic mast cell activation syndrome, secondary mast cell activation disorder, other mast cell activation disorders, other immune related disorders mechanism, NEC, graft-versus-host disease, acute graft-versus-host disease, chronic graft-versus-host disease, acute chronic graft-versus-host disease, unspecified graft-versus-host disease, autoimmune lymphoproliferative syndrome [ALPS], other disorders associated with immune mechanism, NEC , unspecified immune disorder, autoimmune thyroiditis, type 1 diabetes mellitus, other diabetes mellitus with other specified complications, primary adrenocortical insufficiency, autoimmune polyglandabular insufficiency, dementia due to human immunodeficiency virus [HIV] disease (B22.0), multiple sclerosis , Guillain-Barré syndrome, myasthenia gravis without (acute) exacerbation, myasthenia gravis with (acute) exacerbation, cytotoxic myoneural disorders, congenital or acquired myasthenia, Lambert-Eaton syndrome, unspecified, Lambert-Eaton syndrome in diseases classified elsewhere, other specified myoneural disorders, unspecified myoneural disorders, unspecified acute and subacute iridocyclitis, Crohn's disease, ulcerative (chronic) pancolitis, inflammatory polyps of the colon, left-sided colitis, other ulcerative colitis without/with complications, chronic persistent hepatitis, chronic lobular hepatitis, chronic active hepatitis, other chronic hepatitis, unspecified chronic hepatitis, primary biliary cirrhosis, autoimmune hepatitis, celiac disease, pemphigus, bullous pemphigoid, cicatricial pemphigoid, chronic bullous disease of childhood, unspecified acquired epidermosis bullosa, other acquired epidermosis bullosa, other pemphigoid, psoriasis vulgaris , other psoriatic arthropathy, generalized alopecia (capitis), generalized alopecia, ophiasis, other alopecia areata, alopecia areata unspecified, vitiligo, Felty's syndrome, rheumatoid lung disease with rheumatoid arthritis, rheumatoid vasculitis with rheumatoid arthritis unspecified, rheumatoid vasculitis with rheumatoid arthritis, rheumatoid heart disease with

- 73 043393 rheumatoid arthritis, rheumatoid myopathy with rheumatoid arthritis, rheumatoid polyneuropathy with rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis with/without rheumatoid factor, Still's disease in adults, rheumatoid bursitis, rheumatoid nodule, inflammatory polyarthropathy, other specified rheumatoid arthritis, juvenile rheumatoid arthritis, juvenile ankylosing spondylitis, juvenile arthritis, Wegener's granulomatosis without renal involvement, Wegener's granulomatosis with renal involvement, juvenile dermatopolymyositis, polymyositis, dermatopolymyositis, giant cell arteritis with polymyalgia rheumatica, systemic lupus erythematosus, endocarditis in systemic lupus erythematosus, pericarditis in systemic lupus erythematosus chanke, pulmonary disease in systemic lupus erythematosus, glomerular disease in systemic lupus erythematosus, tubulointerstitial neuropathy in systemic lupus erythematosus, progressive systemic sclerosis, CR(E)ST syndrome, systemic sclerosis, dry eye syndrome, polymyalgia rheumatica, systemic connective tissue disease, ankylosing spondylitis, laboratory evidence of human immunodeficiency virus [HIV], other abnormal serum immunologic findings, immunosuppressants, immunoglobulin is treated with the immunosuppressant NTLA or a CD26 antagonist prior to administration of cellular immunotherapy. The NTLA may be selected from a list including: dexamethasone base HED at a dose of 3-12 mg/kg administered orally or over a 15-60 minute intravenous infusion 12-72 hours before administration of cellular immunotherapy. Mice can also be preconditioned with: an agent containing hydrocortisone administered intravenously or orally every about 12 hours at a dose of about 75 to about 300 mg/kg at an interval of about 12 to about 72 hours before administration of cellular immunotherapy. The cortisone-containing agent was administered intravenously or orally every about 12 hours at a dose of about 93 to about 375 mg/kg for about 12 to about 72 hours before administration of the cellular immunotherapy. The prednisolone-containing agent was administered intravenously or orally every about 24 hours at a dose of about 19 to about 75 mg/kg for about 12 to about 60 hours before administration of the cellular immunotherapy. The methylprednisolone-containing agent was administered intravenously or orally every about 24 hours at a dose of about 15 to about 60 mg/kg from about 12 to about 60 hours before the administration of cellular immunotherapy. The triamcinolone-containing agent was administered intravenously or orally every about 24 hours at a dose of about 15 to about 60 mg/kg from about 12 to about 60 hours before the administration of cellular immunotherapy. The paramethasone-containing agent was administered as a single acute dose or cumulative doses of about 7.5 to about 30 mg/kg administered over about 12 to 72 hours prior to cellular immunotherapy. The betamethasone-containing agent was administered as a single acute dose or cumulative doses of about 2.5 to 10 mg/kg administered over about 12 to 72 hours prior to cellular immunotherapy.

Cellular immunotherapy is administered on Day 0 and can be selected from the list of: tolerogenic dendritic cells, tumor infiltrating lymphocytes, adoptive cell transfer, adoptive cell therapy, chimeric antigen receptor cells, genetically engineered TCR cells, regulatory T cell transfer, cell adoptive immunotherapy, cellular immunotherapy, cellular immuno-oncology, in vivo complex (IL-2C) consisting of IL-2 and anti-1b-2 monoclonal antibody (JES6-1), expanded Tregs, T cell receptor (TCR) immunogenicity for vaccination against T cells, autologous polyclonal T cell vaccines (TCV), adoptive transfer of B cell-dependent Tregs (B cells induced a specific subset of regulatory T cells), adoptive transfer of GC-induced or ATF3-deficient G-MDSCs (myeloid suppressor cells ), genetically engineered lymphocytes, redirected autologous T cells, retargeted by RNA, natural killer T cells, NKG2D receptor cells, CD4+ cells, CD8+ cells, CD4+ T cells, CD8+ T cells, mixtures of CD4+ and CD8 T -cells, MDSC, CTL, EBV-CTL, virus-specific cytocytotoxic T lymphocytes (CTL), cytokine-induced killer cells, antigen-pulsed dendritic cells, CMV-CTL, natural dendritic cells, dendritic cells, third-party CTLs donors, autologous γδ T cell therapy, infusion of depleted CD45RA T cells, laboratory processed T cells, HER2Bi activated T cells, autologous tumor vaccine, dendritic cell (DC) based vaccines loaded with allogeneic prostate cell lines, based vaccines dendritic cells/AML, dendritic cell vaccines, genetically modified lymphocytes, dendritic cell therapy, ESO-1 lymphocytes, tumor activated dendritic cells, autologous cell lysate activated dendritic cells, genetically modified immune cells, bone marrow infiltrating lymphocytes, dendritic alpha-galactosylceramide-activated cells, alpha-galactosylceramide-activated natural killer T (NKT) cells, alpha-galactosylceramide-activated natural killer T (NKT) cells and dendritic cells, autologous gamma/delta T cells, activated self-lymphocytes , Epstein-Barr virus-immune T cells derived from a normal HLA-matched or partially matched third-party donor, furin vector, autologous tumor cells transfected with granulocyte macrophage colony-stimulating factor vector plus bi-shRNAi, alpha-galactosylceramide-activated dendritic cells (Chiba-NKT), p53-activated dendritic cells, CMVpp65-specific primary transplant donor-derived T cells, mixed natural killer (NK) cell phenotype cells (CIK cells), dendritic

- 74 043393 antigen activated cells (APDC), DC-CIK, APC activated, alpha-GalCer, zoledronate activated autologous killer lymphocytes (Zak cells), Chiba NKT cells, autologous dendritic cells loaded with autologous tumor lysate or homogenate, CMVpp65 specific T -cells obtained from third-party donors, D-CIK, autologous tumor activation, autologous dendritic cells with multi-epitope peptide TARP, adoptive transfer of T-reg cells (TRACT), modified DLI (donor double negative T cells), polarized dendritic cells 1- type (AlphaDC1), DC-CIK cells antigen-sensitized by autologous tumor tissue, peptide-activated dendritic cells, dendritic cytocytotoxic lymphocyte (DC-CTL) cells, MTCR-transduced autologous peripheral blood lymphocytes, NK cells-like memory cells induced cytokine, LMP-specific DLI-engineered T cells (double-negative related donor T cells), autologous dendritic cells loaded with autologous tumor homogenate, Vigil® engineered autologous cell therapy (EATC), novel antigen reactive cell therapy (NRT), autologous cytokine-induced killer cells, autologous dendritic cell fusions, peptide-specific CTLs, immunoglobulin immunotherapy ACIT-1, PD-1, knockout engineered T cells, DC/AML fusion cells, (DC/PC3), T cells treated in laboratories, fusion tumor cells and dendritic cells, lethally irradiated autologous breast cancer cells, CD4-ZETA gene-modified T cells, EBV-specific immune effector (EBV-IE) cells, herpes virus (HHV)-specific immune effector (TE) cells , mRNAtransfected dendritic cells, allogeneic dendritic cell therapy, cytomegalovirus (CMV) Pp65-specific lymphocytes, peripheral blood mononuclear cells activated by alpha-galactosylceramide, exhausted T cells, donor dendritic cell vaccination, DC vaccine combined with cytokine-induced cells- killer cells, DC vaccine in combination with CIK cells, DC activated by HB-vac, infusion of haploidentical NK cells, ZNK cells, WT1 and MUC1 dendritic cells, ONETreg1 cells, alpha-DC1, autologous T lymphocytes with ADCC, T-cell infusion memory cells, DC1, activated HER-2/Neu, stimulated autologous CD4+ T cells, gamma delta T cells, irradiated allogeneic lung adenocarcinoma cells, CD40LGVAX, irradiated allogeneic lung adenocarcinoma cells combined with a bystander cell line transfected with hCD40L and hGM -CSF, EGFRBi-armed autologous T cells, PD-L-silenced DC, MiHA-loaded, MyDC/pDC, ROR-1.taNK, PDL1.taNK, adjuvant dendritic cell immunotherapy, D-CIK, DOT cells, autologous lysate tumors (TL) plus yeast cell wall particles (YCWP) plus dendritic cells, autologous EBV-specific cytocytotoxic T cells, autologous TLPLDC vaccine (tumor lysate, particle loading, dendritic cells), regulatory T cells, personalized cell vaccine (PERCELLVAC) , CAR-pNK cell, HER2.taNK, MUC16.taNK, DC1s-CTL, (PERCELLVAC2), (PERCELLVAC3), MASCT, CAR-pNK cells, CD33.taNK, umbilical cord blood dendritic cells HCT, umbilical cord regulatory T cells blood, highly active natural killer cells, PD-1 knockout EBV-CTL, DC-CTL combined with CIK, antigen containing dendritic cells, dendritic fusion cells/tumors, transfected dendritic cells, Her2 and TGF-beta CTL, blood T cells and EBV-specific CTLs, autologous breast cancer cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF), genetically engineered leukocytes, epitope-enhanced TARP peptide and TARP peptide-activated dendritic cells, laboratory-processed autologous lymphocytes, multiviral CTLs , cytomegalovirus-specific T cell adoptive transfer (ERaDICATe), GM-K562 cells, kappa-CD28 T lymphocytes, TGFB2 gene-modified antisense-GMCSF autologous tumor cells, autologous tumor cells augmented with Bi-shRNA-furin and granulocyte-monocyte colony-stimulating factor ( GMCSF), donor T cells sensitized with pentadecapeptides of the CMV-PP65 protein, vaccination with dendritic cells derived from monocytes activated by a peptide for the expansion of adoptively transferred CMV-specific cytocytotoxic T lymphocytes, CMV-specific DLIs from a 3-6/6 HLA related member families, autologous T cells in combination with autologous OS-DC, TAA-specific CTL, autologous lymphocytes, autologous tolerogenic dendritic cells, Langerhans dendritic cells, Langerhans dendritic cells, electroporated mRNA encoding tumor-associated antigen, autologous T cells, multiviral cytocytotoxic T cells, autologous tumor cells expressing IL2 ligand and CD40, engineered DC with multiple antigens, dendritic cells activated by WT1 peptide and/or tumor lysate, autologous human cytomegalovirus (HCMV)-specific T cell therapy, Ad/dendritic cell HER2/Neu, WT1 peptivator-activated dendritic cell, donor, multi-virus-specific cytotoxic T lymphocytes, ex-vivo expanded donor regulatory T cells, antigen presenting cells (APC), activated alpha-GalCer, cytokine-induced NK -cells similar to memory cells, re-stimulated tumor-infiltrating lymphocytes, autologous dendritic Langerhans cells, T cells enriched in memory cells, multiantigen-specific expanded

- 75 043393 ski-targeted lymphocytes, TAA-specific CTLs, regulatory dendritic cells, well-matched third-party generated LMP, BARF1 and EBNA1 specific CTLs, activated bone marrow infiltrating lymphocytes, dendritic cells loaded with autologous tumor lysate, autologous dendritic cells with multi-epitope TARP peptide , HPV-16/18 E6/E7-specific T lymphocytes, Epstein-Barr virus-specific T cells, Activated T cells, donor MultiTAA-specific T cells, MultiTAA-specific T cells, type I polarized autologous dendritic cells enriched with vaccine autologous activated T cells, polyvirus-specific cytocytotoxic T lymphocytes (mCTL), allogeneic virus-specific T cell lines (VST), donor regulatory T cells, TCR-modified T cells (TCR), MIC cells, adoptive T cell therapy with activated P53-specific T cells, MUC1-DC-CTL, T cells with modified T cell receptors, negative dendritic cell vaccine, tolDC, CD22-redirected autologous T cells, Dendristim, primary NK cells, gene products modified cell therapy CARTEGFRvIII based on lentiviruses, autologous dendritic cells activated by lysed allogeneic tumor lines, expanded multiantigen-specific lymphocytes, PD-1 knockout engineered T cells, GSC-loaded dendritic cells, adoptive transfer of Treg cells (TRACT), E7 TCR T- PD-1 knockout cells engineered T cells, CAR-Treg (ENTX-DN), chimeric switch receptor modified T cells, neoantigen-doped dendritic cells (DC), pre-activated (PreT) T cells, TSA-CTL ( tumor-specific antigen-induced cytocytotoxic T lymphocytes), allogeneic cell immunotherapy (ACIT-1), autologous OS-DCs, mature dendritic cells, CD8+ NKG2D AKT cells, natural killer (NK) cells - oNKord®, antigen presenting cells sDCord®.

Compared to administering cellular immunotherapy without preconditioning with an NTLA immunosuppressant, NTLA doses of dexamethasone, or a CD26 antagonist, when the patient is preconditioned with an NTLA immunosuppressant, NTLA doses of dexamethasone, or a CD26 antagonist, the administered immunotherapy remains in the bloodstream or at the injection site where it can find and kill its target, resulting in greater destruction or slower growth of a cancerous or neoplastic or autoimmune cell or pathogen. Patients preconditioned with NTLA will have similar or better antitumor effect, improved progression-free survival, reduced disease progression, increased duration of response, improved overall survival, or reduced minimal residual disease compared with patients who are pretreated with radiation or repeated doses of cytotoxic chemotherapy .

Example 7 Postoperative treatment of solid tumors with NTLA and cellular immunotherapy to prevent relapse.

A patient with a solid tumor undergoes surgical removal or reduction, which can release cancerous blast cells and cause eventual relapse. Recurrence can occur in the short term, in cancers such as pancreatic cancer, or in the long term, in cancers such as breast cancer, which can recur up to 20 years after surgery. After recovery from surgery, 1 to 3 days and up to 1 year after surgery, the patient is preconditioned with NTLA in the form of tacrolimus, delivered by injection or oral dose of about 0.48 mg/kg/day to about 10 mg/kg/day . for about 1 to about 4 weeks or as cyclosporine administered in an amount of about 15 to about 100 mg/kg/day for about 7 to about 28 days (daily dose divided by two and administered every 12 hours), or as dexamethasone base or an equivalent dose of another glucocorticoid is from about 3 mg/kg to about 26 mg/kg single acute dose from about 12 to about 72 hours before administration of cellular immunotherapy or a total dose from about 3 mg/kg to about 26 mg /kg administered within about 12 to about 72 hours prior to administration of cellular therapy (most preferably a single acute dose administered between about 36 to about 48 hours prior to administration of cellular immunotherapy) or as a TNF inhibitor administered within for about 3 to about 4 weeks or as an immunotherapy class of rituximab administered at a range of about 375 mg/m ² to about 500 mg/m ² administered every about 7 days, on about day -7 and day -1. After preconditioning, from about 1 day to about 4 days after preconditioning, the patient was administered cellular immunotherapy ranging from about 1 x 10 5 cells/kg body weight to about 1 x 10 ⁷ cells/kg body weight. The preferred cell therapy is an NK cell product, a TCR cell product, a TAC cell product, or a CarT cell product. Disease-free survival increases and overall survival time increases. Patients treated with NTLA will have equal or better antitumor effect, improved progression-free survival, reduced disease progression, increased duration of response, improved overall survival, or reduced minimal residual disease compared with patients who received pre-treatment.

- 76 043393 heavily conditioned by radiation or repeated doses of cytotoxic chemotherapy.

Example 8 Treatment of Postoperative Mammary Tumors in Mice Eight groups of BALB/c mice were injected with 4T1 cells into the mammary fat pad to create a mammary tumor mouse model. After 9-11 days or until the tumor size reaches 3.5-5 mm, the tumors will be surgically removed. One day after the initial removal of the tumor, preconditioning will be carried out in the regimen according to Table. I below. Either syngeneic (NK cells isolated from BALB/c mice; 3 groups) or allogeneic (KIL cells; 3 groups) NK cells were transplanted by intravenous injection into the tail vein after preconditioning. Mice were sacrificed between 30 and 60 days. The groups in this study are in Table. I below.

Table I

Preconditioning Scheme for Example 8: Treatment of Post-Surgical Mammary Tumors in Mice

Group Preconditioning NK cell Protocol 1 Cy/Flu* allogeneic Cyclophosphamide 166 mg/kg, dose administered on days -5, -4, -3 Fludarabine phosphate 10 mg/kg, dose administered on days -5, -4, -3 2 AVM0703 allogeneic AVM0703 148 mg/kg, dosed on day -2 3 CyFlu + AVM0703 allogeneic Cyclophosphamide 166 mg/kg, dose administered on day -5 Fludarabine phosphate 10 mg/kg, dose administered on day -5 AVM0703 148 mg/kg, dosed on day -2 4 Su/Flu * syngeneic Cyclophosphamide 166 mg/kg, dose administered on days -5, -4, -3 Fludarabine phosphate 10 mg/kg, dose administered on days -5, -4, -3 5 AVM0703 syngeneic AVM0703 148 mg/kg, dosed on day -2 6 CyFlu + AVM0703 syngeneic Cyclophosphamide 166 mg/kg, dose administered on day -5 Fludarabine phosphate 10 mg/kg, dose administered on day -5 AVM0703 148 mg/kg, dosed on day -2 7 Carrier allogeneic Carrier only, dose per day -2 (AVM Placebo) 8 Carrier syngeneic Carrier only, dose per day -2 (AVM Placebo)

Method of examination: body weight, blood and spleen for further analysis. The lungs were excised and perfused with Indian ink for visual scoring of metastasis. Mice survival was plotted to compare survival benefits between different treatments.

Expected Outcome: The efficacy of NK cell therapy following AVM0703 preconditioning has been demonstrated to be equivalent or superior to therapy following chemical preconditioning in a mouse model of breast cancer.

Example 9 Treatment of postoperative solid tumors in mice.

Mice were injected subcutaneously into the flank with solid tumor cells. C57B16 mice were injected with B16 or B16-F10 melanoma cells or LLC lung cancer cells; Balb/c mice were injected with RENCA kidney cancer cells or CT26 colon cancer cells. When the tumor reached a noticeable size of 3.5–5 mm, the tumors were completely excised. One day after removal of the primary tumor, the preconditioning schedule was carried out in accordance with the regimen of the table. II. Either syngeneic (NK cells isolated from BALB/c or C57B16 mice) or allogeneic (NK cells isolated from BALB/c or C57B16 mice or KIL cell lines) NK cells were transplanted by intravenous injection into the tail vein after preconditioning . Mice were sacrificed between 30 and 60 days. The groups in this study are in Table. II below.

- 77 043393

Table II

Preconditioning Scheme for Example 9: Treatment of Postoperative Solid Tumors in Mice

Group Preconditioning NK cell Protocol 1 Cy/Flu* allogeneic Cyclophosphamide 166 mg/kg, dose administered on days -5, -4, -3 Fludarabine phosphate 10 mg/kg, dose administered on days -5, -4, -3 2 AVM0703 allogeneic AVM0703 148 mg/kg, dosed on day -2 3 CyFlu + AVM0703 allogeneic Cyclophosphamide 166 mg/kg, dose administered on day -5 Fludarabine phosphate 10 mg/kg, dose administered on day -5 AVM0703 148 mg/kg, dosed on day -2 4 Su/Flu* syngeneic Cyclophosphamide 166 mg/kg, dose administered on days -5, -4, -3 Fludarabine phosphate 10 mg/kg, dose administered on days -5, -4, -3 5 AVM0703 syngeneic AVM0703 148 mg/kg, dosed on day -2 6 CyFlu + AVM0703 syngeneic Cyclophosphamide 166 mg/kg, dose administered on day -5 Fludarabine phosphate 10 mg/kg, dose administered on day -5 AVM0703 148 mg/kg, dosed on day -2 7 Carrier allogeneic Carrier only, dose per day -2 (AVM Placebo) 8 Carrier syngeneic Carrier only, dose per day -2 (AVM Placebo)

Method of examination: body weight, blood and spleen for further analysis. The lungs were excised and perfused with Indian ink for visual scoring of metastasis. Mice survival was plotted to compare survival benefits between different treatments.

Expected Outcome: The efficacy of AVM0703 preconditioning NK cell therapy has been demonstrated to be equivalent or superior to chemotherapy preconditioning therapy in mouse models of solid tumors.

Example 10 Treatment of patients with solid tumors.

Patients with solid tumors were identified, including, but not limited to, prostate cancer, pancreatic cancer, colon cancer, breast cancer, sarcoma, carcinoma, neuroblastoma, blastomas, fibromas, chondromas, lymphomas, adenomas, lung cancer, ependymomas, chromocytomas, histiocytomas, seminomas, uterine cancer, cervical cancer. The patient has previously received NTLA in the form of tacrolimus, delivered by injection or oral dose of about 0.1 mg/kg/day to about 10 mg/kg/day, but preferably from about 0.48 mg/kg to about 10 mg/kg for about 1 to about 4 weeks, or as cyclosporine administered at about 15 to about 100 mg/kg/day for about 7 to about 28 days (daily dose halved and administered every 12 hours) , or as dexamethasone base or an equivalent dose of another glucocorticoid, from about 3 mg/kg to about 26 mg/kg single acute dose from about 12 to about 72 hours before administration of cellular immunotherapy or a total dose from about 3 mg/kg to about 26 mg/kg administered over about 12 to about 72 hours prior to administration of cellular therapy (most preferably, a single acute dose is administered between about 36 to about 48 hours prior to administration of cellular immunotherapy) or as a TNF inhibitor administered within from about 3 to about 4 weeks or as an immunotherapy class of rituximab administered in the range of about 375 mg/m ² to about 500 mg/m ² administered every about 7 days, on about day -7 and day -1. After preconditioning for a period of about 1 day to about 4 days, the patient was administered cellular immunotherapy ranging from about 1 x 10 ⁵ cells/kg body weight to about 1 x 10 7 cells/kg body weight. The preferred cell therapy is an NK cell product, a TCR cell product, a TAC cell product, or a CarT cell product. Minimal residual disease (MRD) decreased, complete remission rate increased, partial remission rate increased, disease-free survival increased, and overall survival time increased. Patients treated with NTLA had equal or better antitumor effect, improved progression-free survival, reduced disease progression, increased duration of response, improved overall survival, or reduced minimal residual disease compared with patients who were pretreated with radiation or repeated doses of cytotoxic chemotherapy.

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Example 11 Treatment of patients with leukemia or lymphoma or myeloma.

A patient with multiple myeloma, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute myelogenous leukemia, or any leukemia, lymphoma, or myeloma was pretreated with an NTLA such as tacrolimus, which was administered by injection or oral dose of about 0.1 mg/kg/day to about 10 mg/kg/day, but preferably from 0.48 mg/kg to about 10 mg/kg over about 1 to about 4 weeks, or as cyclosporine administered at a dose of about 15 to about 100 mg/kg /day for about 7 to about 28 days (daily dose divided in half and administered every 12 hours) or as dexamethasone base or an equivalent dose of another glucocorticoid from about 3 mg/kg to about 26 mg/kg single acute dose from about 12 to about 72 hours prior to administration of cellular immunotherapy, or a total dose of about 3 mg/kg to about 26 mg/kg administered over about 12 to about 72 hours prior to administration of cellular immunotherapy (most preferably, a single acute dose is administered between about 36 to about 48 hours before administration of cellular immunotherapy) either as a TNF inhibitor administered over about 3 to about 4 weeks or as a rituximab-class immunotherapy administered at a range of about 375 mg/m ² to about 500 mg/m ² , administered each of the 7 days, on about day -7 and day -1. After preconditioning for a period of about 1 day to about 4 days, the patient was administered cellular immunotherapy in the range of about 1x105 cells/kg body weight to about 1x107 cells/kg body weight. The preferred cell therapy is an NK cell product, a TCR cell product, a TAC cell product, or a CarT cell product. Minimal residual disease (MRD) decreased, complete remission rate increased, partial remission rate increased, disease-free survival increased, and overall survival time increased. Patients treated with NTLA had equal or better antitumor effect, improved progression-free survival, reduced disease progression, increased duration of response, improved overall survival, or reduced minimal residual disease compared with patients who were pretreated with radiation or repeated doses of cytotoxic chemotherapy . Example 12 Treatment of Patients with Autoimmune Diseases A patient with an autoimmune disease such as, but not limited to: SLE, psoriasis, rheumatoid arthritis, sporiatic arthritis, type I diabetes, multiple sclerosis, Sjögren's syndrome, scleroderma, Graves' disease, Hashimoto's thyroiditis, celiac disease Addison's disease, myasthenia gravis, autoimmune hepatitis, antiphospholipid syndrome, biliary cholangitis, were treated with an NTLA immunosuppressant, with doses of NTLA dexamethasone or a CD26 antagonist. Doses of NTLA dexamethasone (as base) ranged from about 3 mg/kg to about 12 mg/kg, with doses from about 9 mg/kg to about 12 mg/kg being preferred.

B cell numbers are reduced by more than 90% with a dose of dexamethasone NTLA, and since memory B cells make up about 50% of the B cell compartment in people over 20 years of age, memory B cell populations are also reduced by more than 90%. The patient's attacking autoimmune B cells undergo apoptosis, and the patient ceases active autoimmune attacks. The patient's physical symptoms improve or are eliminated. Remission from an autoimmune disease lasts indefinitely in most patients, however, if the patient relapses then re-dose the immunosuppressant NTLA, with doses of the NTLA dexamethasone or the CD26 antagonist. Repeat applications can occur as often as once a month if necessary, but preferably no more than once a year and most preferably no more than once every 5 years.

Example 13 Treatment of residual HIV.

The patient with residual HIV was treated with an NTLA immunosuppressant, NTLA dexamethasone, or a CD26 antagonist. Doses of NTLA dexamethasone (as base) range from about 3 mg/kg to about 12 mg/kg, with doses from about 9 mg/kg to about 12 mg/kg being preferred. The treatment eliminates niches in the spleen where HIV hides and sends infected T cells into the bloodstream, where they can be killed by standard HIV treatments, which include antiretroviral drugs, including but not limited to nucleoside reverse transcriptase inhibitors (NTRIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion and penetration inhibitors, pharmacokinetics, and integrase strand transfer inhibitors (INSTIs).

Example 14. Treatment of lymphomas of the germinal center, for example, Burkitt's lymphoma.

A patient with germinal center lymphoma, such as, but not limited to, Burkitt's lymphoma or diffuse large B-cell lymphoma (DLBCL), is treated with an NTLA immunosuppressant, NTLA dexamethasone, or a CD26 antagonist. Doses of NTLA dexamethasone (as base) range from about 3 mg/kg to about 12 mg/kg, with doses from about 9 mg/kg to about 12 mg/kg being preferred. The treatment eliminates the niches in the spleen where germinal center lymphomas bind and sends the cells into the bloodstream where they can be eliminated more completely or with lower doses of standard chemotherapy such as R-CHOP, or anti-CD20 antibodies such as Rituxan, Bexar or Zevalin, or antibodies to CD22 or CD70, such as Lymphocide or forsetuzumab mafodotin, or Bcl-2 inhibitors, such as oblimersen sodium, ABT-737 (oral form

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Claims (16)

laxa, ABT-263) or fenretinide, or Syk inhibitors such as fostamatinib or tamatinib, or proteasome inhibitors such as BORTEZOMIB (Velcad), or COMPADME, CODOX-M/IVAC. Relapse rates are reduced and disease-free survival rates are improved. Example 15: Conversion of a dose of dexamethasone to an equivalent dose of another glucocorticoid. To calculate the equivalent dosage for another glucocorticoid, the dexamethasone dose was entered into a publicly available glucocorticoid conversion calculator, preferably http://www.medcalc.com. The total dose is then determined based on the half-life of the glucocorticoid. For example, dexamethasone from 3 to 12 mg/kg is converted to prednisone from 19 to 75 mg/kg. Since the biological half-life of prednisone is about 20 hours, whereas the biological half-life of dexamethasone is 36 to 54 hours. Therefore, prednisone would be dosed at 19 to 75 mg/kg every 24 hours for an equivalent biological dose. CLAIM 1. A method of enhancing adoptive cell therapy (ACT) in a human patient, comprising administering to the patient dexamethasone at a dose of at least 3 mg/kg or another glucocorticoid at an equivalent dose, where the method does not include administering a chemotherapy agent for 1 day or more. 2. The method according to claim 1, characterized in that said method includes administering to the patient: dexamethasone at a dose of about 3 mg/kg to about 26 mg/kg, administered at one or more time points from about 12 to about 72 hours before the administration of cellular immunotherapy; hydrocortisone at a dose of about 75 mg/kg to about 300 mg/kg administered every about 12 hours from about 12 to about 72 hours before administration of cellular immunotherapy; cortisone at a dose of about 93 mg/kg to about 375 mg/kg administered every about 12 hours from about 12 to about 72 hours before administration of cellular immunotherapy; prednisolone at a dose of about 19 mg/kg to about 75 mg/kg administered every about 24 hours from about 12 to about 60 hours before administration of cellular immunotherapy; methylprednisolone at a dose of about 15 mg/kg to about 60 mg/kg administered every about 24 hours from about 12 to about 60 hours before administration of cellular immunotherapy; triamcinolone at a dose of about 15 mg/kg to about 60 mg/kg administered every about 24 hours from about 12 to about 60 hours before administration of cellular immunotherapy; paramethasone as a single acute dose or cumulative doses of about 7.5 to about 30 mg/kg administered from about 12 to about 72 hours before administration of cellular immunotherapy; or betamethasone as a single acute dose or cumulative doses of about 2.5 to about 10 mg/kg administered from about 12 to about 72 hours before administration of cellular immunotherapy. 3. The method of claim 1 or 2, wherein the ACT comprises either a cell used to stimulate the immune system to treat a disease in said patient, or a cell derived from an immune line that directly treats said disease. 4. Method according to any one of claims 1 to 3, characterized in that the glucocorticoid is selected from the group consisting of dexamethasone, dexamethasone base, prednisone and methylprednisone. 5. The method according to claim 4, characterized in that the glucocorticoid is dexamethasone. 6. The method according to claim 5, characterized in that dexamethasone is administered at a dose of at least 3 mg/kg, at least 4 mg/kg, at least 5 mg/kg, at least 6 mg/kg, at least at least 7 mg/kg, at least 8 mg/kg, at least 9 mg/kg, at least 10 mg/kg, at least 11 mg/kg or at least 12 mg/kg. 7. The method according to claim 6, characterized in that dexamethasone is administered at a dose of up to 26 mg/kg. 8. The method according to claim 7, characterized in that dexamethasone is administered at a dose of 9 to 12 mg/kg. 9. The method according to any one of claims 1 to 8, wherein the enhanced ACT includes promoting cancer killing, reduced numbers of cells causing autoimmune diseases, or reduced infectious agent load in a patient with a cancer, autoimmune or infectious disease, respectively. 10. Method according to any one of claims 1-9, characterized in that the glucocorticoid is administered before the start of ACT. 11. The method according to claim 10, characterized in that the glucocorticoid is administered at least 12 hours before the start of ACT. 12. The method according to claim 11, characterized in that the glucocorticoid is administered at one or more time points from 72 to 12 hours before the start of ACT. 13. The method according to any one of claims 1 to 12, characterized in that ACT is an adoptive T-cell therapy. 14. Method according to any one of claims 1 to 13, characterized in that the patient is not administered radiation therapy and chemotherapeutic agents. 15. The method according to any one of claims 1 to 14, characterized in that the patient is a cancer patient and the ACT includes the administration of anti-tumor T cells and/or anti-tumor NK cells. 16. Method of administering adoptive cell therapy (ACT) to a human patient in need -