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  • C12N2510/00—Genetically modified cells

Definitions

• the present disclosure relates generally to the use of immune effector cells (e.g., T cells, NK cells, CIK cells, macrophages) engineered to express chimeric antigen receptors (CAR(s)) that target malignant B cells in combination with antibodies (e.g., monoclonal antibodies, antibody-drug conjugates) that target malignant B cells to treat B cell malignancies.
• immune effector cells e.g., T cells, NK cells, CIK cells, macrophages
• CAR(s) chimeric antigen receptors
• Immunotherapy is a promising approach for the treatment of cancer.
• Immunotherapy with cells expressing chimeric antigen receptors (CARs) that target antigens expressed by the tumor has the advantage of targeted therapies that can invoke a rapid and sustained immune response against a cancer.
• CAR therapy has shown promising results in the clinic in treating some hematological cancers, such as B cell malignancies (see, e.g., Novartis (2017) Prescribing
• CAR-T cells with antibodies that block the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) or the programmed death- 1 (PD-1) receptor or the PD-L1 ligand has been suggested to prolong the effector function of CAR-T cells at sites of solid tumors (Gianpietro Dotti, Stephen Gottschalk, Barbara Savoldo and Malcolm K, Brenner Immunol Rev. 2014 January; 257(1); and XU, et al., Oncology Letters 16: 2063-2070, 2018) .
• CTLA-4 cytotoxic T-lymphocyte-associated antigen 4
• PD-1 programmed death- 1
• the present invention is based, at least in part, upon an unexpected and surprising clinical outcome resulting from the consecutive administration of two therapeutic drugs, each having distinctive mechanisms of action.
• the first drug regarded a chimeric antigen receptor-modified T cell immunotherapy.
• the second drug regarded an antibody-drug conjugate used to treat relapsed or refractory B-cell precursor acute lymphoblastic leukemia (see Example section for further details).
• the present invention concerns, at least in part, methods for treating a disease associated with expression of a tumor antigen, for example, a B cell malignancy, in a subject by administering to the subject a combination of a CAR immunotherapy and an antibody, for example an antibody-drug conjugate.
• a tumor antigen for example, a B cell malignancy
• an antibody for example an antibody-drug conjugate
• the invention includes a method of increasing or enhancing the efficacy of a CAR B cell malignancy treatment regimen in a subject comprising administering to the subject a CAR immunotherapy that targets malignant B cells and an antibody that targets malignant B cells.
• the invention includes a method of treating a B cell malignancy in a subject comprising administering to the subject a CAR B cell malignancy treatment regimen and an antibody that targets malignant B cells.
• the antigen binding domain of the CAR molecule targets (e.g., binds to) a tumor antigen that is associated with a B cell malignancy, e.g., expressed by a malignant B cell.
• the tumor antigen is present in a disease chosen from a leukemia or a lymphoma.
• B cell antigen refers to a molecule that is preferentially expressed on the surface of a B cell which can be targeted with an agent which binds thereto.
• the B cell antigen of particular interest is preferentially expressed on malignant B cells compared to other non-malignant B cells or non-B cells of a mammal.
• B cell antigens include CD10, CD19, CD20, CD21, CD22, CD23, CD24, CD25, CD34, CD37, CD38, CD53, CD72, CD73, CD74, CD75, CD77,
• a“B cell malignancy” refers to all types of B cell malignancies found in mammals and known in the art, including, but not limited to solid tumors and hematological cancers.
• hematological cancer refers to all types of hematological cancer and hematopoietic tumors, neoplasm or malignant tumors found in mammals, including, but not limited to leukemias and lymphomas. Examples include, Hodgkin's Disease, Non-Hodgkin's Lymphoma, B- cell Acute Lymphoid Leukemia ("B-ALL”), T-cell Acute Lymphoid Leukemia (“T-ALL”), Acute Lymphoblastic Leukemia (ALL); one or more chronic leukemias including but not limited to, e.g., Chronic Myelogenous Leukemia (CML), Chronic Lymphoid Leukemia (CLL), or other
• Administered "in combination”, as used herein, means that two (or more) different treatments are administered to the subject during the course of the subject's affliction with the disorder, e.g., the two or more treatments are administered after the subject has been diagnosed with the disorder and before the disorder has been cured or eliminated or treatment has ceased for other reasons.
• the administration of one treatment is still occurring when the administration of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as “simultaneous" or "concurrent" administration.
• the administration of one treatment ends before the administration of the other treatment begins.
• the treatment is more effective because of combined administration and results in an unexpectedly superior effect compared to the effect obtained with the individual treatments.
• the first or second treatment is more effective, e.g., an increased or enhanced effect of the first treatment is seen after the second treatment or an equivalent effect is seen with less of the first treatment, than would be seen if the first treatment were administered in the absence of the second treatment, or the analogous situation is seen with the second treatment.
• administration is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment administered in the absence of the other.
• the effect of the two treatments can be partially additive, wholly additive, or greater than additive (i.e., synergistic).
• the administration can be such that an effect of the first treatment administered is still detectable when the second is administered.
• Chimeric Antigen Receptor refers to a recombinant polypeptide construct comprising at least an extracellular antigen binding domain, a transmembrane domain and a cytoplasmic signaling domain (also referred to herein as an“intracellular signaling domain,” a cytoplasmic signaling domain” or a“stimulatory molecule”) comprising a functional signaling domain derived from a stimulatory molecule.
• cytoplasmic signaling domain also referred to herein as an“intracellular signaling domain,” a cytoplasmic signaling domain” or a“stimulatory molecule” comprising a functional signaling domain derived from a stimulatory molecule.
• the terms“Chimeric Antigen Receptor” and“CAR” include CARs that are generally known in the art (see, e.g., Shi et al., Molecular Cancer 2014, 13:219, which is incorporated herein in its entirety).
• the cytoplasmic signaling domain can comprise a primary signaling domain (e.g., a primary signaling domain of CD3-zeta).
• the cytoplasmic signaling domain can further comprise one or more functional signaling domains derived from at least one costimulatory molecule.
• the costimulatory molecule is chosen from 4- IBB (i.e., CD137), CD27, ICOS, and/or CD28.
• a CAR that comprises an antigen binding domain e.g., a single chain variable fragment of a monoclonal antibody (“scFv”)
• a CAR that comprises an antigen binding domain that targets CD19 is referred to as CD19 CAR.
• a CAR that comprises an antigen binding domain (e.g., a scFv) that targets a specific tumor antigen (TA) is also referred to as TA CAR.
• a CAR that comprises an antigen binding domain (e.g., a scFv) that targets a specific B cell antigen (BCA) is also referred to as BCA CAR.
• CAR immunotherapy cancer treatment that targets malignant B cells and “CAR B cell malignancy treatment regimen” and the like refer to treatment of a subject with immune cells (e.g., T cells, NK cells, CIK cells, macrophages) that have been genetically engineered to express chimeric antigen receptors (CARs) and specifically target one or more tumor-specific receptors of malignant B cells.
• CAR immunotherapy is generally known in the art (see, e.g., Shi et al., Molecular Cancer 2014, 13:219, which is incorporated herein in its entirety).
• the CAR constmct can be introduced into immune effector cells (e.g., T cells, NK cells, CIK cells, macrophages) using viral or non-viral techniques known in the art.
• antibody refers to a protein, or polypeptide sequence derived from an immunoglobulin molecule which specifically binds with an antigen.
• Antibodies can be polyclonal or monoclonal, multiple or single chain, or intact immunoglobulins, and may be derived from natural sources or from recombinant sources.
• Antibodies can be tetramers of immunoglobulin molecules.
• the term“antibody” includes functional antibody fragments, including e.g., Fab’, F(ab’)2, Fab, Fv, and scFv fragments.
• Antibodies can be humanized, human, and/or antibody drug- conjugates.
• the term“antibody” includes antibodies that are generally known in the art.
• terapéuticaally effective amount refers to the quantity of a component which is sufficient to yield a desired therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this invention.
• the specific safe and effective amount or therapeutically effective amount will vary with such factors as the particular condition being treated, the physical condition of the patient, the type of mammal or animal being treated, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed and the structure of the compounds (i.e., immune effector cells and/or antibodies).
• the term“enhancing the effect” or“increasing the effect” refers to reducing the population of cancer cells.
• the quantity, number, amount or percentage of cancer cells can be reduced by at least 25%, at least 30%, at least 40%, at least 50%, at least 65%, at least 75%, at least 85%, at least 95%, or at least 99% relative to a negative control.
• the terms “treat”, “treatment”, and “treating” refer to the reduction or amelioration of the progression, severity and/or duration of a cancer or proliferative disorder, or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of a cancer or proliferative disorder resulting from the administration of one or more therapies (e.g., one or more therapeutic agents such as a CAR and antibody of the invention).
• the terms “treat,” “treatment” and “treating” refer to the amelioration of at least one measurable physical parameter of a proliferative disorder, such as growth of a tumor, not necessarily discernible by the patient.
• the terms “treat”, “treatment” and “treating” refer to the inhibition of the progression of a cancer or proliferative disorder, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both. In other embodiments the terms “treat”, “treatment” and “treating” refer to the reduction or stabilization of tumor size or cancerous cell count.
• treating may include enhancing or increasing efficacy, suppressing, inhibiting, preventing, treating, or a combination thereof. Treating refers inter alia to increasing time to disease progression, expediting remission, inducing remission, augmenting remission, speeding recovery, increasing efficacy of or decreasing resistance to alternative therapeutics, or a combination thereof.
• “Suppressing” or “inhibiting” refers inter alia to delaying the onset of tumor associated symptoms, preventing relapse to a disease, decreasing the number or frequency of relapse episodes, increasing latency between symptomatic episodes, reducing the severity of symptoms, reducing the severity of an acute episode, reducing the number of symptoms, reducing the incidence of disease-related symptoms, reducing the latency of symptoms, ameliorating symptoms, reducing secondary symptoms, prolonging patient survival, or a combination thereof.
• the symptoms can be primary or secondary.
• Primary refers to a symptom that is a direct result of the proliferative disorder (e.g., cancer), while, secondary refers to a symptom that is derived from or consequent to a primary cause.
• subject is intended to include living organisms (e.g., mammals, human).
• Relapsed refers to the return or reappearance of a disease (e.g., cancer) or the signs and symptoms of a disease such as cancer after a period of improvement or responsiveness, e.g., after prior treatment of a therapy, e.g., cancer therapy.
• the initial period of responsiveness may involve the level of cancer cells falling below a certain threshold, e.g., below 20%, 10%, 5%, 4%, 3%, 2%, or 1%.
• the reappearance may involve the level of cancer cells rising above a certain threshold, e.g., above 20%, 1%, 10%, 5%, 4%, 3%, 2%, or 1%.
• the reappearance may involve, e.g., a reappearance of blasts in the blood, bone marrow (> 5%), or any extramedullary site, after a complete response.
• a complete response in this context, may involve ⁇ 5% bone marrow blasts.
• a response e.g., complete response or partial response
• the initial period of responsiveness lasts at least 1, 2, 3, 4, 5, or 6 days; at least 1, 2, 3, or 4 weeks; at least 1, 2, 3, 4, 6, 8, 10, or 12 months; or at least 1, 2, 3, 4, or 5 years.
• the present invention is based in part upon the surprising discovery that a CAR immunotherapy cancer treatment regimen that targets malignant B cells in combination with administration of an antibody that targets B cells resulted in a greater therapeutic effect compared to the use of the CAR treatment alone.
• the present invention provides methods of increasing or enhancing the efficacy of a CAR immunotherapy cancer treatment that targets malignant B cells in a subject in need thereof comprising administering to the subject an antibody that targets malignant B cells in combination with the CAR immunotherapy.
• the cancer is a B cell malignancy. More preferably the B cell malignancy is a hematological cancer.
• the CAR immunotherapy comprises immune effector cells (e.g., T cells, NK cells, CIK cells, macrophages) engineered to express a TA CAR or a BCA CAR.
• the immune effector cells target a CD 19 tumor antigen.
• the antibody that targets malignant B cells is a humanized or human monoclonal antibody.
• the antibody that targets malignant B cells is a humanized or human monoclonal antibody that targets a CD22 tumor antigen.
• the present invention includes a method of treating a cancer in a subject in need thereof comprising administering to the subject an antibody that targets malignant B cells in combination with a CAR immunotherapy cancer treatment that targets malignant B cells.
• the cancer is a B cell malignancy. More preferably, the B cell malignancy is a hematologic cancer.
• the CAR immunotherapy comprises immune effector cells (e.g., T cells, NK cells, CIK cells, macrophages) engineered to express a TA CAR or a BCA CAR.
• the immune effector cells target a CD 19 tumor antigen.
• the antibody that targets malignant B cells is a humanized or human monoclonal antibody.
• the antibody that targets malignant B cells is a humanized or human monoclonal antibody that targets a CD22 tumor antigen.
• the present invention also provides methods of reducing or eliminating existing tumor burden, reducing tumor volume, stimulating tumor regression, preventing relapse or increasing overall survival in a subject in need thereof comprising administering to the subject an antibody that targets malignant B cells in combination with a CAR immunotherapy cancer treatment that targets malignant B cells.
• the subject may achieve one or more of the following: 1) increased tolerance to the immune effector cells; 2) increased efficacy of the immune effector cells; 3) reduced likelihood of rejection of the immune effector cells; and/or 4) increased or reduced adverse response that may be caused by the immune effector cells.
• the methods provided herein feature methods that result in increasing or enhancing the therapeutic efficacy of the immune effector cell therapy and/or the antibody therapy for treating a disease associated with the expression of a tumor antigen, e.g., a cancer described herein.
• the present invention provides immune effector cells (e.g., T cells,
• NK cells, CIK cells, macrophages that are engineered to contain one or more CARs that direct the immune effector cells to a malignant B cell. This is achieved through an antigen binding domain on the CAR that is specific for a malignant B cell antigen.
• the B cell antigen is an antigen that is expressed on the surface of the malignant B cell.
• the antigen can be expressed on the surface of any one of the following types of B cells: progenitor B cells (e.g., pre-B cells or pro-B cells), early pro-B cells, late pro-B cells, large pre-B cells, small pre-B cells, immature B cells, e.g., naive B cells, mature B cells, plasma B cells, plasmablasts, memory B cells, B-l cells, B-2 cells, marginal-zone B cells, follicular B cells, germinal center B cells, or regulatory B cells (Bregs).
• progenitor B cells e.g., pre-B cells or pro-B cells
• early pro-B cells e.g., late pro-B cells
• large pre-B cells e.g., large pre-B cells
• small pre-B cells e.g., immature B cells, e.g., naive B cells,
• the present invention encompasses immune effector cells (e.g., T cells, NK cells, CIK cells, macrophages) comprising a recombinant nucleic acid construct comprising sequences encoding a CAR, e.g., a CAR molecule that binds to a tumor antigen (e.g., a TA CAR) or a CAR molecule that binds to a malignant B cell antigen (e.g., a BCA CAR), wherein the CAR comprises an antigen binding domain (e.g., antibody or antibody fragment) that binds specifically to a tumor antigen or a malignant B cell antigen.
• a CAR e.g., a CAR molecule that binds to a tumor antigen (e.g., a TA CAR) or a CAR molecule that binds to a malignant B cell antigen (e.g., a BCA CAR)
• an antigen binding domain e.
• the antigen binding domain of the immune effector cells targets (e.g., binds to) a tumor antigen that is associated with a B cell malignancy, e.g., expressed by a B cell malignancy, preferably a hematological cancer.
• the tumor antigen that is targeted by the immune effector cells is present in a hematological cancer chosen from a leukemia or a lymphoma.
• leukemias include, but are not limited to e.g., B-cell Acute Lymphoid Leukemia ("B-ALL”), T-cell Acute Lymphoid Leukemia (“T-ALL”), Acute Lymphoblastic Leukemia (ALL), Chronic Myelogenous Leukemia (CML) or Chronic Lymphoid Leukemia (CLL).
• B-ALL B-cell Acute Lymphoid Leukemia
• T-ALL T-cell Acute Lymphoid Leukemia
• ALL Acute Lymphoblastic Leukemia
• CML Chronic Myelogenous Leukemia
• CLL Chronic Lymphoid Leukemia
• the leukemia is a relapsed or refractory B-cell precursor Acute Lymphoblastic Leukemia.
• lymphomas include, but are not limited to Hodgkin's Disease, Non-Hodgkin's Lymphoma, Large B-Cell Lymphoma (LBCL), Diffuse Large B-Cell Lymphoma (DLBCL), primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma.
• the lymphoma is a relapsed or refactory B-cell lymphoma.
• the present invention provides CARs that can target the following exemplary B cell antigens including but not limited to: CD10, CD19, CD20, CD21, CD22, CD23, CD24, CD25, CD34, CD37, CD38, CD53, CD72, CD73, CD74, CD75, CD77, CD79a, CD79b, CD80, CD81,
• the CAR targets e.g., binds to CD 19.
• the immune effector cells that are engineered to contain one or more CARs that direct the immune effector cells to a malignant B cell are CD19-directed genetically modified autologous T-cells (e.g., tisagenlecluecel, axicabtagene ciloleucel) or CIK cells.
• the antibodies that target e.g., bind to) malignant B cells target a tumor antigen that is associated with a B cell malignancy, e.g., expressed by a B cell malignancy, preferably a hematological cancer.
• the tumor antigen that is targeted by the antibodies is present in a hematological cancer chosen from a leukemia or a lymphoma.
• leukemias include, but are not limited to e.g., B-cell Acute Lymphoid Leukemia ("B-ALL”), T-cell Acute Lymphoid Leukemia (“T-ALL”), Acute Lymphoblastic Leukemia (ALL), Chronic Myelogenous Leukemia (CML) or Chronic Lymphoid Leukemia (CLL).
• B-ALL B-cell Acute Lymphoid Leukemia
• T-ALL T-cell Acute Lymphoid Leukemia
• ALL Acute Lymphoblastic Leukemia
• CML Chronic Myelogenous Leukemia
• CLL Chronic Lymphoid Leukemia
• the leukemia is a relapsed or refractory B-cell precursor Acute Lymphoblastic Leukemia.
• lymphomas include, but are not limited to Hodgkin's Disease, Non-Hodgkin's Lymphoma, Large B-Cell Lymphoma (LBCL), Diffuse Large B-Cell Lymphoma (DLBCL), primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma.
• the lymphoma is a relapsed or refactory B-cell lymphoma.
• the antibody that targets malignant B cells targets a B cell antigen described herein, including but not limited to, CD19, CD20, CD22, CD123, FLT-3, ROR-1, CD79a, CD79b, CD179b, CD10, or CD34.
• antibodies that target malignant B cells include monoclonal, polyclonal, bi- specific antibodies, antibody conjugates (e.g., antibody-drug conjugates), or fragments thereof that target an antigen expressed on a malignant B cell, e.g., a malignant B cell antigen described herein, e.g., CD19, CD20, CD22, CD52, CD123, FLT-3, ROR-1, CD79a, CD79b, CD179b, CD10, or CD34.
• a malignant B cell antigen described herein e.g., CD19, CD20, CD22, CD52, CD123, FLT-3, ROR-1, CD79a, CD79b, CD179b, CD10, or CD34.
• the antibodies that target malignant B cells include blinatumomab, rituximab, ofatumumab, ocrelizumab, veltuzumab, obinutuzumab, moxetumomab pasudotox, TRU-015, AME133V, Prol31921ibritumomab tiuxetan, tositumumab
• the antibody that targets malignant B cells targets (e.g., binds to) CD22.
• the antibody that targets malignant B cells that targets CD22 includes: an anti-CD22 monoclonal antibody-MMAE conjugate (e.g., DCDT2980S); an scFv of an anti-CD22 antibody, e.g., an scFv of antibody RFB4; an scFv of an anti-CD22 antibody fused to all of or a fragment of Pseudomonas exotoxin-A (e.g., BL22); a humanized anti-CD22
• an anti-CD22 monoclonal antibody-MMAE conjugate e.g., DCDT2980S
• an scFv of an anti-CD22 antibody e.g., an scFv of antibody RFB4
• an scFv of an anti-CD22 antibody fused to all of or a fragment of Pseudomonas exotoxin-A
• the monoclonal antibody e.g., epratuzumab
• the Fv portion of an anti-CD22 antibody which is optionally covalently fused to all or a fragment or (e.g., a 38 KDa fragment of) Pseudomonas exotoxin-A (e.g., moxetumomab pasudotox); or an anti-CD 19/CD22 bispecific antibody, optionally conjugated or linked to a toxin such as a deglycosylated ricin A chain.
• the antibody that targets malignant B cells is conjugated or otherwise bound to a cytotoxic agent or a
• the antibody that targets malignant B cells is conjugated or otherwise bound to a cytotoxic agent (e.g., calicheamicins, ozogamicin).
• a cytotoxic agent e.g., calicheamicins, ozogamicin
• the antibody that targets malignant B cells is a CD22-directed antibody-drug conjugate comprising a recombinant humanized immunoglobulin antibody specific for human CD22 (e.g., inotuzumab), a calicheamicin and a linker that attaches the calicheamicin to the inotuzumab.
• CD22-directed antibody-drug conjugate that targets malignant B cells is moxetumomab pasudox (Lumoxiti®) and inotuzumab ozogamicin (e.g., BESPONSA® (inotuzumab ozogamicin) for Injection).
• Lumoxiti® moxetumomab pasudox
• inotuzumab ozogamicin e.g., BESPONSA® (inotuzumab ozogamicin) for Injection.
• the CAR immunotherapy as described herein is administered to the subject before, during, simultaneously with or after, administration of the antibody that targets malignant B cells.
• the CAR immunotherapy is administered to the subject before or after administration of the antibody that targets malignant B cells.
• the CAR immunotherapy is administered to the subject before administration of the antibody that targets malignant B cells.
• the immune effector cells e.g., T cells, NK cells, CIK cells, macrophages
• a CAR targeting malignant B cells and/or the antibody that targets malignant B cells are administered to the subject using methods known in the art.
• the immune effector cells and/or the antibody are administered parenterally, e.g., subcutaneously,
• the subject is pre-medicated with acetaminophen and an H-l antihistamine prior to administration of the immune effector cells (e.g., T cells, NK cells, CIK cells, macrophages) that are engineered to express a CAR targeting malignant B cells.
• the immune effector cells e.g., T cells, NK cells, CIK cells, macrophages
• the subject is pre-medicated with a corticosteroid, antipyretic and antihistamine prior to administration of the antibody that targets malignant B cells.
• the immune effector cells e.g., T cells, NK cells, CIK cells, macrophages
• a CAR targeting malignant B cells are administered intravenously, e.g., as an intravenous infusion.
• each infusion provides about 104 to 109 cells/kg body weight, in some instances 105 to 106 cells/kg body weight, including all integer values within those ranges.
• Immune effector cell compositions may also be administered multiple times at these dosages.
• the antibody that targets malignant B cells is administered intravenously, e.g., as an intravenous infusion.
• each infusion provides about 0.1-2000 mg of the antibody that targets malignant B cells, including all integer values within this range.
• the antibody that targets malignant B cells is administered at a dose of 0.01 mg/m 2 to 750 mg/m 2 , including all integer values within this range.
• each infusion provides about 0.5-1 mg/m 2 , 0.8-10 mg/m 2 , 10-100 mg/m 2 , 150-175 mg/m 2 , 175-200 mg/m 2 , 200- 225 mg/m 2 , 225-250 mg/m 2 , 250-300 mg/m 2 , 300-325 mg/m 2 , 325-350 mg/m 2 , 350-375 mg/m 2 , 375-400 mg/m 2 , 400-425 mg/m 2 , 425-450 mg/m 2 , 450-475 mg/m 2 , 475-500 mg/m 2 , 500-525 mg/m 2 , 525-550 mg/m 2 , 550-575 mg/m 2 , 575-600 mg/m 2 , 600-625 mg/m 2 , 625-650 mg/m 2 , 650-675 mg/m
• m 2 indicates the body surface area of the subject.
• the antibody that targets malignant B cells is administered at a dosing interval of at least 4 days, e.g., 4, 7, 14, 21, 28, 35 days, or more.
• the antibody that targets malignant B cells is administered at a dosing interval of at least 0.5 weeks, e.g., 0.5, 1, 2, 3, 4, 5, 6, 7, 8 weeks, or more.
• the antibody that targets malignant B cells is administered at a dose and dosing interval described herein for a period of time, e.g., at least 2 weeks, e.g., at least 2, 3, 4,
• the antibody that targets malignant B cells is administered at a dose and dosing interval described herein for a total of at least 2 doses per treatment cycle (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more doses per treatment cycle).
• the antibody that targets malignant B cells is inotuzumab ozogamicin dosed according to the following dosing regimes for Cycle 1 and subsequent cycles depending on the response to treatment:
• the cells expressing chimeric antigen receptors (CARs) that target malignant B cells can be administered before (i.e., prior to), during (i.e., at the same time) or after (i.e, subsequent to) administration of the antibodies that target malignant B cells.
• the cells expressing chimeric antigen receptors (CARs) that target malignant B cells are administered prior to administration of the antibodies that target malignant B cells.
• the cells expressing chimeric antigen receptors (CARs) that target malignant B cells are administered 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 18 hours, 20 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 14 days 28 days, or more, prior to administration of the antibodies that target malignant B cells.
• the cells expressing chimeric antigen receptors (CARs) that target malignant B cells are administered 28 days prior to administration of the antibodies that target malignant B cells.
• Doses of the immune effector cells that are engineered to express a CAR targeting malignant B cells and/or the antibody that targets malignant B cells may be administered once, or more than once.
• the immune effector cells are administered once (i.e., as a single administration) and the antibody is administered once a week, twice a week, three times a week, four times a week, five times a week, six times a week, or seven times a week for a predetermined duration of time.
• the predetermined duration of time may be 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or up to 1 year or more.
• the methods of increasing or enhancing the efficacy of a CAR immunotherapy or the methods of treating a cancer comprise inhibiting the proliferation or reducing the population of cancer cells expressing a tumor antigen described herein, the methods comprising contacting a tumor antigen-expressing cancer cell population (e.g., a B cell malignancy) described herein with immune effector cells (e.g., T cells, NK cells, CIK cells, macrophages) that are engineered to express a CAR targeting malignant B cells in combination with an antibody that binds to a tumor antigen-expressing B cell described herein.
• immune effector cells e.g., T cells, NK cells, CIK cells, macrophages
• the combination of the invention reduces the quantity, number, amount or percentage of cells and/or cancer cells by at least 25%, at least 30%, at least 40%, at least 50%, at least 65%, at least 75%, at least 85%, at least 95%, or at least 99% in a subject with a cancer associated with the expression of a tumor antigen as described herein, relative to a negative control.
• the cancer is a B cell malignancy, e.g., a hematologic cancer.
• the hematological cancer to be treated is chosen from a leukemia or a lymphoma.
• leukemias include, but are not limited to e.g., B-cell Acute Lymphoid Leukemia ("B-ALL”), T-cell Acute Lymphoid Leukemia (“T-ALL”), Acute
• Lymphoblastic Leukemia ALL
• CML Chronic Myelogenous Leukemia
• CLL Chronic Lymphoid Leukemia
• the leukemia is a relapsed or refractory B-cell precursor Acute Lymphoblastic Leukemia.
• lymphomas include, but are not limited to Large B-Cell
• lymphoma is a relapsed or refactory B-cell lymphoma.
• the cells expressing a CAR molecule are administered as a single, low dose which is not expected to provide any clinical benefit to the subject and the antibody that targets malignant B cells is administered at a dose that is not expected to result in complete remission (CR) of the cancer due to a high tumor burden at the time of dosing and/or poor physical condition of the subject.
• a CAR molecule e.g., a CAR molecule that targets malignant B cells described herein
• the immune effector cells expressing a CAR molecule that targets B cells and the antibody that targets malignant B cells can target the same B cell antigen described herein or can target different B cell antigens described herein when used in combination.
• the immune effector cells expressing a CAR molecule that targets a CD 19 malignant B cell antigen can be used in combination with an antibody that targets a CD 19 malignant B cell antigen or with an antibody that targets a CD22 malignant B cell antigen.
• administration of an antibody that targets malignant B cells results in increased or prolonged proliferation of the CAR-expressing cells in a subject, e.g., as compared to a non-treated subject.
• increased proliferation is associated with in an increase in the number of the CAR-expressing cells.
• administration of an antibody that targets malignant B cells results in increased killing of cancer cells (e.g., malignant B cells) by the CAR-expressing cells in a subject, e.g., as compared to a non-treated subject.
• the subjects receive an infusion of the CAR-expressing cells and the antibody that targets malignant B cells described herein prior to transplantation, e.g., allogeneic stem cell transplant, of cells.
• the CAR-expressing cells that target malignant B cells in combination with the antibodies that target malignant B cells described herein may be used in further combination with other known agents and therapies.
• the combination therapy described herein e.g., immune effector cells (e.g., T cells, NK cells, CIK cells, macrophages) that are engineered to express one or more CARs targeting malignant B cells as described herein in combination with an antibody that binds to malignant B cells as described herein, can be administered in combination with at least one additional therapeutic agent.
• the at least one additional therapeutic agent can be administered before, simultaneously or after the combination therapy described herein, in the same or in separate compositions, or sequentially.
• the CAR-expressing cell described herein and/or the antibody that targets B cells can be administered first, and the additional therapeutic agent can be administered second, or the order of administration can be reversed.
• kits that include one or more of the CAR- expressing cells that target malignant B cells and antibodies that target malignant B cells as disclosed herein are provided, whereby such kit may comprise a package insert or other labeling including directions for administration.
• compositions of the present invention may comprise CAR-expressing cells, e.g., a plurality of CAR-expressing cells that target malignant B cells, as described herein, and/or antibodies that target malignant B cells, as described herein, in combination with one or more pharmaceutically or physiologically acceptable carriers, diluents or excipients.
• CAR-expressing cells e.g., a plurality of CAR-expressing cells that target malignant B cells, as described herein, and/or antibodies that target malignant B cells, as described herein, in combination with one or more pharmaceutically or physiologically acceptable carriers, diluents or excipients.
• compositions may comprise buffers such as neutral buffered saline, phosphate buffered saline and the like; carbohydrates such as glucose, mannose, sucrose, dextrose or dextrans, mannitol; proteins; polypeptides or amino acids such as glycine; antioxidants; chelating agents such as EDTA or glutathione; adjuvants (e.g., aluminum hydroxide); human serum albumin, electrolytes (e.g., Plasma-Lyte A); and preservatives (e.g., Cryoserv® dimethylsulfoxide).
• buffers such as neutral buffered saline, phosphate buffered saline and the like
• carbohydrates such as glucose, mannose, sucrose, dextrose or dextrans, mannitol
• proteins polypeptides or amino acids
• antioxidants chelating agents such as EDTA or glutathione
• adjuvants e.g., aluminum hydroxide
• the unexpected clinical result regards a male adult patient, age 27, diagnosed with acute lymphoblastic leukemia (ALL), who had undergone ten rounds of standard of care therapy from which the patient had relapsed.
• ALL acute lymphoblastic leukemia
• This patient was subsequently qualified for enrollment into an experimental clinical phase- l/2a dose-escalating trial, studying the safety and efficacy of a single dose of CAR-modified T cells, designed to target the CD 19 antigen, which is overexpressed on ALL cells and other B cell malignancies.
• the specific population of CAR-modified T cells used in this clinical trial is also known as a population of cytokine induced killer (CIK) cells, as defined by the concurrent expression of CD56 in a subpopulation of these T cells.
• CIK cytokine induced killer
• This patient was dosed with 1 million CAR-expressing T cells per kg body weight, which constitutes the lowest dose in this first-ever clinical trial, per regulatory approval. This dose was not expected to provide any clinical benefit to the patient, but would establish a first safety signal in humans.
• the patient’s bone marrow consisted of 60% blasts, which is considered to be a high amount of tumor burden, relative to the administered dose of CAR-expressing T cells.
• Inotuzumab s therapeutic mechanism of action is able to facilitate tumor cell death.
• the administered dose was not expected to result in a complete remission (CR), because of the high tumor burden at the time of dosing and the poor physical condition of the patient, which is believed to have a negative impact on the therapeutic efficacy of inotuzumab.
• CR cytokine release syndrome
• ICU intensive care unit
• CRS is not typically observed in patients receiving stand-alone inotuzumab therapy (see inotuzumab Package Insert). Instead, CRS is a clinical adverse event seen in correlation with CAR- modified T cell therapy, especially in patients carrying high tumor burden. Therefore, the life- threatening CRS in this patient was an unexpected severe adverse event (SAE), also because of the perceived sub-therapeutic precedent dose of CAR-modified T cells and the absence of observed therapeutic effect of these cells, as measured by VCN and by the expanding tumor burden during the first 28 days after infusion of the CAR-modified T cells.
• SAE serious adverse event
• inotuzumab was administered on Day 28 following infusion of the CAR-modified T cells, meaning that these cells could have been impacted by the administration of inotuzumab, thereby rendering them
• the present invention relates to the design and preparation of polymeric hybrid core-shell nanocaniers of which the core is designed to bind transposons, transposases and/or plasmids and minicircles comprising transposon and/or transposases and the shell is designed to protect the payload, stabilize the nanocanier, provide biocompatibility to the system, enable targeting to specific cells and tissue and promote efficient intracellular release of the payload from the nanocanier.

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