WO2020092696A1 - Activation et expansion ex vivo de lymphocytes t pour une thérapie par transfert adoptif de cellules - Google Patents
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- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
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- A61K39/461—Cellular immunotherapy characterised by the cell type used
- A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
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- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
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Definitions
- the present invention relates generally to the field of medicine. More particularly, it concerns methods and compositions of Thl7 cells for adoptive T cell transfer.
- tumor-specific lymphocytes predominantly CD8+ T cells
- CD8+ T cells tend to progressively lose antitumor function as they expand, showing reduced ability to persist in vivo. This phenomenon creates a dilemma in therapy preparation; on one hand, long-term ex vivo expansion is required to obtain the dose of T cells believed necessary for efficacy, with the trade-off that those cells will be poorer in quality.
- Using more potent T cell subsets like Thl7 cells, shows great potential for overcoming obstacles faced by CD8+ T cells, and may provide opportunities for more rapid cell transfer.
- the present disclosure provides in vitro methods for enhancing proliferation of lymphoid cells, the methods comprising (a) obtaining a sample of cells from a subject, the sample comprising lymphoid cells; and (b) culturing the sample of cells ex vivo in a medium that selectively enhances proliferation of the lymphoid cells, wherein the cells are cultured no more than 14 days.
- the lymphoid cells are T cells, NK cells, NKT cells, or natural tumor infiltrating lymphocytes.
- the lymphoid cells are T cells.
- the T cells are Thl7 T cells, ThO T cells, Thl T cells, or Th9 T cells.
- the T cells are CD8 + T cells.
- the T cells are tumor antigen-specific T cells.
- the tumor antigen may be TRP-l, CD 19, CD20, ROR1, CD22, carcinoembryonic antigen, alphafetoprotein, CA-125, 5T4, MUC-l, epithelial tumor antigen, prostate-specific antigen, melanoma-associated antigen, mutated p53, mutated ras, HER2/Neu, folate binding protein, GD2, CD123, CD33, CD138, CD23, CD30, CD56, c-Met, mesothelin, GD3, HERV-K, IL-l lRalpha, kappa chain, lambda chain, CSPG4, ERBB2, EGFRvIII, VEGFR2, HER2-HER3 in combination, or HER1- HER2 in combination.
- the tumor antigen is TRP-l .
- the T-cells are viral antigen specific T-cells.
- the T-cells can be specific for and HIV antigen, such as HIV-l envelope glycoprotein gpl20, HIV-l envelope glycoprotein gp4l .
- the medium comprises h-IL-6, IL-21, IL-lp, TGFP, anti-IL4, anti- IL2, anti-IFNy, and/or IL-23.
- the medium to generate Thl7 cells may comprise IL- 6, IL-21, IL- 1 b, TGFP, anti-IL4, anti-IL2, anti-IFNy, and IL-23.
- the medium comprises IL-2.
- the medium to generate ThO cells may comprise IL-2.
- the medium comprises IL-4, TGFP, and/or anti-IFNy
- the medium to generate Th9 cells may comprise IL-4, TGFP, and anti-IFNy
- the medium to generate Thl cells may comprise IL-2, IL-12, and anti-IL4.
- the methods further comprise purifying or enriching T cells (or a T cell subset) in the sample prior to step (b).
- enriching T cells in the sample comprises collecting a mononuclear cell fraction or collecting a Thl7 T cell fraction.
- the cells are cultured no more than 12 days, no more than 10 days, no more than 8 days, no more than 6 days, or no more than 4 days. In some aspects, the cells are cultured no more than 12 hours. In some aspects, culturing the tumor antigen-specific T cells results in less than one doubling of the tumor antigen-specific T cells. In some aspects, the tumor antigen-specific T cells result in at least one doubling of the tumor antigen-specific T cells. [0009] In some aspects, the sample of cells has an initial volume of between 20 and 200 mL when obtained from the subject.
- the sample of cells has an initial volume of between about 50 and 200 mL, 50 and lOOmL, or 100 and 200 mL when obtained from the subject.
- the sample is a cryopreserved sample.
- the sample of cells is from umbilical cord blood, is a peripheral blood sample, was obtained by apheresis, was obtained by venipuncture, or is a subpopulation of T cells.
- the methods further comprise integrating a DNA encoding a chimeric antigen receptor (CAR) into the genome of the cells, to provide a population of transgenic CAR-expressing T cells.
- the methods further comprise integrating a DNA encoding a T-cell receptor into the genome of the cells, to provide a population of transgenic T- cell receptor-expressing T cells.
- CAR chimeric antigen receptor
- T cell compositions made by any one of the present embodiments.
- the T cells are Thl7 T cells, ThO T cells, Thl T cells, or Th9 T cells.
- the T cells are CD8 + T cells.
- the disease is a cell proliferative disease.
- the cell proliferative disease is a cancer, wherein the T cells are tumor antigen-specific T cells.
- kits for providing a T-cell response in a human subject having a disease comprising administering an effective amount of T cells made by any one of the present embodiments.
- the disease is a cancer, wherein the T cells are tumor antigen-specific T cells.
- the subject has undergone a previous anti-cancer therapy.
- the subject is in remission.
- the subject is free of symptoms of the cancer but comprises detectable cancer cells.
- the methods further comprise administering a second anti-cancer therapy to the subject.
- the second anti-cancer therapy is a checkpoint blockade inhibitor.
- kits for providing a T-cell response in a human subject having a disease comprising (a) obtaining a sample of cells from a subject, the sample comprising T cells; (b) culturing the sample of cells ex vivo in a medium that selectively enhances proliferation of tumor antigen-specific T cells, wherein the cells are cultured no more than 14 days; and (c) administering an effective amount of the tumor antigen-specific T cells to the subject to provide a T cell response.
- the disease is a cancer
- the T cells are tumor antigen-specific
- the tumor antigen is TRP-l, CD 19, CD20, ROR1, CD22, carcinoembryonic antigen, alphafetoprotein, CA-125, 5T4, MUC-l, epithelial tumor antigen, prostate-specific antigen, melanoma-associated antigen, mutated p53, mutated ras, HER2/Neu, folate binding protein, HIV-l envelope glycoprotein gpl20, HIV-l envelope glycoprotein gp4l, GD2, CD123, CD33, CD138, CD23, CD30, CD56, c-Met, mesothelin, GD3, HERV-K, IL- 1 lRalpha, kappa chain, lambda chain, CSPG4, ERBB2, EGFRvIII, VEGFR2, HER2-HER3 in combination, or HER1-HER2 in combination.
- the tumor antigen is TRP-l.
- the T cells are Thl7 T cells, ThO T cells, Thl T cells, or Th9 T cells.
- the T cells are CD8 + T cells.
- the subject has undergone a previous anti-cancer therapy.
- the subject is in remission.
- the subject is free of symptoms of the cancer but comprises detectable cancer cells.
- the methods further comprise administering a second anti-cancer therapy to the subject.
- the second anti-cancer therapy is a checkpoint blockade inhibitor.
- the methods further comprise purifying or enriching T cells in the sample prior to step (b).
- enriching T cells in the sample comprises collecting a mononuclear cell fraction. In some aspects, enriching T cells in the sample comprises collecting a Thl 7 T cell fraction, ThO T cell fraction, Thl T cell fraction, or Th9 T cell fraction.
- the cells are cultured no more than 12 days, no more than 10 days, no more than 8 days, no more than 6 days, or no more than 4 days. In some aspects, the cells are cultured no more than 12 hours. In some aspects, culturing the tumor antigen-specific T cells results in less than one doubling of the tumor antigen-specific T cells. In some aspects, the tumor antigen-specific T cells result in at least one doubling of the tumor antigen-specific T cells. In some aspects, the cells are administered immediately after being cultured.
- FIGS. 1A-1G Four day ex vivo expansion yields human and murine Thl7 cells with potent antitumor efficacy.
- Thl7 cells were expanded in parallel cultures from 12 hour to l4-day time points.
- B Schematic of ACT sequence. B16F10 tumors are established in mice from cultures 7 days (tumor ⁇ 50 mm 2 ) to 12+ days (tumor -140 mm 2 ). Animals were irradiated 5 Gy one day prior to ACT.
- FIGS. 2A-2I Four-day expanded human and murine Thl7 cells have greater potency on a per cell basis.
- A Schematic of ACT sequence. Tumors are established 7-12 days prior to host preconditioning with 5Gy TBI; one day following TBI, T cells are adoptively transferred.
- C Survival of mice from experiments in B); results compiled from both experiments. Kaplan Meier curve compared with log rank test.
- D Frequency of transferred Thl7 cells in peripheral blood 5 days post treatment. 15 mice/group.
- FIGS. 3A-3H Day-4 Thl7 cells exhibit an activated phenotype.
- B Gene array heat map displays (+/-) log2 fold change versus naive TRP-l CD4 + T cells compiled from 6 animals.
- C Forward and side scatter of TRP-l Thl7 cells prior to TRP-l peptide activation (Day 0) versus 4, 7, and 14 days post-activation.
- D FACS histograms and
- E-F gene array depicting TRP-l T cell surface expression of activation and costimulatory markers, with mean fluorescence intensity quantified in D).
- n 6 independent cultures. One sample t test of differences.
- G Heat map of (+/-) log2 fold change of gene expression versus naive TRP-l CD4 + T cells. Compiled from 6 animals.
- FIGS. 4A-4C Day-4 Thl7 cells induce a robust cytokine storm in immunocompetent hosts.
- FIGS. 5A-5G Antitumor efficacy of expanded tumor-specific CD8 + T cells is not improved by four-day culture.
- A ACT schematic. Pmel-l transgenic T cells were TCR activated with luM hgplOO and expanded 4, 7, or 14 days. Cells were cryopreserved at indicated time point. C57BL6 mice were given B16F 10 tumors subcutaneously (0.4e6) and given 5Gy TBI. T cells were thawed and reactivated with hgplOO-pulsed irradiated feeder cells (splenocytes) 12 hours prior to adoptive transfer on day 0.
- splenocytes irradiated feeder cells
- FIGS. 1-10 show that IL-2 complexed with anti-IL-2 was given intraperitoneally to mice in three injections on days 0, 2, and 4 post transfer.
- B Engraftment of CD8 + T cells in the peripheral blood seven days post transfer,
- C Average tumor curves and
- D single tumor curves are shown.
- TRP-l CD4 + T cells were activated with TRP-l peptide, polarized to Thl7 phenotype, and infused into mice with B16F10 melanoma. T cell dose ranging from lOk cells up to l0e6 cells was administered to animals.
- FIGS. 7A-7B Four-day expanded human and murine CD8 + T cells express peak levels of surface activation markers.
- FIGS. 8A-8B Expanded Thl7 cells differentially express chemokine receptors and ligands. Heat maps display (+/-) log2 fold change of ex vivo expanded TRP-l Thl7 cells relative to naive, unactivated TRP-l Thl7 cells.
- A Chemokine receptors and (B) chemokines are shown. Gene array conducted on spleens compiled from 6 TRP-lanimals.
- FIGS. 9A-9E Day-4 Thl7 cells protect against local rechallenge and distant lung metastasis.
- A Schematic of ACT sequence.
- FIGS. 10A-10E Treatment with Day-4 Thl7 cells promotes vitiligo and increases resident memory cell frequency in skin.
- A Schematic of ACT sequence.
- B Vitiligo patterns from animals treated with 0.4e6 D4 Thl7 cells compared to untreated animals.
- FIG. 11 Schematic depicting mechanism of increased potency four days after ex vivo activation via study of costimulatory markers, cytokine production, and gene profiling.
- FIGS. 12A-12B (A) ACT of T helper subsets after 4 days of expansion. (B) Th9 cells benefit from shortened expansion protocol with overall survival significantly improved. DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
- Adoptive T cell transfer (ACT) therapy mediates potent immunity in patients with bulky metastatic malignancies, but proves difficult to translate clinically due to production costs, time, and labor required to generate the large number of tumor-specific lymphocytes believed necessary to yield objective responses.
- Current practices of ACT in the clinic involve expansion of T cells for 1-2 months to generate a large number of tumor-specific lymphocytes, which is believed necessary to yield objective responses.
- Unfortunately, such long-term expansion requires a robust financial and time investment, and often excludes patients with aggressive disease because the time needed to expand T cells exceeds their life expectancy.
- the present disclosure provides a method of shortened ex vivo expansion using Thl7 cells, such as to treat melanoma.
- Thl7 cells expanded four days could robustly regress large established melanoma as effectively as more than 10 million (more than 50-fold more) Thl7 cells expanded for two weeks. Younger cultures had an effector memory phenotype, and engrafted and persisted in murine peripheral blood more efficiently than long-term cultures.
- Thl7 cells expanded four days induced a unique cytokine storm in vivo , with heightened detection of IL-6 and IL-17, as well as chemokines G-CSF, MCP-l and KC compared to two-week expansion.
- Such findings have significant clinical implications as reducing expansion of T cells may alleviate current clinical barriers and streamline the progression of immunotherapy to the clinic.
- T cell activated ex vivo with either cognate antigen or aCD3/CD28 magnetic beads exhibits a peak activation status with a superior ability to proliferate and consume both cytokines and growth factors within the first five days of expansion, which applies to both murine and human T cells.
- This phenomenon where cells could be removed from a patient, manipulated ex vivo for a mere 12 hours up to 5 days before reinfusion into the patient has even broader implications beyond T cells to include engineered B cells, Natural Killer cells, NK-T cells, macrophages, neutrophils, or any other somatic cell, for superior antitumor effects.
- the present methods could be used as an improvement to current protocols for generating therapeutic T cells for adoptive transfer.
- the present methods could apply to generating tumor-infiltrating lymphocyte (TIL) products or CAR-T cell products for treating human malignancies.
- TIL tumor-infiltrating lymphocyte
- “a” or“an” may mean one or more.
- the words“a” or“an” when used in conjunction with the word“comprising,” the words“a” or“an” may mean one or more than one.
- the term“antigen” is a molecule capable of being bound by an antibody or T-cell receptor.
- An antigen is additionally capable of inducing a humoral immune response and/or cellular immune response leading to the production of B and/or T lymphocytes.
- the term“patient” or“subject” refers to a living mammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, or transgenic species thereof.
- the patient or subject is a primate.
- Non limiting examples of human patients are adults, juveniles, infants and fetuses.
- Treating” or treatment of a disease or condition refers to executing a protocol, which may include administering one or more drugs to a patient, in an effort to alleviate signs or symptoms of the disease. Desirable effects of treatment include decreasing the rate of disease progression, ameliorating or palliating the disease state, and remission or improved prognosis. Alleviation can occur prior to signs or symptoms of the disease or condition appearing, as well as after their appearance. Thus,“treating” or“treatment” may include“preventing” or“prevention” of disease or undesirable condition. In addition,“treating” or“treatment” does not require complete alleviation of signs or symptoms, does not require a cure, and specifically includes protocols that have only a marginal effect on the patient.
- “Prevention” or“preventing” includes: (1) inhibiting the onset of a disease in a subject or patient which may be at risk and/or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease, and/or (2) slowing the onset of the pathology or symptomatology of a disease in a subject or patient which may be at risk and/or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease.
- pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues, organs, and/or bodily fluids of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.
- “Pharmaceutically acceptable salts” means salts of compounds disclosed herein which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity.
- Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as l,2-ethanedisulfonic acid, 2 -hydroxy ethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4'-methylenebis(3-hydroxy-2-ene- 1 -carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-ene-l -carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid,
- Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases.
- Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide.
- Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-m ethylgl ucam i ne and the like. It should be recognized that the particular anion or cation forming a part of any salt of this invention is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002).
- A“pharmaceutically acceptable carrier,”“drug carrier,” or simply“carrier” is a pharmaceutically acceptable substance formulated along with the active ingredient medication that is involved in carrying, delivering and/or transporting a chemical agent.
- Drug carriers may be used to improve the delivery and the effectiveness of drugs, including for example, controlled-release technology to modulate drug bioavailability, decrease drug metabolism, and/or reduce drug toxicity. Some drug carriers may increase the effectiveness of drug delivery to the specific target sites.
- carriers include: liposomes, microspheres (e.g ., made of poly(lactic-co- glycolic) acid), albumin microspheres, synthetic polymers, nanofibers, protein-DNA complexes, protein conjugates, erythrocytes, virosomes, and dendrimers.
- Tumors for which the present treatment methods are useful include any malignant cell type, such as those found in a solid tumor or a hematological tumor.
- Exemplary solid tumors can include, but are not limited to, a tumor of an organ selected from the group consisting of pancreas, colon, cecum, stomach, brain, head, neck, ovary, kidney, larynx, sarcoma, lung, bladder, melanoma, prostate, and breast.
- Exemplary hematological tumors include tumors of the bone marrow, T or B cell malignancies, leukemias, lymphomas, blastomas, myelomas, and the like.
- cancers that may be treated using the methods provided herein include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, leukemia, squamous cell cancer, lung cancer (including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung), cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer (including gastrointestinal cancer and gastrointestinal stromal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, various types of head and neck cancer, melanoma, superficial spreading melanoma, lentigo malignant melanoma, acral lentiginous melanomas, nodular melanomas, as well as B
- the cancer may specifically be of the following histological type, though it is not limited to these: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyp; adenocarcinoma, familial polyposis coli; solid carcinoma; carcinoid tumor, malignant; branchiolo-alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma;
- compositions and methods of the present embodiments involve administration of a population of cultured lymphoid cells, e.g., tumor antigen-specific T cells, in combination with a second or additional therapy.
- Therapeutic and prophylactic methods and compositions can be provided in a combined amount effective to achieve the desired effect. This process may involve administering both a cell-based therapy and a second therapy.
- a tissue, organ, or cell can be exposed to one or more compositions or pharmacological formulation(s) comprising one or more of the agents (i.e., a cell-based therapy or a second agent), or by contacting the tissue, organ, and/or cell with two or more distinct compositions or formulations, wherein one composition provides 1) a cell-based therapy, 2) a second agent, or 3) both a cell-based therapy and a second agent. Also, it is contemplated that such a combination therapy can be used in conjunction with surgical therapy.
- a cell-based therapy may be administered before, during, after, or in various combinations relative to a second treatment.
- the administrations may be in intervals ranging from concurrently to minutes to days to weeks.
- the cell-based therapy is provided to a patient separately from a second agent, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that the two treatments would still be able to exert an advantageously combined effect on the patient.
- a course of treatment will last 1-90 days or more (this such range includes intervening days). It is contemplated that the cell-based therapy may be given on any day of day 1 to day 90 (this such range includes intervening days) or any combination thereof, and another treatment is given on any day of day 1 to day 90 (this such range includes intervening days) or any combination thereof. Within a single day (24-hour period), the patient may be given one or multiple administrations of the treatment(s). Moreover, after a course of treatment, it is contemplated that there is a period of time at which no treatment is administered.
- This time period may last 1-7 days, and/or 1-5 weeks, and/or 1-12 months or more (this such range includes intervening days), depending on the condition of the patient, such as their prognosis, strength, health, etc. It is expected that the treatment cycles would be repeated as necessary.
- a cell-based therapy is“A” and a second therapy is“B”: A/B/A B/A/B B/B/A A/A/B A/B/B B/A/A A/B/B/B B/A/B/B/B
- chemotherapeutic agents may be used in accordance with the present embodiments.
- the term“chemotherapy” refers to the use of drugs to treat cancer.
- a “chemotherapeutic agent” is used to connote a compound or composition that is administered in the treatment of cancer. These agents or drugs are categorized by their mode of activity within a cell, for example, whether and at what stage they affect the cell cycle. Alternatively, an agent may be characterized based on its ability to directly cross-link DNA, to intercalate into DNA, or to induce chromosomal and mitotic aberrations by affecting nucleic acid synthesis.
- chemotherapeutic agents include alkylating agents, such as thiotepa and cyclosphosphamide; alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide, and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; cally statin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); do
- DNA damaging factors include what are commonly known as g-rays, X-rays, and/or the directed delivery of radioisotopes to tumor cells.
- Other forms of DNA damaging factors are also contemplated, such as microwaves, proton beam irradiation (U.S. Patents 5,760,395 and 4,870,287), and UV-irradiation. It is most likely that all of these factors affect a broad range of damage on DNA, on the precursors of DNA, on the replication and repair of DNA, and on the assembly and maintenance of chromosomes.
- Dosage ranges for X-rays range from daily doses of 50 to 200 roentgens for prolonged periods of time (3 to 4 wk), to single doses of 2000 to 6000 roentgens.
- Dosage ranges for radioisotopes vary widely, and depend on the half-life of the isotope, the strength and type of radiation emitted, and the uptake by the neoplastic cells.
- immunotherapies may be used in combination or in conjunction with methods of the embodiments.
- immunotherapeutics generally, rely on the use of immune effector cells and molecules to target and destroy cancer cells.
- Rituximab (RITUXAN®) is such an example.
- the immune effector may be, for example, an antibody specific for some marker on the surface of a tumor cell.
- the antibody alone may serve as an effector of therapy or it may recruit other cells to actually affect cell killing.
- the antibody also may be conjugated to a drug or toxin (chemotherapeutic, radionuclide, ricin A chain, cholera toxin, pertussis toxin, etc.) and serve merely as a targeting agent.
- the effector may be a lymphocyte carrying a surface molecule that interacts, either directly or indirectly, with a tumor cell target.
- Various effector cells include cytotoxic T cells and NK cells.
- the tumor cell must bear some marker that is amenable to targeting, i.e ., is not present on the majority of other cells.
- Common tumor markers include CD20, carcinoembryonic antigen, tyrosinase (p97), gp68, TAG-72, HMFG, Sialyl Lewis Antigen, MucA, MucB, PLAP, laminin receptor, Erb B, and pl55.
- An alternative aspect of immunotherapy is to combine anticancer effects with immune stimulatory effects.
- Immune stimulating molecules also exist including: cytokines, such as IL-2, IL-4, IL-12, GM- CSF, gamma-IFN, chemokines, such as MIP-l, MCP-l, IL-8, and growth factors, such as FLT3 ligand.
- cytokines such as IL-2, IL-4, IL-12, GM- CSF, gamma-IFN, chemokines, such as MIP-l, MCP-l, IL-8, and growth factors, such as FLT3 ligand.
- immunotherapies currently under investigation or in use are immune adjuvants, e.g., Mycobacterium bovis , Plasmodium falciparum , dinitrochlorobenzene, and aromatic compounds (U.S. Patents 5,801,005 and 5,739,169; Hui and Hashimoto, 1998; Christodoulides et al, 1998); cytokine therapy, e.g, interferons a, b, and g, IL-l, GM-CSF, and TNF (Bukowski et al., 1998; Davidson et al, 1998; Hellstrand et al, 1998); gene therapy, e.g., TNF, IL-l, IL-2, and p53 (Qin et al, 1998; Austin-Ward and Villaseca, 1998; U.S.
- immune adjuvants e.g., Mycobacterium bovis , Plasmodium falciparum , dinitrochlorobenzene, and aromatic compounds
- Patents 5,830,880 and 5,846,945) ; and monoclonal antibodies, e.g, anti-CD20, anti-ganglioside GM2, and anti-pl85 (Hollander, 2012; Hanibuchi etal, 1998; U.S. Patent 5,824,311). It is contemplated that one or more anti-cancer therapies may be employed with the antibody therapies described herein.
- the immunotherapy may be an immune checkpoint inhibitor.
- Immune checkpoints either turn up a signal (e.g, co-stimulatory molecules) or turn down a signal.
- Inhibitory immune checkpoints that may be targeted by immune checkpoint blockade include adenosine A2A receptor (A2AR), B7-H3 (also known as CD276), B and T lymphocyte attenuator (BTLA), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4, also known as CD152), indoleamine 2,3-dioxygenase (IDO), killer-cell immunoglobulin (KIR), lymphocyte activation gene-3 (LAG3), programmed death 1 (PD-l), T-cell immunoglobulin domain and mucin domain 3 (TIM-3) and V-domain Ig suppressor of T cell activation (VISTA).
- the immune checkpoint inhibitors target the PD-l axis and/or CTLA-4.
- the immune checkpoint inhibitors may be drugs such as small molecules, recombinant forms of ligand or receptors, or, in particular, are antibodies, such as human antibodies (e.g., International Patent Publication WO2015016718; Pardoll, Nat Rev Cancer, 12(4): 252-64, 2012; both incorporated herein by reference).
- Known inhibitors of the immune checkpoint proteins or analogs thereof may be used, in particular chimerized, humanized or human forms of antibodies may be used.
- alternative and/or equivalent names may be in use for certain antibodies mentioned in the present disclosure. Such alternative and/or equivalent names are interchangeable in the context of the present disclosure. For example, it is known that lambrolizumab is also known under the alternative and equivalent names MK-3475 and pembrolizumab.
- the PD-l binding antagonist is a molecule that inhibits the binding of PD-l to its ligand binding partners.
- the PD-l ligand binding partners are PDL1 and/or PDL2.
- a PDL1 binding antagonist is a molecule that inhibits the binding of PDL1 to its binding partners.
- PDL1 binding partners are PD-l and/or B7-1.
- the PDL2 binding antagonist is a molecule that inhibits the binding of PDL2 to its binding partners.
- a PDL2 binding partner is PD-l .
- the antagonist may be an antibody, an antigen binding fragment thereof, an immunoadhesin, a fusion protein, or oligopeptide.
- Exemplary antibodies are described in U.S. Patent Nos. 8,735,553, 8,354,509, and 8,008,449, all incorporated herein by reference.
- Other PD- 1 axis antagonists for use in the methods provided herein are known in the art such as described in U.S. Patent Publication Nos. 20140294898, 2014022021, and 20110008369, all incorporated herein by reference.
- the PD-l binding antagonist is an anti -PD-l antibody (e.g ., a human antibody, a humanized antibody, or a chimeric antibody).
- the anti- PD-l antibody is selected from the group consisting of nivolumab, pembrolizumab, and CT-011.
- the PD-l binding antagonist is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-l binding portion of PDL1 or PDL2 fused to a constant region (e.g, an Fc region of an immunoglobulin sequence).
- the PD-l binding antagonist is AMP- 224.
- Nivolumab also known as MDX-l 106-04, MDX-1106, ONO-4538, BMS-936558, and OPDIVO ® , is an anti-PD-l antibody described in W02006/121168.
- Pembrolizumab also known as MK-3475, Merck 3475, lambrolizumab, KEYTRUDA ® , and SCH- 900475, is an anti-PD-l antibody described in W02009/114335.
- CT-011 also known as hBAT or hBAT-l, is an anti-PD-l antibody described in W02009/101611.
- AMP -224 also known as B7- DCIg, is a PDL2-Fc fusion soluble receptor described in W02010/027827 and WO2011/066342.
- CTLA-4 cytotoxic T-lymphocyte-associated protein 4
- CD152 cytotoxic T-lymphocyte-associated protein 4
- the complete cDNA sequence of human CTLA-4 has the Genbank accession number L15006.
- CTLA-4 is found on the surface of T cells and acts as an“off’ switch when bound to CD80 or CD86 on the surface of antigen-presenting cells.
- CTLA4 is a member of the immunoglobulin superfamily that is expressed on the surface of Helper T cells and transmits an inhibitory signal to T cells.
- CTLA4 is similar to the T-cell co-stimulatory protein, CD28, and both molecules bind to CD80 and CD86, also called B7-1 and B7-2 respectively, on antigen-presenting cells.
- CTLA4 transmits an inhibitory signal to T cells, whereas CD28 transmits a stimulatory signal.
- Intracellular CTLA4 is also found in regulatory T cells and may be important to their function. T cell activation through the T cell receptor and CD28 leads to increased expression of CTLA-4, an inhibitory receptor for B7 molecules.
- the immune checkpoint inhibitor is an anti-CTLA-4 antibody (e.g ., a human antibody, a humanized antibody, or a chimeric antibody), an antigen binding fragment thereof, an immunoadhesin, a fusion protein, or oligopeptide.
- an anti-CTLA-4 antibody e.g ., a human antibody, a humanized antibody, or a chimeric antibody
- an antigen binding fragment thereof e.g a human antibody, a humanized antibody, or a chimeric antibody
- an immunoadhesin e.g., a human antibody, a humanized antibody, or a chimeric antibody
- an antigen binding fragment thereof e.g., an immunoadhesin, a fusion protein, or oligopeptide.
- Anti-human-CTLA-4 antibodies (or VH and/or VL domains derived therefrom) suitable for use in the present methods can be generated using methods well known in the art.
- art recognized anti-CTLA-4 antibodies can be used.
- An exemplary anti-CTLA-4 antibody is ipilimumab (also known as 10D1, MDX- 010, MDX- 101, and Yervoy®) or antigen binding fragments and variants thereof (see, e.g. , WO
- the antibody comprises the heavy and light chain CDRs or VRs of ipilimumab. Accordingly, in one embodiment, the antibody comprises the CDR1, CDR2, and CDR3 domains of the VH region of ipilimumab, and the CDR1, CDR2 and CDR3 domains of the VL region of ipilimumab. In another embodiment, the antibody competes for binding with and/or binds to the same epitope on CTLA-4 as the above- mentioned antibodies. In another embodiment, the antibody has at least about 90% variable region amino acid sequence identity with the above- mentioned antibodies (e.g, at least about 90%, 95%, or 99% variable region identity with ipilimumab).
- CTLA-4 ligands and receptors such as described in U.S. Patent Nos. 5844905, 5885796 and International Patent Application Nos. WO1995001994 and WO1998042752; all incorporated herein by reference, and immunoadhesins such as described in U.S. Patent No. 8329867, incorporated herein by reference.
- the immune therapy could be adoptive immunotherapy, which involves the transfer of autologous antigen- specific T cells generated ex vivo.
- the T cells used for adoptive immunotherapy can be generated either by expansion of antigen-specific T cells or redirection of T cells through genetic engineering (Park, Rosenberg et al. 2011).
- CARs transgenic T cell receptors or chimeric antigen receptors
- CARs are synthetic receptors consisting of a targeting moiety that is associated with one or more signaling domains in a single fusion molecule.
- the binding moiety of a CAR consists of an antigen-binding domain of a single-chain antibody (scFv), comprising the light and variable fragments of a monoclonal antibody joined by a flexible linker. Binding moieties based on receptor or ligand domains have also been used successfully.
- the signaling domains for first generation CARs are derived from the cytoplasmic region of the CD3zeta or the Fc receptor gamma chains. CARs have successfully allowed T cells to be redirected against antigens expressed at the surface of tumor cells from various malignancies including lymphomas and solid tumors (Jena, Doth et al. 2010).
- the present application provides for a combination therapy for the treatment of cancer wherein the combination therapy comprises adoptive T cell therapy and a checkpoint inhibitor.
- the adoptive T cell therapy comprises autologous and/or allogenic T-cells.
- the autologous and/or allogenic T-cells are targeted against tumor antigens. D. Surgery
- Curative surgery includes resection in which all or part of cancerous tissue is physically removed, excised, and/or destroyed and may be used in conjunction with other therapies, such as the treatment of the present embodiments, chemotherapy, radiotherapy, hormonal therapy, gene therapy, immunotherapy, and/or alternative therapies.
- Tumor resection refers to physical removal of at least part of a tumor.
- treatment by surgery includes laser surgery, cryosurgery, electrosurgery, and microscopically-controlled surgery (Mohs’ surgery).
- a cavity may be formed in the body.
- Treatment may be accomplished by perfusion, direct injection, or local application of the area with an additional anti-cancer therapy. Such treatment may be repeated, for example, every 1, 2, 3, 4, 5, 6, or 7 days, or every 1, 2, 3, 4, and 5 weeks or every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. These treatments may be of varying dosages as well.
- agents may be used in combination with certain aspects of the present embodiments to improve the therapeutic efficacy of treatment.
- additional agents include agents that affect the upregulation of cell surface receptors and GAP junctions, cytostatic and differentiation agents, inhibitors of cell adhesion, agents that increase the sensitivity of the hyperproliferative cells to apoptotic inducers, or other biological agents. Increases in intercellular signaling by elevating the number of GAP junctions would increase the anti- hyperproliferative effects on the neighboring hyperproliferative cell population.
- cytostatic or differentiation agents can be used in combination with certain aspects of the present embodiments to improve the anti-hyperproliferative efficacy of the treatments.
- Inhibitors of cell adhesion are contemplated to improve the efficacy of the present embodiments.
- cell adhesion inhibitors are focal adhesion kinase (FAKs) inhibitors and Lovastatin. It is further contemplated that other agents that increase the sensitivity of a hyperproliferative cell to apoptosis, such as the antibody c225, could be used in combination with certain aspects of the present embodiments to improve the treatment efficacy. III.
- Thl 7 cells expanded four days demonstrate enhanced tumor immunity: Given the robust antitumor properties of CD4 + Thl7 cells, it was hypothesized that even few Thl7 cells could effectively treat tumor-bearing mice. If so, it was thought that ex vivo culture time needed to generate these cells could be shortened— an objective that is clinically relevant for reducing the cost and time needed to treat patients.
- TRP-l specific CD4 + T cells (Muranski et al, 2008) were polarized to a Thl7 phenotype and were expanded from as little time as 12 hours post TCR activation with TRP-l peptide up to the amount of time usually used in clinical protocols to generate TIL products for patients (14 days post TCR activation) (FIG.
- Thl7 cells were infused into C57BL/6J mice bearing established B16F10 melanoma preconditioned with 5 Gy total body irradiation (TBI) (FIG. 1B). It was determined that four days was the minimum time of expansion with which a therapeutic Thl 7 cell product able to eradicate tumors could be generated (FIG. 1C).
- Thl 7 cells induce superior antitumor immunity on a per cell basis: As Day-4 Thl7 cells mediate potent tumor immunity in lower doses versus cells expanded for longer duration, it was posited that in equal number, Day-4 Thl 7 cells would generate enhanced responses to melanoma. Fewer than 300k Thl7 cells expanded either 4, 7, or 14 days were infused into lymphodepleted mice with B16F10 melanoma (FIG. 2A). Strikingly, 10/16 animals treated with Day-4 Thl7 cells survived the duration of the experiment compared to 0/8 Day-7 and 1/16 Day-l4 treated animals (FIGS. 2B-C).
- the antitumor potential of a Day-4 CAR Thl 7 cell versus a Day-7 CAR Thl 7 cell was determined on a per cell basis. Tumor growth was tracked in NSG mice bearing established mesothelioma after treatment with le 6 Day-4 versus Day-7 CAR Thl7 cells (FIG. 2F). Day-4 Thl7 cells induced enhanced tumor regression compared to Day-7 expanded cells (FIG. 2G). In the peripheral blood and tumor, CAR + cells persisted superiorly approximately one-month post transfer if expanded only four days post activation (FIGS. 2H-I). Collectively, these findings suggest that Day-4 Thl7 cells possess greater antitumor potential versus long-term expanded Thl7 cells.
- Thl7 cells are highly activated four days post stimulation: Thl7 cells treated with a PI3K6-inhibitor CAL-101 have a less differentiated memory phenotype and regress tumors to a far greater degree than untreated Thl7 cells (Majchrzak el al, 2017). It was hypothesized Thl7 cells expanded for shorter duration would be less differentiated and thus more efficacious than Thl7 cells expanded one to two weeks. In contrast to this idea, it was found that, regardless of expansion time, Thl7 cells possess an effector memory profile (CD44 hi CD62L 1 °) in vitro (FIG. 3A).
- Thl7 cells may be associated with their antitumor potential, as it was found that cells expanded for 4 days were more blastic via side and forward scatter than those expanded for longer duration (FIG. 3C). It was also confirmed this concept by analyzing gene and protein expression of activation markers on Thl7 cells kinetically. Indeed, it was determined that four days after peptide-TCR activation, these Thl7 cells express peak levels of ⁇ L-2Ra, ICOS, CD28, and 0x40 which diminish over time (FIGS. 3D- E). In contrast, all activated cells similarly express CD69 and CD95 regardless of expansion time (FIGS. 3D, 3F).
- human T cells expressed heightened IL-2Ra, ICOS, and 0x40 at 4 days after activation with either aCD3/aCD28 or aCD3/aICOS magnetic beads (FIG. 7).
- Murine CD8 + T cells also express high levels of IL-2Ra and ICOS four days after peptide-specific stimulation (FIG. 7).
- Thl7 cells are highly activated in vitro prior to infusion and can induce potent tumor regression when infused into mice, it was posited that these cells may also be more functional, marked by their capacity to secrete more cytokines versus Thl7 cohorts expanded longer. Indeed, Thl7 cells expanded only four days were potently multifunctional (FIG. 3G-H), secreting highest levels of IL-17A, IL-17F, and IL-22 relative to day 7 or day l4-Thl7 cells (FIG. 3G). Based on gene array analysis, Day-4 Thl7 cells also express higher CCL9, CCL17, and CXCL1, suggesting ability to induce immune cell chemotaxis (FIG. 8). Collectively, the findings indicate that Thl7 cells are highly activated and functional 4 days after stimulation, which may support their acute function in vivo as well as long-term immune responses to tumors.
- IL-17 is known to induce inflammatory cytokine production such as IL-6 and G-CSF from stromal cells (Fossiez el al, 1996), and previous reports have shown that donor Thl7 cells induce dendritic cell and granulocyte recruitment to lung tumors via induction of chemokine release (Martin-Orozco el al, 2009). Since Day-4 Thl7 cells produce copious IL-17, it was suspected that heightened IL-17 would be able to be detected in the blood of treated mice. To address this question, Thl7 cells expanded for 12 hours as well as for 2, 4, 7 or 14 days were transferred into mice.
- TRP-l T cells were cultured in polarizing media: for ThO cells, this was comprised of IL-2, for Thl cells was comprised of IL-2, IL-12, and anti-IL4, and for Th9 cells was comprised of IL-4, TGFP, and anti-IFNy
- the cells were cultured for only four days and then transferred to C57BL/6 mice and the tumor size was measured over time (FIG. 12A). It was observed that the T helper subsets, particularly ThO and Th9 resulted in decreased tumor size. In particular, the Th9 cells benefited from the shortened expansion protocol with significantly improved overall survival relative to Th9 cells expanded longer term (FIG. 12B).
- mice were purchased from the Jackson laboratories and bred in house at the Medical University of South Carolina (MUSC) Hollings Cancer Center comparative medicine department.
- C57BL/6 CD45.1 mice were purchased from NCI Frederick laboratories for indicated studies.
- Tumor experiments were conducted with mice aged 6-10 weeks.
- NSG mice were housed in microisolator cages to maintain specific-pathogen free conditions and provided bottle access to acidified, autoclaved water and food. All housing and experiments were conducted in accordance with MUSC’s Institutional Animal Care and Use Committee (IACUC) procedures and with the supervision and support of the Division of Lab Animal Resources (DLAR). All studies and procedures were IACUC approved prior to execution.
- B16F10 (H-2 b ) melanoma cell line was obtained from Nicholas P. Restifo and Ml 08 mesothelioma was obtained from Carl H. June and used for in vivo tumor studies.
- TRP-1 cells TRP-l transgenic T cells were activated in the presence of irradiated
- IL- 23 and IL-2 were added in concentrations of 20ng/mL and 50IU/mL, respectively. From day -4 and onward, cells were split to a density of 0.8e6/mL and fresh media added with 100IU IL-2/mL as needed. At indicated time points, cells were cryopreserved in media containing 90% FBS and 10% DMSO. For adoptive transfer experiments, cells were thawed and incubated at 37°C overnight prior to transfer.
- Pmel cells Pmel transgenic T cells were activated in the presence of 1 mM human gplOO (hgplOO) peptide. Cells were plated at a concentration of le6/mL for activation in a 24-well plate in the presence of 100IU IL-2/mL. From day 3 onward, cells were split to a concentration of 0.8e6 cells/mL supplemented with fresh media containing 100IU IL-2/mL. At indicated time points, cells were cryopreserved as described previously, and thawed one day prior to transfer.
- CD8 + T cells were reactivated with luM peptide pulsed irradiated feeder cells (lOGy) at a 1 feeder cell: 10T cell ratio overnight as described previously (Klebanoff et al, 2009). All T cells are cultured in RPMI based complete medium.
- Human normal donor peripheral T cells Peripheral blood from healthy donors (de- identified) were purchased as a buffy coat (Plasma Consultants). Lymphocytes were separated from buffy coat using Lymphocyte Separation Medium (Mediatech). CD4 + T cells were isolated from PBMCs via untouched magnetic bead isolation kit (Dynabeads, Invitrogen) and rested overnight at 37°C in media containing 20 IU IL-2/mL.
- CD4 + T cells were then activated using magnetic beads decorated with antibodies targeting CD3 and ICOS at a 1 bead: 5 T cell ratio, and polarized to the Thl7 phenotype using the following cocktail of cytokines: lOng/mL hIL-lB, lOng/mL rhIL-6, 20 ng/mL IL-23, 10 ug/mL anti-hIL-4 and lOug/mL anti-hIFN-y.
- CD4 + cell cultures were maintained with 100IU IL-2/mL over duration of expansion.
- mice C57BL/6: 0.4e6 B16F10 cells were resuspended in sterile PBS and injected subcutaneously on the abdomen of mice. Tumors were permitted to grow indicated number of days per experiment, ranging from 5-12 days to generate tumors of target sizes.
- TBI 5Gy total body irradiation
- mice received intraperitoneal injections of rhIL-2 (l.5pg, NIH preclinical repository) complexed with anti-hIL-2 (7.5pg, clone 5355, R&D Systems) on days 0, 2, and 4 post ACT.
- NSG Ml 08 was injected subcutaneously in matrigel 50 days prior to adoptive transfer. Thl7 meso-CAR T cells were resuspended in sterile PBS and transferred via tail vein injection.
- Peripheral blood was obtained at indicated time points by mandibular vein blood collection into 0.125 M EDTA, subjected to red blood cell lysis (Biolegend), and assayed via flow cytometry.
- Spleens, lymph nodes, and tumors were taken from animals and processed into single cell suspension by mechanical dissociation over a 70 mM filter.
- M108 tumors were minced and digested in lmg/mL collagenase type II (Life Technologies) at 37°C for 1 hour. Skin processing was conducted as previously described 51 . Skin patches approximately 2cm x 2cm were removed from the abdomen of the animal where tumor was originally placed.
- Skin was minced and incubated in buffer containing 3mg/mL collagenase IV (Worthing Biochemical), and 0.2mg/mL DNase (Sigma) in Hank’s balanced salt solution (HBSS) at 37°C for 45 minutes with stirring. Digestion was neutralized with RPMI containing lO%FBS and lOmM EDTA. Digested and processed tissue was filtered prior to assay.
- HBSS Hank’s balanced salt solution
- Flow cytometry was performed using a BDFACSVerse instrument and analyzed using FlowJo software (Tree Star). For extracellular staining, samples were suspended in FACS buffer (PBS + 2% FBS) and incubated with antibodies for 20 minutes. For intracellular staining, cells were activated in the presence of PMA/Ionomycin with Monensin and Brefeldin A (Biolegend) for 4 hours, followed by fixation and permeabilization according to manufacturer’s protocol (BioLegend).
- ELISA T cells used for ELISA kinetics were washed and plated each indicated day at 2e5 cells/200uL in fresh media for 18 hours. Supernatant was collected and frozen prior to analysis for IL-17A, IL-17F, and IL-22 by DuoSet ELISA kits (R&D Systems) per manufacturer instructions.
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Abstract
L'invention concerne des méthodes de propagation ex vivo de cellules immunitaires. L'invention concerne également des compositions de cellules effectrices immunitaires destinées à être utilisées pour traiter une maladie (par exemple le cancer).<i />
Applications Claiming Priority (2)
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US201862753416P | 2018-10-31 | 2018-10-31 | |
US62/753,416 | 2018-10-31 |
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WO2020092696A1 true WO2020092696A1 (fr) | 2020-05-07 |
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PCT/US2019/059041 WO2020092696A1 (fr) | 2018-10-31 | 2019-10-31 | Activation et expansion ex vivo de lymphocytes t pour une thérapie par transfert adoptif de cellules |
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014186469A2 (fr) * | 2013-05-14 | 2014-11-20 | Board Of Regents, The University Of Texas System | Application à des humains de lymphocytes t comprenant un récepteur antigénique chimérique (car) |
WO2017072251A1 (fr) * | 2015-10-28 | 2017-05-04 | Life Technologies As | Multiplication sélective de différentes sous-populations de cellules t par la modification de signaux de surface cellulaire et du rapport des signaux |
WO2017165245A2 (fr) * | 2016-03-19 | 2017-09-28 | F1 Oncology, Inc. | Procédés et compositions pour la transduction de lymphocytes et leur expansion régulée |
WO2018089423A1 (fr) * | 2016-11-09 | 2018-05-17 | Musc Foundation For Research Development | Axe métabolique régulé cd38-nad+ en immunothérapie antitumorale |
WO2018106732A1 (fr) * | 2016-12-05 | 2018-06-14 | Juno Therapeutics, Inc. | Production de cellules modifiées pour une thérapie cellulaire adoptive |
WO2018157171A2 (fr) * | 2017-02-27 | 2018-08-30 | Juno Therapeutics, Inc. | Compositions, articles manufacturés et méthodes associées au dosage en thérapie cellulaire |
-
2019
- 2019-10-31 WO PCT/US2019/059041 patent/WO2020092696A1/fr active Application Filing
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014186469A2 (fr) * | 2013-05-14 | 2014-11-20 | Board Of Regents, The University Of Texas System | Application à des humains de lymphocytes t comprenant un récepteur antigénique chimérique (car) |
WO2017072251A1 (fr) * | 2015-10-28 | 2017-05-04 | Life Technologies As | Multiplication sélective de différentes sous-populations de cellules t par la modification de signaux de surface cellulaire et du rapport des signaux |
WO2017165245A2 (fr) * | 2016-03-19 | 2017-09-28 | F1 Oncology, Inc. | Procédés et compositions pour la transduction de lymphocytes et leur expansion régulée |
WO2018089423A1 (fr) * | 2016-11-09 | 2018-05-17 | Musc Foundation For Research Development | Axe métabolique régulé cd38-nad+ en immunothérapie antitumorale |
WO2018106732A1 (fr) * | 2016-12-05 | 2018-06-14 | Juno Therapeutics, Inc. | Production de cellules modifiées pour une thérapie cellulaire adoptive |
WO2018157171A2 (fr) * | 2017-02-27 | 2018-08-30 | Juno Therapeutics, Inc. | Compositions, articles manufacturés et méthodes associées au dosage en thérapie cellulaire |
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