Methods and combinations for treatment and t cell modulation

Abstract

To provide a method for rescuing T cell activity.SOLUTION: The present invention provides a method comprising exposing a plurality of T cells having an exhausted phenotype to an effective amount of an immunomodulatory compound selected from the group consisting of: thalidomide analogs; thalidomide derivatives; compounds that interact with and / or bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of Ikaros (IKZF1); inhibitors of Aiolos (IKZF3); and compounds that enhance or promote ubiquitination, depletion and / or degradation of Ikaros (IKZF1) and / or Aiolos (IKZF3).SELECTED DRAWING: None

Description

Technical Field

[0001] Cross-reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 62 / 757,755, filed on Nov. 8, 2018, and U.S. Provisional Patent Application No. 62 / 826,928, filed on Mar. 29, 2019, the contents of which are hereby incorporated by reference in their entirety for all purposes.

[0002] Incorporation by Reference of Sequence Listing This application is being filed with an electronic sequence listing. The sequence listing is provided as a file named 735042019440SeqList.txt, created on Nov. 7, 2019, which is 320 kilobytes in size. The information in the electronic form of the sequence listing is hereby incorporated by reference in its entirety.

[0003] Field In some aspects, the present disclosure relates to methods, compositions, and uses that include immunotherapy (e.g., adoptive cell therapy, e.g., T cell therapy) and immunomodulatory compounds such as structural or functional analogs or derivatives of thalidomide and / or inhibitors of E3-ubiquitin ligase. The provided methods, compositions, and uses include methods, compositions, and uses for combination therapies that include administration or use of one or more immunomodulatory compounds in combination with T cell therapies such as genetically engineered T cell therapies that include cells engineered with recombinant receptors such as chimeric antigen receptor (CAR)-expressing T cells. Also provided are compositions for use in the methods, methods of administration to a subject, articles of manufacture, and kits. In some aspects, the methods and cell characteristics provide an increase or improvement in the activity, efficacy, persistence, expansion, and / or proliferation of T cells for adoptive cell therapy or endogenous T cells mobilized by immunotherapeutic agents.

Background Art

[0004] Background For example, various strategies are available for immunotherapy involving the administration of engineered T cells for adoptive therapy. For example, strategies are available for engineering T cells that express genetically engineered antigen receptors such as CARs, and for administering compositions containing such cells to a subject. At the time of administration to a subject, there is a need for improvement of strategies for improving the efficacy of the cells, for example, improving the persistence, activity, and / or proliferation of the cells. Methods, compositions, kits, and systems are provided that address such needs. SUMMARY OF THE INVENTION

[0005] Summary A method for rescuing T cell activity, the method comprising exposing a plurality of T cells having an exhausted phenotype to an effective amount of an immunomodulatory compound selected from thalidomide analogs; thalidomide derivatives; compounds that interact with and / or bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of Ikaros (IKZF1); inhibitors of Aiolos (IKZF3); and compounds that enhance or promote ubiquitination, depletion, and / or degradation of Ikaros (IKZF1) and / or Aiolos (IKZF3). In some aspects of the methods provided herein, the one or more T cells include T cells that express a recombinant receptor that specifically binds to a target antigen.

[0006] A method for preventing, or suppressing, or reducing, or delaying the onset of T cell depletion, comprising exposing a plurality of T cells to an effective amount of an immunomodulatory compound selected from the group consisting of thalidomide analogs; thalidomide derivatives; compounds that interact with and / or bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of ikaros (IKZF1); inhibitors of aiolos (IKZF3); and compounds that enhance or promote the ubiquitination, depletion, and / or degradation of ikaros (IKZF1) and / or aiolos (IKZF3), wherein at least a portion of the exposing step is performed under conditions that would induce, or are capable of inducing, a depleted phenotype in the plurality of T cells in the absence of the compound, is provided herein.

[0007] A method for reducing or delaying the onset of T cell depletion, comprising exposing a plurality of T cells to an effective amount of an immunomodulatory compound selected from the group consisting of thalidomide analogs; thalidomide derivatives; compounds that interact with and / or bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of ikaros (IKZF1); inhibitors of aiolos (IKZF3); and compounds that enhance or promote the ubiquitination, depletion, and / or degradation of ikaros (IKZF1) and / or aiolos (IKZF3), wherein at least a portion of the exposing step is performed in conditions that would induce, or are capable of inducing, a depleted phenotype in the plurality of T cells in the absence of the compound, is provided herein.

[0008] A method for increasing T cell activity or efficacy and preventing, suppressing, reducing, or delaying the onset of T cell depletion, the method comprising exposing a plurality of T cells to an effective amount of an immunomodulatory compound selected from thalidomide analogs; thalidomide derivatives; compounds that interact with and / or bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of Ikaros (IKZF1); inhibitors of Aiolos (IKZF3); and compounds that enhance or promote the ubiquitination, depletion, and / or degradation of Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein at least a portion of the exposing step is performed under conditions that would induce or can induce a depleted phenotype in the plurality of T cells in the absence of the compound, as provided herein.

[0009] In some embodiments of any of the methods provided herein, the conditions include T cell stimulation conditions optionally including exposure to at least one T cell stimulatory agent capable of stimulating a signal in the plurality of T cells, the signal optionally including a primary signal and / or a co-stimulatory signal. In some embodiments, the conditions include a sustained, repeated, extended, or long-term exposure to at least one T cell stimulatory agent.

[0010] In some embodiments of any of the methods provided herein, the at least one T cell stimulatory agent includes a polyclonal agent, an antigen specifically recognized by a receptor expressed on the plurality of T cells, or an agent to which the antigen receptor expressed by the plurality of T cells binds. In some embodiments, the at least one T cell stimulatory agent is or includes PMA and ionomycin, or is or includes a T cell receptor agonist or a T cell receptor complex agonist. In some embodiments, the agent specifically binds to a member of the TCR complex, and optionally, the agent specifically binds to CD3, optionally CD3 zeta.

[0011] In some embodiments of any of the methods provided herein, at least one T cell stimulator comprises an anti-CD3 antibody. In some embodiments, at least one T cell stimulator specifically binds to a T cell costimulatory molecule, and optionally, the T cell costimulatory molecule is CD28, CD137 (4-1-BB), OX40, CD40L, or ICOS, or at least one T cell stimulator further comprises an agent that specifically binds to a T cell costimulatory molecule, and optionally, the T cell costimulatory molecule is CD28, CD137 (4-1-BB), OX40, CD40L, or ICOS. In some embodiments, at least one T cell stimulator comprises an anti-CD28 antibody. In some embodiments, at least one T cell stimulator comprises or further comprises an MHC-peptide complex recognized by an antigen receptor expressed by one or more of a plurality of T cells, or an antigen recognized by an antigen receptor expressed by one or more of a plurality of T cells. In some embodiments, one or more of a plurality of T cells express a recombinant antigen receptor that binds to a target antigen. In some embodiments, at least one T cell stimulator binds to the recombinant antigen receptor. In some embodiments, at least one T cell stimulator is or comprises an anti-idiotypic antibody specific for the recombinant antigen receptor. In some embodiments, at least one T cell stimulator is or comprises a target antigen or a portion thereof recognized by or bound by the recombinant antigen receptor, and / or the condition comprises exposure to the target antigen. In some embodiments of any of the methods provided herein, the recombinant antigen receptor is a recombinant T cell receptor (TCR). In some embodiments, the recombinant antigen receptor is a chimeric antigen receptor (CAR).

[0012] In some aspects of any of the methods provided herein, one or more T cells are primary human T cells, optionally derived from a subject. In some aspects, the step of exposing the T cells to an effective amount of an immunomodulatory compound is performed ex vivo. In other aspects, the exposing step is performed in vivo, and the exposing step comprises administering the compound to the subject, and optionally, if the T cells are derived from the subject, the administration of the compound is to the subject; and / or the exposing step comprises administering the plurality of T cells to the subject, and optionally, if the T cells are derived from the subject, the administration of the compound is to the subject. In some aspects of any of the methods provided herein, the step of exposing the T cells to an effective amount of an immunomodulatory compound comprises the administration of the compound, and prior to the exposing step, the subject has been administered a composition comprising a plurality of T cells for the subject for treating a disease or condition, and optionally, the target antigen is associated with the disease or condition.

[0013] In some aspects of any of the methods provided herein, the step of exposing the T cells to an effective amount of an immunomodulatory compound comprises the administration of the compound, and prior to the exposing step, the subject has been administered a composition containing a plurality of T cells for the subject for treating a disease or condition, and optionally, the target antigen is associated with the disease or condition; or the exposing comprises administering the T cells to the subject for treating a disease or condition, and optionally, the target antigen is associated with the disease or condition, and prior to the exposing step, the subject has been administered the compound; or the exposing comprises administering the T cells to the subject for treating a disease or condition, and optionally, the target antigen is associated with the disease or condition, and comprises administering the compound to the subject.

[0014] A method of treatment comprising the step of administering an immunomodulatory compound to a subject, wherein the immunomodulatory compound is selected from thalidomide analogs; thalidomide derivatives; compounds that interact with and / or bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of ikaros (IKZF1); inhibitors of aiolos (IKZF3); and compounds that enhance or promote ubiquitination, depletion, and / or degradation of ikaros (IKZF1) and / or aiolos (IKZF3), (a) the subject has been administered a T cell therapy comprising a dose of T cells that express a recombinant antigen receptor that binds to a target antigen prior to administration of the compound, or (b) prior to or at the time of administration of the compound, the subject or a blood sample derived from the subject contains or has been confirmed to contain one or more T cells that express a recombinant antigen receptor, and at the time of administration of the compound: (i) one or more of the recombinant receptor-expressing T cells in the subject have a depleted phenotype; (ii) it has been determined that one or more of the recombinant receptor-expressing T cells in the subject have a depleted phenotype; (iii) a depleted phenotype of one or more recombinant receptor-expressing T cells, or a marker or parameter indicative thereof, has been detected or measured in the subject or in a biological sample derived from the subject; (iv) at least 10% or at least about 10%, at least 20% or at least about 20%, at least 30% or at least about 30%, at least 40% or at least about 40%, or at least 50% or at least about 50% of the total recombinant receptor-expressing T cells in a biological sample derived from the subject have a depleted phenotype; and / or (v) more than 10% or more than about 10%, more than 20% or more than about 20%, more than 30% or more than about 30%, more than 40% or more than about 40%, or more than 50% or more than about 50% of the recombinant receptor-expressing T cells in a biological sample derived from the subject have a depleted phenotype compared to the percentage of recombinant receptor-expressing cells with a depleted phenotype in an equivalent biological sample at a previous time point, a method is provided herein.

[0015] A method of treatment is provided herein that includes the following steps: (a) selecting a subject as a candidate for administration of an immunomodulatory compound, wherein the selected subject has exhausted recombinant receptor-expressing T cells; and (b) administering an immunomodulatory compound to the subject, wherein the immunomodulatory compound is selected from the group consisting of thalidomide analogs; thalidomide derivatives; compounds that interact with and / or bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of ikaros (IKZF1); inhibitors of aiolos (IKZF3); and compounds that enhance or promote ubiquitination, depletion, and / or degradation of ikaros (IKZF1) and / or aiolos (IKZF3).

[0016] In some embodiments of any of the methods provided herein, the selected subject's or tissue, tumor, biological fluid, or biological sample derived therefrom comprises (i) one or more T cells that express a recombinant antigen receptor that binds to a target antigen and have an exhausted phenotype; (ii) a plurality of T cells that express a recombinant antigen receptor that binds to a target antigen, wherein at least 10% or at least about 10%, at least 20% or at least about 20%, at least 30% or at least about 30%, at least 40% or at least about 40%, at least 50% or at least about 50%, at least 60% or at least about 60%, at least 70% or at least about 70%, or at least 80% or at least about 80% of the T cells in the tissue, fluid, tumor, or sample that express the recombinant receptor have an exhausted phenotype; and / or (iii) a plurality of T cells that express a recombinant antigen receptor that binds to a target antigen, wherein the percentage or number of T cells in the selected subject's or tissue, tumor, biological fluid, or biological sample derived therefrom that express the recombinant receptor and have an exhausted phenotype is more than 10% or about 10% more, more than 20% or about 20% more, more than 30% or about 30% more, more than 40% or about 40% more, or more than 50% or about 50% more, or more than 2-fold, or more than 3-fold, or more than 5-fold, or more than 10-fold compared to the percentage or number of T cells in the subject-derived fluid, tissue, tumor, or sample at an earlier time point or in an equivalent fluid, tissue, tumor, or sample that expressed the recombinant receptor and had an exhausted phenotype. In some embodiments of any of the methods provided herein, prior to administration of the compound, the subject has been administered a plurality of T cells that express the recombinant receptor, and the earlier time point is immediately prior to administration of the plurality of T cells that express the recombinant antigen receptor to the subject.

[0017] In some embodiments of any of the methods provided herein, said selection of said subject comprises determining that the selected subject's or tissue, tumor, biological fluid, or biological sample derived therefrom comprises (i) one or more T cells that express a recombinant antigen receptor that binds to a target antigen and have an exhausted phenotype; (ii) a plurality of T cells that express a recombinant antigen receptor that binds to a target antigen, and at least 10% or at least about 10%, at least 20% or at least about 20%, at least 30% or at least about 30%, at least 40% or at least about 40%, at least 50% or at least about 50%, at least 60% or at least about 60%, at least 70% or at least about 70%, or at least 80% or at least about 80% of the T cells in the tissue, fluid, tumor, or sample that express the recombinant receptor have an exhausted phenotype; and / or (iii) a plurality of T cells that express a recombinant antigen receptor that binds to a target antigen, and more than 10% or about 10% more, more than 20% or about 20% more, more than 30% or about 30% more, more than 40% or about 40% more, or more than 50% or about 50% more, or more than 2-fold more, or more than 3-fold more, or more than 5-fold more, or more than 10-fold more than the percentage or number of T cells that expressed the recombinant receptor and had an exhausted phenotype in the subject-derived fluid, tissue, tumor, or sample at an earlier time point in the selected subject's or tissue, tumor, biological fluid, or biological sample derived therefrom, or in an equivalent fluid, tissue, tumor, or sample, have an exhausted phenotype.

[0018] In some embodiments of any of the methods provided herein, prior to administration of said compound, said subject has been administered a plurality of T cells that express a recombinant receptor, optionally, said earlier time point is after administration of the T cells and before said selection.

[0019] In some embodiments of any of the methods provided herein, the previous time point is after administration to the selected subject of the T cells expressing the recombinant receptor and either at or before the time when the peak or maximum level of T cells expressing the recombinant receptor becomes detectable in the subject's blood; at a time within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days or more before the determination or selection.

[0020] In some embodiments of any of the methods provided herein, at the time of administration of the T cell therapy, the subject has a disease or condition; at the time of administration of the T cell therapy and at the time of administration of the compound, the subject has a disease or condition; at the time of administration of the T cell therapy, the subject has a disease or condition and at the time of administration of the compound, in the subject after administration of the T cell therapy, the disease or condition is considered to be recurrent, or progressive, or non-responsive to the compound.

[0021] In some embodiments of any of the methods provided herein, an exhausted phenotype for a T cell or population of T cells includes an increase in the level or degree of surface expression of one or more exhaustion markers, optionally 2, 3, 4, 5, or 6 exhaustion markers, on one or more T cells, or the percentage of the population of T cells that exhibit surface expression, compared to a reference T cell population under the same conditions. In other embodiments, an exhausted phenotype for a T cell or population of T cells includes a decrease in the level or degree of activity exhibited by the T cell or population of T cells upon exposure to an antigen or antigen receptor-specific agent, compared to a reference T cell population under the same conditions.

[0022] In some embodiments of any of the methods provided herein, an increase in a level, degree, or percentage is 1.2-fold or about 1.2-fold, 1.5-fold or about 1.5-fold, 2.0-fold or about 2.0-fold, 3-fold or about 3-fold, 4-fold or about 4-fold, 5-fold or about 5-fold, 6-fold or about 6-fold, 7-fold or about 7-fold, 8-fold or about 8-fold, 9-fold or about 9-fold, 10-fold or about 10-fold, or greater than any of these. In some embodiments, a decrease in a level, degree, or percentage is 1.2-fold or about 1.2-fold, 1.5-fold or about 1.5-fold, 2.0-fold or about 2.0-fold, 3-fold or about 3-fold, 4-fold or about 4-fold, 5-fold or about 5-fold, 6-fold or about 6-fold, 7-fold or about 7-fold, 8-fold or about 8-fold, 9-fold or about 9-fold, 10-fold or about 10-fold, or greater than any of these.

[0023] In some embodiments of any of the methods provided herein, the reference T cell population is optionally a population of T cells having a non-depleted phenotype that is from the same subject from which one or more T cells having a depleted phenotype are derived, or of the same species as the subject, or is a population of naive T cells, or a population of central memory T cells, or a population of stem central memory T cells. In some embodiments, the reference T cell population is (a) a population matched to the subject that includes bulk T cells isolated from the blood of the subject from which one or more T cells having a depleted phenotype are derived, optionally, the bulk T cells do not express a recombinant receptor, and / or (b) obtained from a subject from which one or more T cells having a depleted phenotype are derived, prior to administration of a dose of T cells that express a recombinant receptor. In other embodiments, the reference T cell population is a composition comprising a sample of a T cell therapy, or a pharmaceutical composition comprising T cells that express a recombinant receptor, prior to its administration to the subject, optionally, the composition is a cryopreserved sample.

[0024] In some aspects of any of the methods provided herein, one or more of the one or more depleting markers are inhibitory receptors. In some aspects, one or more of the one or more depleting markers are selected from among PD-1, CTLA-4, TIM-3, LAG-3, BTLA, 2B4, CD160, CD39, VISTA, and TIGIT. In some aspects, the activity is one or more of proliferation, cytotoxicity, or production of one or a combination of inflammatory cytokines, and optionally, the one or combination of cytokines is selected from IL-2, IFN-gamma, and TNF-alpha. In some aspects, the exposure to the antigen or antigen receptor-specific agent comprises incubation with the antigen or antigen receptor-specific agent, optionally an agent that binds to a recombinant receptor, and the antigen is optionally a target antigen.

[0025] In some aspects of any of the methods provided herein, the antigen or antigen receptor-specific agent includes antigen-expressing target cells, optionally including cells of said disease, disorder, or condition. In some aspects, the target antigen is associated with, specific to, and / or expressed on cells or tissues of a disease, disorder, or condition. In certain aspects, the target antigen is a tumor antigen. In some aspects, the target antigen is αvβ6 integrin (avb6 integrin), B cell maturation antigen (BCMA), BAFF-R, B7-H3, B7-H6, carbonic anhydrase 9 (CA9; also known as CAIX or G250), cancer / testis antigen, cancer / testis antigen 1B (CTAG; also known as NY-ESO-1 and LAGE-2), carcinoembryonic antigen (CEA), cyclin, cyclin A2, C-C motif chemokine ligand 1 (CCL-1), CD19, CD20, CD22, CD23, CD24, CD30, CD33, CD38, CD44, CD44v6, CD44v7 / 8, CD123, CD133, CD138, CD171, CS-1, chondroitin sulfate proteoglycan 4 (CSPG4), epidermal growth factor protein (EGFR), truncated epidermal growth factor protein (tEGFR), epidermal growth factor receptor variant type III (EGFR vIII), epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), ephrin B2, ephrin receptor A2 (EPHa2), estrogen receptor, Fc receptor-like 5 (FCRL5;Fc receptor homolog 5, also known as FCRH5, fetal acetylcholine receptor (fetal AchR), folate-binding protein (FBP), folate receptor alpha, ganglioside GD2, O-acetylated GD2 (OGD2), ganglioside GD3, glycoprotein 100 (gp100), glypican-3 (GPC3), G protein-coupled receptor 5D (GPCR5D), Her2 / neu (receptor tyrosine kinase erb-B2), Her3 (erb-B3), Her4 (erb-B4), erbB dimer, human high molecular weight-melanoma associated antigen (HMW-MAA), hepatitis B surface antigen, human leukocyte antigen A1 (HLA-A1), human leukocyte antigen A2 (HLA-A2), IL-22 receptor alpha (IL-22Rα), IL-13 receptor alpha 2 (IL-13Rα2), kinase insert domain receptor (kdr), kappa light chain, L1 cell adhesion molecule (L1-CAM), CE7 epitope of L1-CAM, leucine rich repeat containing 8 family member A (LRRC8A), Lewis Y, melanoma associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, MAGE-A10, mesothelin (MSLN), c-Met, murine cytomegalovirus (CMV), mucin 1 (MUC1), MUC16, natural killer group 2 member D (NKG2D) ligand, Melan-A (MART-1), neural cell adhesion molecule (NCAM), tumor fetal antigen, preferentially expressed antigen in melanoma (PRAME), progesterone receptor, prostate specific antigen, prostate stem cell antigen (PSCA), prostate specific membrane antigen (PSMA), receptor tyrosine kinase-like orphan receptor 1 (ROR1), survivin, TACI, trophoblast glycoprotein (TPBG; also known as 5T4), tumor associated glycoprotein 72 (TAG72), tyrosinase-related protein 1 (TRP1; also known as TYRP1 or gp75), tyrosinase-related protein 2 (TRP2;Selected from among dopachrome tautomerase, also known as dopachrome delta-isomerase, or DCT, vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor 2 (VEGFR2), Wilms tumor 1 (WT-1), pathogen-specific antigen or pathogen-expressed antigen, or antigen associated with a universal tag, and / or a biotinylated molecule, and / or a molecule expressed by HIV, HCV, HBV or other pathogens.;

[0026] In some embodiments of any of the methods provided herein, the disease or condition is a B cell malignancy or a B cell-derived malignancy. In some embodiments, the target antigen is CD20, CD19, CD22, ROR1, CD45, CD21, CD5, CD33, Ig kappa, Ig lambda, CD79a, CD79b, or CD30. In certain embodiments, the target antigen is CD19. In some embodiments of any of the methods provided herein, the disease or condition is multiple myeloma. In some embodiments, the target antigen is BCMA, G protein-coupled receptor class C group 5 member D (GPRC5D), CD38 (cyclic ADP ribose hydrolase), CD138 (syndecan-1, syndecan, SYN-1), CS-1 (CS1, CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24), BAFF-R, TACI, or FcRH5. In certain embodiments, the target antigen is BCMA.

[0027] In some embodiments of any of the methods provided herein, the biological sample is a blood sample. In some embodiments, the biological sample is a tumor sample, optionally a tumor biopsy sample.

[0028] (a) administering a T cell therapy to a subject having cancer, the T cell therapy comprising a dose of T cells expressing a recombinant antigen receptor that binds to a target antigen; and (b) Thalidomide analogs; thalidomide derivatives; compounds that interact with and / or bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of Ikaros (IKZF1); inhibitors of Aiolos (IKZF3); and immunomodulatory compounds selected from compounds that enhance or promote ubiquitination and / or depletion and / or degradation of Ikaros (IKZF1) and / or Aiolos (IKZF3), administering to a subject A method of treatment comprising, whereby, after said therapy and said administration of said compound, factors indicative of increased expansion or activity of T cells expressing a recombinant receptor and factors indicative of durability of response are increased as compared to a reference method, said reference method comprising administering alone in (a) or the administration in (a) without administration of an immunomodulatory compound; said factor indicative of increased expansion or activity being (i) a measurement of the maximum number of T cells observed in the blood or cancer of the subject after said administration, (ii) the number of days elapsed between said administration and the attainment of the maximum number of said T cells in the blood or cancer of the subject, or (iii) the area under the curve (AUC) of CAR-expressing cells over time, (iv) the degree of response in the subject, a method is provided herein.

[0029] In some embodiments of any of the methods provided herein, the measure of durability of response is the time to progression-free survival, overall survival, or duration of best response. In some embodiments, the reference method comprises administration of IL-2.

[0030] A method of treatment is provided herein comprising the following steps: (a) administering to a subject having cancer a T cell therapy, said T cell therapy comprising a dose of T cells expressing a recombinant antigen receptor that binds to a target antigen, and (b) Immunomodulatory compounds selected from thalidomide analogs; thalidomide derivatives; compounds that interact with and / or bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of Ikaros (IKZF1); inhibitors of Aiolos (IKZF3); and compounds that enhance or promote ubiquitination and / or depletion and / or degradation of Ikaros (IKZF1) and / or Aiolos (IKZF3). (1) After exposure of T cells to an antigen or an antigen receptor-specific agent, an increase in the antigen-specific or antigen receptor-driven activity of naive or undepleted T cells in a subject optionally containing T cells expressing the recombinant receptor, compared to the absence of the administration of the compound; or (2) After exposure of T cells to an antigen or an antigen receptor-specific agent, preventing, suppressing, or delaying the onset of a depleted phenotype in naive or undepleted T cells in a subject optionally containing T cells expressing the recombinant receptor, compared to the absence of the administration of the compound; or (3) Reversing the depleted phenotype in depleted T cells in a subject optionally containing T cells expressing the recombinant receptor, compared to the absence of the administration of the compound to the subject. Administering to a subject in an effective amount, duration, and / or frequency therefor.

[0031] In some aspects of any of the methods provided herein, the amount, duration, and / or frequency are effective to (i) result in an increase in antigen-specific or antigen receptor-driven activity and (ii) prevent, suppress, or delay the onset of the exhausted phenotype and / or reverse the exhausted phenotype. In some aspects, the amount, duration, and / or frequency are effective to (i) result in an increase in antigen-specific or antigen receptor-driven activity and (ii) prevent, suppress, or delay the onset of the exhausted phenotype. In other aspects, the amount, duration, and / or frequency are effective to (i) result in an increase in antigen-specific or antigen receptor-driven activity and (ii) prevent, suppress, or delay the onset of the exhausted phenotype and reverse the exhausted phenotype.

[0032] A method of treatment is provided herein that includes the following steps: (a) administering a T cell therapy to a subject having cancer, the T cell therapy including a dose of T cells that express a recombinant antigen receptor that binds to a target antigen; and (b) an immunomodulatory compound selected from thalidomide analogs; thalidomide derivatives; compounds that interact with and / or bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of ikaros (IKZF1); inhibitors of aiolos (IKZF3); and compounds that enhance or promote ubiquitination and / or depletion and / or degradation of ikaros (IKZF1) and / or aiolos (IKZF3), (1) resulting in an increase in antigen-specific or antigen receptor-driven activity of naive or unexhausted T cells, optionally including T cells that express the recombinant receptor, in a subject compared to in the absence of administration of the compound after exposure of the T cells to an antigen or an antigen receptor-specific agent; or (2) After exposure of T cells to an antigen or an antigen receptor-specific agent, preventing, suppressing, or delaying the onset of an exhausted phenotype in naive or unexhausted T cells in a subject optionally containing T cells expressing the recombinant receptor, compared to in the absence of said administration of the compound; or (3) Reversing an exhausted phenotype in exhausted T cells in a subject optionally containing T cells expressing the recombinant receptor, compared to in the absence of said administration of the subject. Administering to a subject in an amount, duration, and / or frequency effective therefor.

[0033] In some embodiments of any of the methods provided herein, the amount, duration, and / or frequency is effective to (i) result in an increase in antigen-specific or antigen receptor-driven activity and (ii) prevent, suppress, or delay the onset of the exhausted phenotype and / or reverse the exhausted phenotype. In some embodiments, the amount, duration, and / or frequency is effective to (i) result in an increase in antigen-specific or antigen receptor-driven activity and (ii) prevent, suppress, or delay the onset of the exhausted phenotype. In other embodiments, the amount, duration, and / or frequency is effective to (i) result in an increase in antigen-specific or antigen receptor-driven activity and (ii) prevent, suppress, or delay the onset of the exhausted phenotype and reverse the exhausted phenotype.

[0034] In some embodiments of any of the methods provided herein, the immunomodulatory compound is administered in an effective amount of 1 mg to 50 mg or about 1 mg to 50 mg per day of administration, 1 mg to 25 mg or about 1 mg to 25 mg per day of administration, 1 mg to 10 mg or about 1 mg to 10 mg per day of administration, 1 mg to 5 mg or about 1 mg to 5 mg per day of administration, 5 mg to 50 mg or about 5 mg to 50 mg per day of administration, 5 mg to 25 mg or about 5 mg to 25 mg per day of administration, 5 mg to 10 mg or about 5 mg to 10 mg per day of administration. In some embodiments, administration of the compound is carried out in a cycling regimen that includes administration of an effective amount of the compound (i) daily over a period longer than 1 week, (ii) daily for no more than 6 days per week over a period longer than 1 week, (ii) daily for no more than 5 days per week over a period longer than 1 week; or (iv) daily for no more than 4 days per week over a period longer than 1 week. In certain embodiments, administration of the compound is carried out in a cycling regimen that includes administration of an effective amount of the compound daily for no more than 5 days per week over a period longer than 1 week.

[0035] In some embodiments of any of the methods provided herein, the compound depletes or degrades Ikaros (IKZF1).

[0036] In some embodiments of any of the methods provided herein, the compound has the following structure: The compound of TIFF2025087780000001.tif24128, or a pharmaceutically acceptable salt thereof, wherein One of X and Y is -C(O)- and the other of X and Y is -C(O)- or -CH 2 -; (1)R 1 , R 2 , R 3 , and R 4Each of them is independently a halo, alkyl of 1 to 4 carbon atoms, or alkoxy or has 1 to 4 carbon atoms, or (2)R 1 、R 3 、R 4 、and R 5 One of them is -NHR a where R 1 、R 2 、R 3 、and R 4 The rest are hydrogen, where R a is hydrogen or alkyl of 1 to 8 carbon atoms; R 5 is hydrogen or alkyl of 1 to 8 carbon atoms, benzyl, or halo; Provided that X and Y are -C(O)- and (i) each of R 1 、R 2 、R 3 、and R 4 is fluoro; or (ii) when one of R 1 、R 2 、R 3 、and R 4 is amino, R 5 is other than hydrogen.

[0037] In some embodiments of any of the methods provided herein, the compound has the following structure: The compound of TIFF2025087780000002.tif21128, or a pharmaceutically acceptable salt thereof, wherein one of X and Y is -C(O)- and the other of X and Y is -C(O)- or -CH 2 - and R 5 is hydrogen or lower alkyl. In some embodiments, the compound has the following structure: 3-(4-Amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione having TIFF2025087780000003.tif23128, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, inclusion compound, or polymorph thereof, or comprising the same. In some embodiments, the compound is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione.

[0038] In some embodiments, the compound has the following structure: 3-(5-Amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione having TIFF2025087780000004.tif29128, or a compound comprising the same, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, inclusion compound, or polymorph thereof (also referred to as Compound 1). In some embodiments, the compound is 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

[0039] In some embodiments of any of the methods provided herein, the immunomodulatory compound is administered in an effective amount of 1 mg to 50 mg or about 1 mg to 50 mg, 1 mg to 25 mg or about 1 mg to 25 mg, 1 mg to 10 mg or about 1 mg to 10 mg, 1 mg to 5 mg or about 1 mg to 5 mg, 5 mg to 50 mg or about 5 mg to 50 mg, 5 mg to 25 mg or about 5 mg to 25 mg, 5 mg to 10 mg or about 5 mg to 10 mg per day, and optionally, the administration is daily over a period of a cycling regimen.

[0040] In some embodiments of any of the methods provided herein, the compound has the following structure: The compound of TIFF2025087780000005.tif24128, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein, Z is C=O or CH 2 and; R 11 is -Z 1 -R 13 and; R 12 is H or (C 1 -C 6 ) alkyl; Z 1 is a 6- to 10-membered aryl, heteroaryl, or heterocycle, each of which may be substituted with one or more halogens; or a bond; R 13 is -(CH 2 ) n -aryl, -O-(CH 2 ) n -aryl, or -(CH 2 ) n -O-aryl (wherein aryl may be substituted with one or more of the following: (C 1 -C 6 ) alkyl; itself substituted with one or more halogens; (C 1 -C 6 ) alkoxy, itself substituted with one or more halogens; oxo; amino; carboxyl; cyano; hydroxyl; halogen; deuterium; one or more (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, or halogen-substituted 6- to 10-membered aryl or heteroaryl; -CONH 2 ; or -COO-(C 1 -C 6 ) alkyl (wherein alkyl may be substituted with one or more halogens)); -(CH 2 ) n -heterocycle, -O-(CH 2 ) n-Complex ring, or -(CH 2 ) n -O-complex ring (wherein the complex ring may be substituted with one or more of the following: (C 1 -C 6 )alkyl, itself optionally substituted with one or more halogens; (C 1 -C 6 )alkoxy, itself substituted with one or more halogens; oxo; amino; carboxyl; cyano; hydroxyl; halogen; deuterium; one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or aryl or heteroaryl of 6 to 10 members optionally substituted with halogen; -CONH 2 ; or -COO-(C 1 -C 6 )alkyl (wherein the alkyl may be optionally substituted with one or more halogens)); or -(CH 2 ) n -Heteroaryl, -O-(CH 2 ) n -Heteroaryl, or -(CH 2 ) n -O-heteroaryl (wherein the heteroaryl may be optionally substituted with one or more of the following: (C 1 -C 6 )alkyl, itself optionally substituted with one or more halogens; (C 1 -C 6 )alkoxy, itself substituted with one or more halogens; oxo; amino; carboxyl; cyano; hydroxyl; halogen; deuterium; one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or aryl or heteroaryl of 6 to 10 members optionally substituted with halogen; -CONH 2 ; or -COO-(C 1 -C 6Alkyl (wherein the alkyl may be substituted with one or more halogens)) and; and n is 0, 1, 2, or 3.

[0041] In some embodiments, the compound is TIFF2025087780000006.tif27128 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In certain embodiments, the compound is the A crystal form of the hydrochloride salt of TIFF2025087780000007.tif27128. In some embodiments the XRPD pattern of the A crystal form of the hydrochloride salt of TIFF2025087780000008.tif27128 has XRPD peaks located at or approximately at the following positions: 9.69, 12.82, 15.09, 15.94, 16.76, 17.65, 19.44, 19.80, 22.30, 22.47, 22.95, 23.02, 24.29, 24.48, 24.70, 26.27, 26.77, 27.60, 29.43, 29.72, and 32.91 degrees of 2θ, characterized by having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or all of them.

[0042] In some embodiments of any of the methods provided herein, the immunomodulatory compound is administered at 0.1 mg to 1 mg or about 0.1 mg to 1 mg per day, 0.1 mg to 0.6 mg or about 0.1 mg to 0.6 mg per day, 0.1 mg to 0.3 mg or about 0.1 mg to 0.3 mg per day, and optionally, the administration is daily over a period in a cycling regimen.

[0043] A method of treatment is provided herein, comprising the following steps: (a) administering T cell therapy to a subject having cancer, the T cell therapy comprising a dose of T cells expressing a recombinant antigen receptor that binds to a target antigen; and (b) to the subject, the following structure: Administering a compound having TIFF2025087780000009.tif36128, 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or a compound containing the same, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion compound, or polymorph (Compound 1), wherein the administration of the compound comprises administering an effective amount of the compound per day for no more than 5 days per week over a period longer than 1 week, in a cycling regimen.

[0044] In some embodiments of any of the methods provided herein, administration of the compound is initiated subsequent to initiation of administration of the T cell therapy. In some embodiments, administration of the compound is initiated simultaneously with the T cell therapy and / or within 1 day before or after initiation of administration of the T cell therapy.

[0045] In some embodiments, administration of the compound is initiated 1 day or about 1 day, or within 1 day or about 1 day, before or after initiation of administration of the T cell therapy.

[0046] To a subject having cancer, the following structure: A method of treatment comprising administering a compound having TIFF2025087780000010.tif36128, 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or a compound containing the same, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion compound, or polymorph (Compound 1), wherein the subject has been administered a T cell therapy comprising a dose of genetically engineered T cells expressing a recombinant antigen receptor prior to administration of the compound, and the administration of the compound is carried out in a cycling regimen comprising administration of an effective amount of the compound per day for no more than 5 days per week over a period longer than 1 week, is provided herein. In some embodiments, the cancer is a B cell malignancy, a B cell-derived malignancy, a non-blood cancer, or a solid tumor.

[0047] In some embodiments of any of the methods provided herein, the target antigen is a tumor antigen, and optionally, the target antigen is associated with and specific to cancer cells or tissues and / or is expressed thereon. In some embodiments, the target antigen is B cell maturation antigen (BCMA), αvβ6 integrin (avb6 integrin), BAFF-R, B7-H3, B7-H6, carbonic anhydrase 9 (CA9; also known as CAIX or G250), cancer testis antigen, cancer / testis antigen 1B (CTAG; also known as NY-ESO-1 and LAGE-2), carcinoembryonic antigen (CEA), cyclin, cyclin A2, C-C motif chemokine ligand 1 (CCL-1), CD5, CD19, CD20, CD21, CD22, CD23, CD24, CD30, CD38, CD44, CD44v6, CD44v7 / 8, CD45, CD79a, CD79b, CD123, CD133, CD138, CD171, CS-1, chondroitin sulfate proteoglycan 4 (CSPG4), epidermal growth factor protein (EGFR), truncated epidermal growth factor protein (tEGFR), epidermal growth factor receptor variant type III (EGFR vIII), epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), ephrin B2, ephrin receptor A2 (EPHa2), estrogen receptor, Fc receptor-like 5 (FCRL5;Fc receptor homolog 5, also known as FCRH5, fetal acetylcholine receptor (fetal AchR), folate-binding protein (FBP), folate receptor alpha, ganglioside GD2, O-acetylated GD2 (OGD2), ganglioside GD3, glycoprotein 100 (gp100), glypican-3 (GPC3), G protein-coupled receptor 5D (GPCR5D), Her2 / neu (receptor-type tyrosine kinase erb-B2), Her3 (erb-B3), Her4 (erb-B4), erbB dimer, human high-molecular weight-melanoma-associated antigen (HMW-MAA), hepatitis B surface antigen, human leukocyte antigen A1 (HLA-A1), human leukocyte antigen A2 (HLA-A2), Ig kappa, Ig lambda, IL-22 receptor alpha (IL-22Rα), IL-13 receptor alpha 2 (IL-13Rα2), kinase insert domain receptor (kdr), L1 cell adhesion molecule (L1-CAM), CE7 epitope of L1-CAM, leucine-rich repeat-containing 8 family member A (LRRC8A), Lewis Y, melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, MAGE-A10, mesothelin (MSLN), c-Met, murine cytomegalovirus (CMV), mucin 1 (MUC1), MUC16, natural killer group 2 member D (NKG2D) ligand, Melan-A (MART-1), neural cell adhesion molecule (NCAM), tumor fetal antigen, melanoma-predominantly expressed antigen (PRAME), progesterone receptor, prostate-specific antigen, prostate stem cell antigen (PSCA), prostate-specific membrane antigen (PSMA), ROR1, survivin, TACI, trophoblast glycoprotein (TPBG; also known as 5T4), tumor-associated glycoprotein 72 (TAG72), tyrosinase-related protein 1 (TRP1; also known as TYRP1 or gp75), tyrosinase-related protein 2 (TRP2;(also known as dopachrome tautomerase, dopachrome delta-isomerase, or DCT), vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor 2 (VEGFR2), Wilms tumor 1 (WT-1), a pathogen-specific antigen or a pathogen-expressed antigen. In certain embodiments, the B cell malignancy is a lymphoma. In some embodiments, the lymphoma is a non-Hodgkin lymphoma (NHL). In some embodiments, the NHL is an aggressive NHL, diffuse large B cell lymphoma (DLBCL), DLBCL-NOS, optionally transformed low grade; EBV-positive DLBCL-NOS; T cell / histiocyte-rich large B cell lymphoma; primary mediastinal large B cell lymphoma (PMBCL); follicular lymphoma (FL), optionally, follicular lymphoma grade 3B (FL3B); and / or high grade B cell lymphoma with rearrangement of MYC and BCL2 and / or BCL6 with a DLBCL histology (double / triple hit).;

[0048] In some embodiments of any of the methods provided herein, the subject is identified or is identified as having a status of Eastern Cooperative Oncology Group Performance Status (ECOG) of 1 or less.

[0049] In some embodiments of any of the methods provided herein, the target antigen is CD20, CD19, CD22, ROR1, CD45, CD21, CD5, CD33, Ig kappa, Ig lambda, CD79a, CD79b, or CD30. In certain embodiments, the target antigen is CD19. In some embodiments, the target antigen is not CD20, CD19, CD22, ROR1, CD45, CD21, CD5, CD33, Ig kappa, Ig lambda, CD79a, CD79b, or CD30. In some embodiments, the cancer is multiple myeloma. In some embodiments, the target antigen is BCMA, G protein-coupled receptor class C group 5 member D (GPRC5D), CD38 (cyclic ADP-ribose hydrolase), CD138 (syndecan-1, syndecan, SYN-1), CS-1 (CS1, CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24), BAFF-R, TACI, or FcRH5.

[0050] In some embodiments of any of the methods provided herein, at the end of a period, if the subject exhibits partial response (PR) or stable disease (SD), the method further comprises continuing the cycling regimen after the end of the period. In some embodiments, at 6 months or about 6 months, if the subject exhibits partial response (PR) or stable disease (SD) after treatment, the cycling regimen is continued for more than 6 months. In other embodiments, the cycling regimen is continued until the subject achieves a complete response (CR) after treatment, or until the cancer progresses or recurs following remission after treatment.

[0051] In some aspects of any of the methods provided herein, administration of the compound is initiated at or after the time when the peak or maximum level of the cells of the T cell therapy becomes detectable in the subject's blood. In some aspects, administration of the compound is initiated about 14 to about 35 days after the start of administration of the T cell therapy. In certain aspects, administration of the compound is initiated about 21 to about 35 days after the start of administration of the T cell therapy. In other aspects, administration of the compound is initiated about 21 to about 28 days after the start of administration of the T cell therapy. In some aspects, administration of the compound is initiated 21 days or about 21 days, 22 days or about 22 days, 23 days or about 23 days, 24 days or about 24 days, 25 days or about 25 days, 26 days or about 26 days, 27 days or about 27 days, or 28 days or about 28 days after the start of administration of the T cell therapy. In certain aspects, administration of the compound is initiated 28 days or about 28 days after the start of administration of the T cell therapy. In some aspects of any of the methods provided herein, at the start of administration of the compound, the subject does not exhibit severe toxicity after administration of the T cell therapy.

[0052] In some aspects of any of the methods provided herein, severe toxicity is severe cytokine release syndrome (CRS), optionally grade 3 or higher, persistent grade 3 or higher, or grade 4 or 5 CRS; and / or severe toxicity is severe neurotoxicity, optionally grade 3 or higher, persistent grade 3 or higher, or grade 4 or 5 neurotoxicity.

[0053] In some embodiments of any of the methods provided herein, if a subject exhibits toxicity, optionally hematotoxicity, after administration of a compound, administration of the compound is stopped and / or the cycling regimen is modified. In some embodiments, the toxicity is selected from severe neutropenia, optionally febrile neutropenia, and prolonged grade 3 or higher neutropenia. In some embodiments, administration of the compound is resumed after the subject no longer exhibits toxicity. In some embodiments, the cycling regimen is modified after administration of the compound is resumed. In some embodiments, the modified cycling regimen includes administering a reduced amount of the compound and / or decreasing the frequency of administration of the compound. In certain embodiments, the modified cycling regimen includes administering a reduced amount of the compound. In some embodiments, the dose of the compound is reduced, and the reduced amount is from 1 mg or about 1 mg to 2 mg or about 2 mg per day for no more than 5 days per week. In some embodiments, the reduced amount is 1 mg or about 1 mg or 2 mg or about 2 mg per day for no more than 5 days per week. In some embodiments, the cycling regimen is not modified after administration of the compound is resumed. In some embodiments, the cycling regimen includes administering a compound at about 2 mg or less per day for no more than 5 days per week. In certain embodiments, the cycling regimen includes administering a compound at 1 mg or about 1 mg per day for no more than 5 days per week.

[0054] In some embodiments of any of the methods provided herein, the compound is a solvate of or comprises (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione. In some embodiments, the compound is or comprises (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione.

[0055] In some embodiments of any of the methods provided herein, the compound is a solvate of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione or comprises the same. In some embodiments, the compound is a hydrate of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione or comprises the same. In some embodiments, the compound is a pharmaceutically acceptable salt of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione or comprises the same. In certain embodiments, the compound is 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione or comprises the same.

[0056] In some embodiments of any of the methods provided herein, the compound is administered orally. In some embodiments, if the subject has achieved complete response (CR) at 6 months, the period extends for 6 months or about 6 months after the start of administration of the T cell therapy. In other embodiments, the cycling regimen is continued over the duration even if the subject has achieved complete response (CR) at a point prior to the end of the period. In some embodiments, the subject achieves complete response (CR) during and prior to the end of the period.

[0057] In some embodiments of any of the methods provided herein, if at the end of the period the subject exhibits partial response (PR) or stable disease (SD), the method further comprises continuing the cycling regimen after the end of the period. In some embodiments of any of the methods provided herein, if at 6 months or about 6 months after treatment the subject exhibits partial response (PR) or stable disease (SD), the cycling regimen is continued for more than 6 months. In some embodiments, the cycling regimen is continued until the subject achieves complete response (CR) after treatment or until the cancer progresses or recurs following remission after treatment.

[0058] In some embodiments of any of the methods provided herein, administration of the compound is initiated at or after the time when the peak or maximum level of the cells of the T cell therapy becomes detectable in the subject's blood. In some embodiments of any of the methods provided herein, administration of the compound is initiated about 14 to about 35 days after the start of administration of the T cell therapy. In some embodiments of any of the methods provided herein, administration of the compound is initiated about 21 to about 35 days after the start of administration of the T cell therapy. In some embodiments of any of the methods provided herein, administration of the compound is initiated about 21 to about 28 days after the start of administration of the T cell therapy. In some embodiments of any of the methods provided herein, administration of the compound is initiated 21 days or about 21 days, 22 days or about 22 days, 23 days or about 23 days, 24 days or about 24 days, 25 days or about 25 days, 26 days or about 26 days, 27 days or about 27 days, or 28 days or about 28 days after the start of administration of the T cell therapy.

[0059] In some embodiments of any of the methods provided herein, administration of the compound is initiated 28 days or about 28 days after the start of administration of the T cell therapy. In some embodiments of any of the methods provided herein, at the start of administration of the compound, the subject does not exhibit severe toxicity after administration of the T cell therapy. In some embodiments, severe toxicity is severe cytokine release syndrome (CRS), optionally grade 3 or higher, long-term grade 3 or higher, or grade 4 or 5 CRS; and / or severe toxicity is severe neurotoxicity, optionally grade 3 or higher, long-term grade 3 or higher, or grade 4 or 5 neurotoxicity.

[0060] In some aspects of any of the methods provided herein, if a subject exhibits toxicity, optionally hematotoxicity, after administration of a compound, administration of the compound is stopped and / or the cycling regimen is modified. In some aspects, the toxicity is selected from severe neutropenia, optionally febrile neutropenia, and prolonged grade 3 or higher neutropenia. In some aspects, administration of the compound is resumed after the subject no longer exhibits toxicity. In some aspects, the cycling regimen is modified after administration of the compound is resumed. In some aspects, the modified cycling regimen includes administering a reduced amount of the compound and / or decreasing the frequency of administration of the compound. In certain aspects, the modified cycling regimen includes administering a reduced amount of the compound. In some aspects, the dose of the compound is reduced, and the reduced amount is from 1 mg or about 1 mg to 2 mg or about 2 mg per day for no more than 5 days per week. In certain aspects, the reduced amount is 1 mg or about 1 mg or 2 mg or about 2 mg per day for no more than 5 days per week. In some aspects, the cycling regimen is not modified after administration of the compound is resumed. In some aspects, the cycling regimen includes administration of the compound at about 2 mg or less per day for no more than 5 days per week. In some aspects, the cycling regimen includes administration of the compound at 1 mg or about 1 mg per day for no more than 5 days per week.

[0061] In some embodiments of any of the methods provided herein, the compound is a solvate of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione or comprises the same. In some embodiments of any of the methods provided herein, the compound is a hydrate of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione or comprises the same. In some embodiments of any of the methods provided herein, the compound is a pharmaceutically acceptable salt of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione or comprises the same. In some embodiments of any of the methods provided herein, the compound is 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione or comprises the same. In some embodiments of any of the methods provided herein, the compound is administered orally.

[0062] In some embodiments of any of the methods provided herein, administration of the compound reverses an exhausted phenotype in recombinant receptor-expressing T cells in a subject; prevents, suppresses, or delays the onset of an exhausted phenotype in recombinant receptor-expressing T cells in a subject; or reduces the level or degree of an exhausted phenotype in recombinant receptor-expressing T cells in a subject; or reduces the percentage of the total number of recombinant receptor-expressing T cells in a subject that have an exhausted phenotype.

[0063] In some embodiments of any of the methods provided herein, initiation of administration of the compound is subsequent to administration of a T cell therapy, and following administration of the compound or initiation thereof, the subject demonstrates recovery or rescue of antigen-specific or tumor-specific activity or function of recombinant receptor-expressing T cells in the subject, and optionally, the recovery, rescue, and / or initiation of administration of the compound is at a time point after recombinant receptor-expressing T cells in the subject or in the subject's blood have demonstrated an exhausted phenotype.

[0064] In some embodiments of any of the methods provided herein, administration of the compound results in an increase in antigen-specific or antigen receptor-driven activity of naive or undepleted T cells in a subject optionally comprising T cells expressing the recombinant receptor, as compared to in the absence of said administration of the compound, after exposure of the T cells to an antigen or an antigen receptor-specific agent; or (b) prevents, suppresses, or delays the onset of a depleted phenotype in naive or undepleted T cells in a subject optionally comprising T cells expressing the recombinant receptor, as compared to in the absence of said administration of the compound, after exposure of the T cells to an antigen or an antigen receptor-specific agent; or (c) administration in an amount, frequency, and / or duration effective to reverse a depleted phenotype in depleted T cells in a subject optionally comprising T cells expressing the recombinant receptor, as compared to in the absence of said administration of the compound to the subject. In some embodiments, administration of the compound comprises administration in an amount, frequency, and / or duration effective to (i) result in an increase in said activity and (ii) prevent, suppress, or delay the onset of said depleted phenotype and / or reverse said depleted phenotype. In some embodiments, the T cells in the subject comprise T cells expressing the recombinant receptor and / or the antigen is a target antigen.

[0065] In some aspects of any of the methods provided herein, an exhausted phenotype for a T cell or population of T cells is an increase in the level or degree of surface expression of one or more exhaustion markers, optionally two, three, four, five, or six exhaustion markers, on one or more T cells, or the percentage of T cells in the population that exhibit surface expression, compared to a reference T cell population under the same conditions; or a decrease in the level or degree of activity exhibited by the T cell or population of T cells upon exposure to an antigen or antigen receptor-specific agent, compared to a reference T cell population under the same conditions. In some aspects, the increase in level, degree, or percentage is 1.2-fold or about 1.2-fold, 1.5-fold or about 1.5-fold, 2.0-fold or about 2.0-fold, 3-fold or about 3-fold, 4-fold or about 4-fold, 5-fold or about 5-fold, 6-fold or about 6-fold, 7-fold or about 7-fold, 8-fold or about 8-fold, 9-fold or about 9-fold, 10-fold or about 10-fold, or greater than 10-fold. In other aspects, the decrease in level, degree, or percentage is 1.2-fold or about 1.2-fold, 1.5-fold or about 1.5-fold, 2.0-fold or about 2.0-fold, 3-fold or about 3-fold, 4-fold or about 4-fold, 5-fold or about 5-fold, 6-fold or about 6-fold, 7-fold or about 7-fold, 8-fold or about 8-fold, 9-fold or about 9-fold, 10-fold or about 10-fold, or greater than 10-fold.

[0066] In some aspects of any of the methods provided herein, the reference T cell population is optionally a population of T cells known to have a non-exhausted phenotype that is from the same subject from which one or more T cells having an exhausted phenotype are derived, or of the same species as the subject, or a population of naive T cells, or a population of central memory T cells, or a population of stem central memory T cells.

[0067] In some aspects of any of the methods provided herein, the reference T cell population is a population matched to a subject comprising bulk T cells isolated from the blood of a subject from which one or more T cells having an exhausted phenotype are derived, optionally, the bulk T cells do not express a recombinant receptor, and / or (b) are obtained from a subject from which one or more T cells having an exhausted phenotype are derived prior to administration of a dose of T cells that express a recombinant receptor. In some aspects, the reference T cell population is a composition comprising a sample of a T cell therapy, or a pharmaceutical composition comprising T cells that express a recombinant receptor, prior to its administration to a subject, optionally, the composition is a cryopreserved sample.

[0068] In some aspects of any of the methods provided herein, one or more exhaustion markers are inhibitory receptors. In some aspects, one or more exhaustion markers are selected from PD-1, CTLA-4, TIM-3, LAG-3, BTLA, 2B4, CD160, CD39, VISTA, and TIGIT.

[0069] In some aspects of any of the methods provided herein, the activity is one or more of proliferation, cytotoxicity, or production of one or a combination of inflammatory cytokines, optionally, the cytokine or combination of cytokines is selected from IL-2, IFN-gamma, and TNF-alpha. In some aspects, the exposure to the antigen or antigen receptor-specific agent comprises incubation with the antigen or antigen receptor-specific agent, optionally, an agent that binds to a recombinant receptor, the antigen is optionally a target antigen. In some aspects, the antigen or antigen receptor-specific agent comprises antigen-expressing target cells, optionally, cells of the disease, disorder, or condition. In certain aspects, the target antigen is a human antigen.

[0070] In some aspects of any of the methods provided herein, the subject is human. In some aspects of any of the methods provided herein, the recombinant antigen receptor is a chimeric antigen receptor that specifically binds to a target antigen. In some aspects, the chimeric antigen receptor (CAR) comprises an extracellular antigen recognition domain that specifically binds to a target antigen and an intracellular signaling domain that contains an ITAM. In some aspects, the intracellular signaling domain comprises the CD3-zeta (CD3ζ) chain, optionally including the signaling domain of the human CD3-zeta chain. In some aspects, the chimeric antigen receptor (CAR) further comprises a co-stimulatory signaling region. In other aspects, the co-stimulatory signaling region comprises CD28 or 4-1BB, optionally including the signaling domain of human CD28 or human 4-1BB. In some aspects, the co-stimulatory domain is or comprises the signaling domain of human 4-1BB.

[0071] In some aspects of any of the methods provided herein, the CAR comprises a scFv specific for a target antigen; a transmembrane domain; optionally, a cytoplasmic signaling domain derived from a costimulatory molecule, which may be or include 4-1BB, optionally human 4-1BB; and optionally, a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule, which may be or include a CD3 zeta signaling domain, optionally a human CD3 zeta signaling domain; and optionally, the CAR further comprises a spacer between the transmembrane domain and the scFv; the CAR comprises, in order, a scFv specific for a target antigen; a transmembrane domain; optionally, a cytoplasmic signaling domain derived from a costimulatory molecule, which may be or include a 4-1BB signaling domain, optionally a human 4-1BB signaling domain; and optionally, a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule, which is a CD3 zeta signaling domain; or the CAR comprises, in order, a scFv specific for a target antigen; a spacer; a transmembrane domain, optionally, a cytoplasmic signaling domain derived from a costimulatory molecule which is a 4-1BB signaling domain, and optionally, a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule, which may be or include a CD3 zeta signaling domain.

[0072] In some aspects of any of the methods provided herein, the dose of genetically engineered T cells is 1×10 5 ~5×10 8 or about 1×10 5 ~5×10 8 total CAR-expressing T cells, 1×10 6 ~2.5×10 8 or about 1×10 6 ~2.5×10 8 total CAR-expressing T cells, 5×10 6 ~1×10 8 or about 5×10 6 ~1×10 8 total CAR-expressing T cells, 1×10 7 ~2.5×10 8or about 1×10 7 ~2.5×10 8 total CAR-expressing T cells, 5×10 7 ~1×10 8 or about 5×10 7 ~1×10 8 total CAR-expressing T cells (including the values at both ends). In some embodiments of any of the methods provided herein, the dose of genetically engineered T cells is at least 1×10 5 or at least about 1×10 5 CAR-expressing cells, at least 2.5×10 5 or at least about 2.5×10 5 CAR-expressing cells, at least 5×10 5 or at least about 5×10 5 CAR-expressing cells, at least 1×10 6 or at least about 1×10 6 CAR-expressing cells, at least 2.5×10 6 or at least about 2.5×10 6 CAR-expressing cells, at least 5×10 6 or at least about 5×10 6 CAR-expressing cells, at least 1×10 7 or at least about 1×10 7 CAR-expressing cells, at least 2.5×10 7 or at least about 2.5×10 7 CAR-expressing cells, at least 5×10 7 or at least about 5×10 7 CAR-expressing cells, at least 1×10 8 or at least about 1×10 8 CAR-expressing cells, at least 2.5×10 8 or at least about 2.5×10 8 CAR-expressing cells, or at least 5×10 8 or at least about 5×10 8 CAR-expressing cells. In certain embodiments, the dose of genetically engineered T cells is 5×10 7 or about 5×10 7comprises total CAR-expressing T cells. In other embodiments, the dose of the genetically engineered T cells is 1×10 8 or about 1×10 8 CAR-expressing cells.

[0073] In some embodiments of any of the methods provided herein, the dose of the cells is administered parenterally, optionally intravenously.

[0074] In some embodiments of any of the methods provided herein, the T cells are primary T cells obtained from a subject. In some embodiments, the T cells are autologous to the subject. In other embodiments, the T cells are allogeneic to the subject.

[0075] In some embodiments of any of the methods provided herein, the dose of the genetically engineered T cells comprises CD4+ T cells expressing CAR and CD8+ T cells expressing CAR, and administration of the dose comprises administering a plurality of separate compositions, the plurality of separate compositions comprising a first composition comprising one of CD4+ T cells and CD8+ T cells, and a second composition comprising the other of CD4+ T cells or CD8+ T cells.

[0076] In some embodiments of any of the methods provided herein, prior to administration, the subject is preconditioned with lymphodepletion therapy comprising administration of fludarabine and / or cyclophosphamide. In some embodiments of any of the methods provided herein, the method further comprises administering to the subject, immediately prior to administration, lymphodepletion therapy comprising administration of fludarabine and / or cyclophosphamide. In some embodiments, the lymphodepletion therapy is about 200-400 mg / m 2 , optionally 300 mg / m 2 or about 300 mg / m 2 (including both end values) of cyclophosphamide, and / or about 20-40 mg / m 2 , optionally 30 mg / m 2including daily administration of fludarabine for 2 to 4 days, optionally 3 days, or lymphodepletion therapy includes administration of about 500 mg / m 2 of cyclophosphamide. In some embodiments, lymphodepletion therapy is 300 mg / m 2 or about 300 mg / m 2 of cyclophosphamide and about 30 mg / m 2 of fludarabine, including daily administration for 3 days; and / or lymphodepletion therapy is 500 mg / m 2 or about 500 mg / m 2 of cyclophosphamide and about 30 mg / m 2 of fludarabine, including daily administration for 3 days.

[0077] In some embodiments of any of the methods provided herein, at least 35%, at least 40%, or at least 50% of the subjects treated according to the method achieve a complete response (CR) that is durable or durable in at least 60, 70, 80, 90, or 95% of the subjects who achieve CR over 6 months or more or 9 months or more; and / or at least 60, 70, 80, 90, or 95% of the subjects who achieve CR by 6 months remain in response, remain in CR, and / or survive or survive without aversion over 3 months or more and / or 6 months or more and / or 9 months or more; and / or at least 50%, at least 60%, or at least 70% of the subjects treated according to the method achieve an objective response (OR), optionally the OR is durable over 6 months or more or 9 months or more or durable in at least 60, 70, 80, 90, or 95% of the subjects who achieve OR; and / or at least 60, 70, 80, 90, or 95% of the subjects who achieve OR by 6 months remain in response or survive over 3 months or more and / or 6 months or more.

[0078] Also provided herein is a kit comprising: (a) a T cell therapy comprising a dose of T cells expressing a recombinant antigen receptor that binds to a target antigen; and (b) an immunomodulatory compound selected from the group consisting of thalidomide analogs; thalidomide derivatives; compounds that interact with and / or bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of Ikaros (IKZF1); inhibitors of Aiolos (IKZF3); and compounds that enhance or promote ubiquitination and / or depletion and / or degradation of Ikaros (IKZF1) and / or Aiolos (IKZF3); and (c) instructions for administering the compound and / or the T cell therapy according to any of the methods provided herein. [Invention 1001] A method for rescuing T cell activity, comprising: exposing a plurality of T cells having a depleted phenotype to an effective amount of an immunomodulatory compound selected from the group consisting of thalidomide analogs; thalidomide derivatives; compounds that interact with and / or bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of Ikaros (IKZF1); inhibitors of Aiolos (IKZF3); and compounds that enhance or promote ubiquitination, depletion, and / or degradation of Ikaros (IKZF1) and / or Aiolos (IKZF3). [Invention 1002] The method of Invention 1001, wherein the one or more T cells comprise T cells expressing a recombinant receptor that specifically binds to a target antigen. [Invention 1003] A method for increasing T cell activity or efficacy and for preventing or suppressing the onset of T cell depletion, reducing or delaying it, comprising: A method comprising exposing a plurality of T cells to an effective amount of an immunomodulatory compound selected from the group consisting of thalidomide analogs; thalidomide derivatives; compounds that interact with and / or bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of Ikaros (IKZF1); inhibitors of Aiolos (IKZF3); and compounds that enhance or promote the ubiquitination, depletion, and / or degradation of Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein at least a portion of the exposing step is performed under conditions that induce or are capable of inducing a phenotype that is depleted in a plurality of T cells in the absence of the compound, The method. [Inventive Concept 1004] A method for reducing or delaying the onset of T cell depletion, A method comprising exposing a plurality of T cells to an effective amount of an immunomodulatory compound selected from the group consisting of thalidomide analogs; thalidomide derivatives; compounds that interact with and / or bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of Ikaros (IKZF1); inhibitors of Aiolos (IKZF3); and compounds that enhance or promote the ubiquitination, depletion, and / or degradation of Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein at least a portion of the exposing step is performed under conditions that induce or are capable of inducing a phenotype that is depleted in a plurality of T cells in the absence of the compound, The method. [Inventive Concept 1005] The method of Inventive Concept 1003 or Inventive Concept 1004, wherein the conditions comprise T cell stimulating conditions including exposure to at least one T cell stimulatory agent capable of stimulating a signal in a plurality of T cells, the signal optionally including a primary signal and / or a co-stimulatory signal. [Inventive Concept 1006] The method of the present invention 1005, wherein the condition comprises a persistent, repeated, extended, or long-term exposure to at least one T cell stimulant. [The present invention 1007] The method of the present invention 1005 or 1006, wherein the at least one T cell stimulant comprises a polyclonal agent, an antigen specifically recognized by a receptor expressed on a plurality of T cells, or an agent to which an antigen receptor expressed by a plurality of T cells binds. [The present invention 1008] The method according to any one of the present inventions 1005 to 1007, wherein the at least one T cell stimulant comprises an anti-CD3 antibody. [The present invention 1009] The method of the present invention 1008, wherein the at least one T cell stimulant further comprises an agent that specifically binds to a T cell costimulatory molecule, and optionally, the T cell costimulatory molecule is CD28, CD137 (4-1-BB), OX40, CD40L, or ICOS. [The present invention 1010] The method of the present invention 1009, wherein the at least one T cell stimulant comprises an anti-CD28 antibody. [The present invention 1011] The method according to any one of the present inventions 1003 to 1010, wherein one or more of the plurality of T cells express a recombinant antigen receptor that binds to a target antigen. [The present invention 1012] The method of the present invention 1011, wherein the at least one T cell stimulant binds to the recombinant antigen receptor. [The present invention 1013] The method of the present invention 1012, wherein the at least one T cell stimulant is or comprises an anti-idiotype antibody specific for the recombinant antigen receptor. [The present invention 1014] The method of the present invention 1012, wherein the at least one T cell stimulant is or comprises a target antigen or a portion thereof recognized by or bound to the recombinant antigen receptor, and / or the condition comprises an exposure to the target antigen. [The present invention 1015] The method according to any one of aspects 1012 to 1014 of the present invention, wherein the recombinant antigen receptor is a recombinant T cell receptor (TCR). [Aspect 1016 of the present invention] The method according to any one of aspects 1012 to 1014 of the present invention, wherein the recombinant antigen receptor is a chimeric antigen receptor (CAR). [Aspect 1017 of the present invention] The method according to any one of aspects 1001 to 1016 of the present invention, wherein one or more T cells are optionally primary human T cells derived from a subject. [Aspect 1018 of the present invention] The method according to any one of aspects 1001 to 1017 of the present invention, wherein the step of exposing is performed ex vivo. [Aspect 1019 of the present invention] The method according to any one of aspects 1001 to 1017 of the present invention, wherein the step of exposing is performed in vivo. [Aspect 1020 of the present invention] The method according to aspect 1019 of the present invention, wherein the step of exposing comprises administering a compound to a subject, and optionally, the T cells are derived from the subject and the administration of the compound is to the subject. [Aspect 1021 of the present invention] The method according to aspect 1020 of the present invention, wherein the exposure comprises the administration of the compound, and prior to the step of exposing, the subject has been administered a composition comprising a plurality of T cells for the subject for treating a disease or condition, and optionally, the target antigen is associated with the disease or condition. [Aspect 1022 of the present invention] The method according to any one of aspects 1019 to 1021 of the present invention, wherein the step of exposing comprises administering the plurality of T cells to a subject, and optionally, when the T cells are derived from the subject, the administration of the compound is to the subject. [Aspect 1023 of the present invention] The exposure comprises administering the plurality of T cells to the subject for treating a disease or condition, and optionally, the target antigen is associated with the disease or condition, and prior to the step of exposing, the subject has been administered the compound; or said exposure comprises administration of said plurality of T cells to said subject for treating a disease or condition, optionally wherein the target antigen is associated with the disease or condition, and further comprises administration of said compound to said subject, The method of the invention 1022. [The invention 1024] A method of treatment comprising the step of administering an immunomodulatory compound to a subject, wherein the immunomodulatory compound is selected from the group consisting of thalidomide analogs; thalidomide derivatives; compounds that interact with and / or bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of ikaros (IKZF1); inhibitors of aiolos (IKZF3); and compounds that enhance or promote ubiquitination, depletion, and / or degradation of ikaros (IKZF1) and / or aiolos (IKZF3), (a) the subject has been administered a T cell therapy comprising a dose of T cells that express a recombinant antigen receptor that binds to a target antigen prior to administration of the compound, or (b) prior to or at the time of administration of the compound, the subject or a blood sample derived from the subject is confirmed to contain or is found to contain one or more T cells that express a recombinant antigen receptor, at the time of administration of the compound, one or more of the recombinant receptor-expressing T cells in the subject have a depleted phenotype, The method. [The invention 1025] at the time of administration of the compound, a depleted phenotype of one or more of the recombinant receptor-expressing T cells, or a marker or parameter indicative thereof, is detected or measured in the subject or in a biological sample derived from the subject, the method of the invention 1024. [The invention 1026] The method of the present invention 1024 or 1025, wherein at least 10% or at least about 10%, at least 20% or at least about 20%, at least 30% or at least about 30%, at least 40% or at least about 40%, or at least 50% or at least about 50% of the total recombinant receptor-expressing T cells in a biological sample from a subject have an exhausted phenotype. [The present invention 1027] The method according to any one of the present inventions 1024 to 1026, wherein the percentage of recombinant receptor-expressing T cells in a biological sample from a subject having an exhausted phenotype is more than 10% or more than about 10%, more than 20% or more than about 20%, more than 30% or more than about 30%, more than 40% or more than about 40%, or more than 50% or more than about 50% compared to the percentage of recombinant receptor-expressing cells having an exhausted phenotype in an equivalent biological sample at a previous time point. [The present invention 1028] (a) Selecting a subject as a candidate for administration of an immunomodulatory compound, wherein the selected subject has exhausted recombinant receptor-expressing T cells; and (b) Administering an immunomodulatory compound to the subject, wherein the immunomodulatory compound is selected from the group consisting of thalidomide analogs; thalidomide derivatives; compounds that interact with and / or bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of ikaros (IKZF1); inhibitors of aiolos (IKZF3); and compounds that enhance or promote the ubiquitination, depletion, and / or degradation of ikaros (IKZF1) and / or aiolos (IKZF3). A method of treatment comprising. [The present invention 1029] The tissue, tumor, biological fluid, or biological sample from or of the selected subject is One or more T cells that express a recombinant antigen receptor that binds to a target antigen and have an exhausted phenotype. The method of the present invention 1028 comprising. [The present invention 1030] The method of the present invention 1029, wherein the tissue, tumor, biological fluid, or biological sample contains a plurality of T cells expressing a recombinant antigen receptor that binds to a target antigen, and at least 10% or at least about 10%, at least 20% or at least about 20%, at least 30% or at least about 30%, at least 40% or at least about 40%, at least 50% or at least about 50%, at least 60% or at least about 60%, at least 70% or at least about 70%, or at least 80% or at least about 80% of the T cells in the tissue, body fluid, tumor, or sample expressing the recombinant receptor have an exhausted phenotype. [The present invention 1031] The tissue, tumor, biological fluid, or biological sample contains a plurality of T cells expressing a recombinant antigen receptor that binds to a target antigen, The percentage or number of T cells expressing a recombinant receptor having an exhausted phenotype in a body fluid, tissue, tumor, or sample derived from the subject at an earlier time point in a tissue, tumor, body fluid, or sample of a selected subject expressing a recombinant antigen receptor or a body fluid, tissue, tumor, or sample equivalent thereto is more than 10% or about 10% more, more than 20% or about 20% more, more than 30% or about 30% more, more than 40% or about 40% more, or more than 50% or about 50% more, or more than 2-fold, or more than 3-fold, or more than 5-fold, or more than 10-fold compared to that in the body fluid, tissue, tumor, or sample derived from the subject at an earlier time point, and has the exhausted phenotype. The method of the present invention 1029 or the present invention 1030. [The present invention 1032] The method of the present invention 1027 or the present invention 1030, wherein prior to administration of the compound, the subject has been administered a plurality of T cells expressing a recombinant receptor, and the earlier time point is immediately prior to administration of the plurality of T cells expressing a recombinant antigen receptor to the subject. [The present invention 1033] The method of the present invention 1027 or the present invention 1030, wherein prior to administration of the compound, the subject has been administered a plurality of T cells expressing a recombinant receptor, and the earlier time point is after administration of the T cells and before the selection. [The present invention 1034] At a previous time point After administration of the T cells expressing the recombinant receptor to the selected subject, and when or before the peak level or maximum level of the T cells expressing the recombinant receptor becomes detectable in the subject's blood; Within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, or more before the determination or selection is a method of the present invention 1027 or the present invention 1030 or the present invention 1033. [The present invention 1035] At the time of administration of the T cell therapy, the subject had a disease or condition; or At the time of administration of the T cell therapy and at the time of administration of the compound, the subject has a disease or condition, is a method of any one of the present inventions 1024 to 1034. [The present invention 1036] At the time of administration of the T cell therapy, the subject has a disease or condition, and at the time of administration of the compound, in the subject after administration of the T cell therapy, the disease or condition has recurred, or is progressing, or is considered non-responsive to the compound, is a method of any one of the present inventions 1020 to 1035. [The present invention 1037] The exhausted phenotype regarding the T cell or population of T cells is an increase in the level or degree of surface expression, or the percentage of the T cell population showing surface expression, of one or more exhaustion markers, optionally 2, 3, 4, 5, or 6 exhaustion markers, on one or more T cells, compared to a reference T cell population under the same conditions; or a decrease in the level or degree of activity exhibited by the T cell or population of T cells upon exposure to an antigen or antigen receptor-specific agent, compared to a reference T cell population under the same conditions comprising a method of any one of the present inventions 1001 to 1036. [The present invention 1038] The method of the present invention 1037, wherein the increase in the level, degree, or percentage is 1.2-fold or about 1.2-fold, 1.5-fold or about 1.5-fold, 2.0-fold or about 2.0-fold, 3-fold or about 3-fold, 4-fold or about 4-fold, 5-fold or about 5-fold, 6-fold or about 6-fold, 7-fold or about 7-fold, 8-fold or about 8-fold, 9-fold or about 9-fold, 10-fold or about 10-fold, or greater than 10-fold. [The present invention 1039] The method of the present invention 1037, wherein the decrease in the level, degree, or percentage is 1.2-fold or about 1.2-fold, 1.5-fold or about 1.5-fold, 2.0-fold or about 2.0-fold, 3-fold or about 3-fold, 4-fold or about 4-fold, 5-fold or about 5-fold, 6-fold or about 6-fold, 7-fold or about 7-fold, 8-fold or about 8-fold, 9-fold or about 9-fold, 10-fold or about 10-fold, or greater than 10-fold. [The present invention 1040] The method according to any one of the present inventions 1037 to 1039, wherein the reference T cell population is optionally a population of T cells that is known to have a non-depleted phenotype, derived from the same subject from which one or more T cells having a depleted phenotype are derived, or of the same species as the subject, or a population of naive T cells, or a population of central memory T cells, or a population of stem central memory T cells. [The present invention 1041] (a) The reference T cell population is a population suitable for the subject, comprising bulk T cells isolated from the blood of the subject from which one or more T cells having a depleted phenotype are derived, and optionally, the bulk T cells do not express a recombinant receptor, and / or (b) The reference T cell population is obtained from a subject from which one or more T cells having a depleted phenotype are derived, prior to administration of a dose of T cells that express a recombinant receptor. The method according to any one of the present inventions 1037 to 1040. [The present invention 1042] The reference T cell population is a composition comprising a sample of a T cell therapy or a pharmaceutical composition comprising T cells expressing a recombinant receptor, prior to its administration to a subject, and optionally, the composition is a cryopreserved sample, any of the methods of the invention 1037-1040. [The invention 1043] Any of the methods of the invention 1037-1042, wherein one or more of the one or more exhaustion markers is an inhibitory receptor. [The invention 1044] Any of the methods of the invention 1037-1043, wherein one or more of the one or more exhaustion markers is selected from among PD-1, CTLA-4, TIM-3, LAG-3, BTLA, 2B4, CD160, CD39, VISTA, and TIGIT. [The invention 1045] The activity is one or more of proliferation, cytotoxicity, or production of one or a combination of inflammatory cytokines, and optionally, the one or a combination of the cytokines is selected from the group consisting of IL-2, IFN-gamma, and TNF-alpha, any of the methods of the invention 1037-1044. [The invention 1046] The exposure to the antigen or antigen receptor-specific agent comprises incubation with the antigen or antigen receptor-specific agent, optionally, an agent that binds to the recombinant receptor, and the antigen is optionally a target antigen, any of the methods of the invention 1037-1045. [The invention 1047] The method of the invention 1046, wherein the antigen or antigen receptor-specific agent comprises antigen-expressing target cells, optionally, cells of the disease, disorder, or condition. [The invention 1048] Any of the methods of the invention 1002 and 1011-1047, wherein the target antigen is associated with, specific to, and / or expressed on cells or tissues of a disease, disorder, or condition. [The invention 1049] Any of the methods of the invention 1002 and 1011-1048, wherein the target antigen is a tumor antigen. [The present invention 1050] The target antigen is αvβ6 integrin (avb6 integrin), B cell maturation antigen (BCMA), BAFF-R, B7-H3, B7-H6, carbonic anhydrase 9 (CA9; also known as CAIX or G250), cancer / testis antigen, cancer / testis antigen 1B (CTAG; also known as NY-ESO-1 and LAGE-2), carcinoembryonic antigen (CEA), cyclin, cyclin A2, C-C motif chemokine ligand 1 (CCL-1), CD19, CD20, CD22, CD23, CD24, CD30, CD33, CD38, CD44, CD44v6, CD44v7 / 8, CD123, CD133, CD138, CD171, CS-1, chondroitin sulfate proteoglycan 4 (CSPG4), epidermal growth factor protein (EGFR), truncated epidermal growth factor protein (tEGFR), type III epidermal growth factor receptor variant (EGFR vIII), epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), ephrin B2, ephrin receptor A2 (EPHa2), estrogen receptor, Fc receptor-like 5 (FCRL5;Fc receptor homolog 5, also known as FCRH5, fetal acetylcholine receptor (fetal AchR), folate-binding protein (FBP), folate receptor alpha, ganglioside GD2, O-acetylated GD2 (OGD2), ganglioside GD3, glycoprotein 100 (gp100), glypican-3 (GPC3), G protein-coupled receptor 5D (GPCR5D), Her2 / neu (receptor-type tyrosine kinase erb-B2), Her3 (erb-B3), Her4 (erb-B4), erbB dimer, human high-molecular weight-melanoma-associated antigen (HMW-MAA), hepatitis B surface antigen, human leukocyte antigen A1 (HLA-A1), human leukocyte antigen A2 (HLA-A2), IL-22 receptor alpha (IL-22Rα), IL-13 receptor alpha 2 (IL-13Rα2), kinase insert domain receptor (kdr), kappa light chain, L1 cell adhesion molecule (L1-CAM), CE7 epitope of L1-CAM, leucine-rich repeat-containing 8 family member A (LRRC8A), Lewis Y, melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, MAGE-A10, mesothelin (MSLN), c-Met, murine cytomegalovirus (CMV), mucin 1 (MUC1), MUC16, natural killer group 2 member D (NKG2D) ligand, Melan-A (MART-1), neural cell adhesion molecule (NCAM), tumor fetal antigen, preferentially expressed antigen in melanoma (PRAME), progesterone receptor, prostate-specific antigen, prostate stem cell antigen (PSCA), prostate-specific membrane antigen (PSMA), receptor-type tyrosine kinase-like orphan receptor 1 (ROR1), survivin, TACI, trophoblast glycoprotein (TPBG; also known as 5T4), tumor-associated glycoprotein 72 (TAG72), tyrosinase-related protein 1 (TRP1; also known as TYRP1 or gp75), tyrosinase-related protein 2 (TRP2;Any method of the present invention 1002 and 1011 to 1048, selected from dopachrome tautomerase, dopachrome delta-isomerase, also known as DCT, vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor 2 (VEGFR2), Wilms tumor 1 (WT-1), pathogen-specific antigen or pathogen-expressed antigen, or antigen related to a universal tag, and / or a biotinylated molecule, and / or a molecule expressed by HIV, HCV, HBV or other pathogens; [The present invention 1051] Any method of the present invention 1001 to 1042, wherein the disease or condition is a B cell malignancy or a B cell-derived malignancy. [The present invention 1052] Any method of the present invention 1002 and 1011 to 1051, wherein the target antigen is CD20, CD19, CD22, ROR1, CD45, CD21, CD5, CD33, Ig kappa, Ig lambda, CD79a, CD79b, or CD30. [The present invention 1053] Any method of the present invention 1002 and 1011 to 1052, wherein the target antigen is CD19. [The present invention 1054] Any method of the present invention 1001 to 1051, wherein the disease or condition is multiple myeloma. [The present invention 1055] Any method of the present invention 1002 and 1011 to 1051 and 1054, wherein the target antigen is BCMA, G protein-coupled receptor class C group 5 member D (GPRC5D), CD38 (cyclic ADP ribose hydrolase), CD138 (syndecan-1, syndecan, SYN-1), CS-1 (CS1, CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24), BAFF-R, TACI, or FcRH5. [The present invention 1056] Any method of the present invention 1002 and 1011 to 1051 and 1055, wherein the target antigen is BCMA. [The present invention 1057] The method according to any one of the inventions 1026, 1027, and 1029 to 1056, wherein the biological sample is a blood sample. [Invention 1058] The method according to any one of the inventions 1026, 1027, and 1029 to 1056, wherein the biological sample is a tumor sample, optionally a tumor biopsy sample. [Invention 1059] (a) administering a T cell therapy to a subject having cancer, the T cell therapy comprising a dose of T cells expressing a recombinant antigen receptor that binds to a target antigen; and (b) an immunomodulatory compound selected from the group consisting of thalidomide analogs; thalidomide derivatives; compounds that interact with and / or bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of Ikaros (IKZF1); inhibitors of Aiolos (IKZF3); and compounds that enhance or promote ubiquitination and / or depletion and / or degradation of Ikaros (IKZF1) and / or Aiolos (IKZF3), (1) increasing the antigen-specific or antigen receptor-driven activity of naive or undepleted T cells in a subject optionally comprising T cells expressing the recombinant receptor, compared to in the absence of the administration of the compound, after exposure of the T cells to an antigen or an antigen receptor-specific agent; or (2) preventing, suppressing, or delaying the onset of a depleted phenotype in naive or undepleted T cells in a subject optionally comprising T cells expressing the recombinant receptor, compared to in the absence of the administration of the compound, after exposure of the T cells to an antigen or an antigen receptor-specific agent; or (3) reversing the depleted phenotype in depleted T cells in a subject optionally comprising T cells expressing the recombinant receptor, compared to in the absence of the administration of the compound in the subject administering to the subject in an effective amount, duration, and / or frequency comprising a method of treatment. [Invention 1060] wherein the amount, duration, and / or frequency is (i) resulting in an increase in antigen-specific or antigen receptor-driven activity, and (ii) preventing, suppressing, or delaying the onset of the exhaustion phenotype and / or reversing the exhaustion phenotype of the method of the invention 1059. [invention 1061] wherein the amount, duration, and / or frequency is (i) resulting in an increase in antigen-specific or antigen receptor-driven activity, and (ii) preventing, suppressing, or delaying the onset of the exhaustion phenotype of the method of the invention 1059 or the invention 1060. [invention 1062] wherein the amount, duration, and / or frequency is (i) resulting in an increase in antigen-specific or antigen receptor-driven activity, and (ii) preventing, suppressing, or delaying the onset of the exhaustion phenotype and reversing the exhaustion phenotype of the method of the invention 1059 or the invention 1060. [invention 1063] (a) administering a T cell therapy to a subject having cancer, the T cell therapy comprising a dose of T cells expressing a recombinant antigen receptor that binds to a target antigen; and (b) an immunomodulatory compound selected from the group consisting of thalidomide analogs; thalidomide derivatives; compounds that interact with and / or bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of ikaros (IKZF1); inhibitors of aiolos (IKZF3); and compounds that enhance or promote ubiquitination and / or depletion and / or degradation of ikaros (IKZF1) and / or aiolos (IKZF3) (1) After exposure of T cells to an antigen or an antigen receptor-specific agent, in a subject optionally comprising T cells expressing the recombinant receptor, an increase in antigen-specific or antigen receptor-driven activity of naive or undepleted T cells as compared to in the absence of administration of the compound; or (2) After exposure of T cells to an antigen or an antigen receptor-specific agent, prevention, suppression, or delay of the onset of a depleted phenotype in naive or undepleted T cells in a subject optionally comprising T cells expressing the recombinant receptor as compared to in the absence of administration of the compound; or (3) Reversal of a depleted phenotype in depleted T cells in a subject optionally comprising T cells expressing the recombinant receptor as compared to in the absence of administration of the compound to the subject administering to the subject in an amount, duration, and / or frequency effective to A method of treatment comprising. [Inventive concept 1064] wherein the amount, duration, and / or frequency is (i) effective to effect an increase in the antigen-specific or antigen receptor-driven activity, and (ii) effective to prevent, suppress, or delay the onset of the depleted phenotype and / or reverse the depleted phenotype The method of inventive concept 1063. [Inventive concept 1065] wherein the amount, duration, and / or frequency is (i) effective to effect an increase in the antigen-specific or antigen receptor-driven activity, and (ii) effective to prevent, suppress, or delay the onset of the depleted phenotype The method of inventive concept 1063 or inventive concept 1064. [Inventive concept 1066] wherein the amount, duration, and / or frequency is (i) effective to effect an increase in the antigen-specific or antigen receptor-driven activity, and (ii) preventing, suppressing, or delaying the onset of said wasting phenotype and reversing said wasting phenotype The method of the invention 1063 or the method of the invention 1064, which is effective for [Invention 1067] The method according to any one of inventions 1001 to 1066, wherein the compound depletes or degrades Ikaros (IKZF1). [Invention 1068] The compound has the following structure: TIFF2025087780000011.tif24128 or a pharmaceutically acceptable salt thereof, wherein one of X and Y is -C(O)- and the other of X and Y is -C(O)- or -CH 2 -; (1) each of R 1 , R 2 , R 3 , and R 4 is independently halo, alkyl of 1 to 4 carbon atoms, or alkoxy or 1 to 4 carbon atoms, or (2) one of R 1 , R 3 , R 4 , and R 5 is -NHR a and the remainder of R 1 , R 2 , R 3 , and R 4 is hydrogen, where R a is hydrogen or alkyl of 1 to 8 carbon atoms; R 5 is hydrogen or alkyl of 1 to 8 carbon atoms, benzyl, or halo; provided that when X and Y are -C(O)- and (i) each of R 1 , R 2 , R 3 , and R 4 is fluoro, or (ii) one of R 1 , R 2 , R 3 , and R 4 is amino, then R5 is other than hydrogen, any method of the present invention 1001 to 1067. [the present invention 1069] wherein the compound has the following structure: the compound of TIFF2025087780000012.tif21128, or a pharmaceutically acceptable salt thereof, wherein one of X and Y is -C(O)-, and the other of X and Y is -C(O)- or -CH 2 -, and R 5 is hydrogen or lower alkyl, any method of the present invention 1001 to 1068. [the present invention 1070] wherein the compound has the following structure: 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione having TIFF2025087780000013.tif23128, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, inclusion compound, or polymorph thereof, or any method of the present invention 1001 to 1069 including the same. [the present invention 1071] any method of the present invention 1001 to 1070, wherein the compound is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione. [the present invention 1072] wherein the compound has the following structure: 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione having TIFF2025087780000014.tif36128 or a compound including the same, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, inclusion compound, or polymorph thereof, or any method of the present invention 1001 to 1067. [the present invention 1073] The method according to any one of the present inventions 1001 to 1067 and 1072, wherein the compound is 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. [The present invention 1074] The method according to any one of the present inventions 1020 to 1073, wherein the immunomodulatory compound is administered in an effective amount of 1 mg to 50 mg or about 1 mg to 50 mg per day, 1 mg to 25 mg or about 1 mg to 25 mg per day, 1 mg to 10 mg or about 1 mg to 10 mg per day, 1 mg to 5 mg or about 1 mg to 5 mg per day, 5 mg to 50 mg or about 5 mg to 50 mg per day, 5 mg to 25 mg or about 5 mg to 25 mg per day, 5 mg to 10 mg or about 5 mg to 10 mg per day, and optionally, the administration is daily over a duration in a cycling regimen. [The present invention 1075] The compound is the following structure: The compound of TIFF2025087780000015.tif24128, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein, Z is C=O or CH 2 ; R 11 is -Z 1 -R 13 ; R 12 is H or (C 1 -C 6 ) alkyl; Z 1 is a 6- to 10-membered aryl, heteroaryl, or heterocyclic ring, each of which may be substituted with one or more halogens; or a bond; R 13 is -(CH 2 ) n -aryl, -O-(CH 2 ) n -aryl, or -(CH 2 ) n-O-aryl (wherein the aryl may be substituted with one or more of the following: (C 1 -C 6 ) alkyl; itself optionally substituted with one or more halogens; (C 1 -C 6 ) alkoxy, itself substituted with one or more halogens; oxo; amino; carboxyl; cyano; hydroxyl; halogen; deuterium; one or more (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, or aryl or heteroaryl having 6 to 10 members optionally substituted with halogen; -CONH 2 ; or -COO-(C 1 -C 6 ) alkyl (wherein the alkyl may be optionally substituted with one or more halogens)); -(CH 2 ) n -heterocyclic ring, -O-(CH 2 ) n -heterocyclic ring, or -(CH 2 ) n -O-heterocyclic ring (wherein the heterocyclic ring may be optionally substituted with one or more of the following: (C 1 -C 6 ) alkyl, itself optionally substituted with one or more halogens; (C 1 -C 6 ) alkoxy, itself substituted with one or more halogens; oxo; amino; carboxyl; cyano; hydroxyl; halogen; deuterium; one or more (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, or aryl or heteroaryl having 6 to 10 members optionally substituted with halogen; -CONH 2 ; or -COO-(C 1 -C 6 ) alkyl (wherein the alkyl may be optionally substituted with one or more halogens)); or -(CH2 ) n -heteroaryl, -O-(CH 2 ) n -heteroaryl, or -(CH 2 ) n -O-heteroaryl (wherein the heteroaryl may be substituted with one or more of the following: (C 1 -C 6 )alkyl, itself optionally substituted with one or more halogens; (C 1 -C 6 )alkoxy, itself substituted with one or more halogens; oxo; amino; carboxyl; cyano; hydroxyl; halogen; deuterium; one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or aryl or heteroaryl of 6 to 10 members optionally substituted with halogen; -CONH 2 ; or -COO-(C 1 -C 6 )alkyl (wherein the alkyl may be optionally substituted with one or more halogens)) and; and n is 0, 1, 2, or 3, any method of the present invention from 1001 to 1067. [The present invention 1076] wherein the compound is TIFF2025087780000016.tif27128 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, any method of the present invention from 1001 to 1067 and 1075. [The present invention 1077] wherein the compound is the A crystal form of the hydrochloride salt of TIFF2025087780000017.tif27128, any method of the present invention from 1001 to 1067, 1075, and 1076. [The present invention 1078] The method of the present invention 1077 is characterized by XRPD peaks of the A crystal form of the hydrochloride of TIFF2025087780000018 located at or approximately at the following positions: 9.69, 12.82, 15.09, 15.94, 16.76, 17.65, 19.44, 19.80, 22.30, 22.47, 22.95, 23.02, 24.29, 24.48, 24.70, 26.27, 26.77, 27.60, 29.43, 29.72, and 32.91 degrees of 2θ, where 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or all of them are located. [The present invention 1079] Any method of the present invention 1020 - 1067 and 1075 - 1078, wherein the immunomodulatory compound is administered at 0.1 mg to 1 mg or about 0.1 mg to 1 mg per day, 0.1 mg to 0.6 mg or about 0.1 mg to 0.6 mg per day, 0.1 mg to 0.3 mg or about 0.1 mg to 0.3 mg per day, and optionally, the administration is daily over a period in a cycling regimen. [The present invention 1080] Any method of the present invention 1020 - 1079, wherein the administration of the compound is initiated subsequent to the initiation of the administration of the T cell therapy. [The present invention 1081] Any method of the present invention 1059 - 1080, wherein the cancer is a B cell malignancy, a B cell - derived malignancy, a non - hematological cancer, or a solid tumor. [The present invention 1082] Any method of the present invention 1059 - 1081, wherein the target antigen is a tumor antigen, and optionally, the target antigen is associated with and specific to the cancer cells or tissues and / or is expressed thereon. [The present invention 1083] The target antigen is B cell maturation antigen (BCMA), αvβ6 integrin (avb6 integrin), BAFF-R, B7-H3, B7-H6, carbonic anhydrase 9 (CA9; also known as CAIX or G250), cancer testis antigen, cancer / testis antigen 1B (CTAG; also known as NY-ESO-1 and LAGE-2), carcinoembryonic antigen (CEA), cyclin, cyclin A2, C-C motif chemokine ligand 1 (CCL-1), CD5, CD19, CD20, CD21, CD22, CD23, CD24, CD30, CD38, CD44, CD44v6, CD44v7 / 8, CD45, CD79a, CD79b, CD123, CD133, CD138, CD171, CS-1, chondroitin sulfate proteoglycan 4 (CSPG4), epidermal growth factor protein (EGFR), truncated epidermal growth factor protein (tEGFR), epidermal growth factor receptor variant III (EGFR vIII), epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), ephrin B2, ephrin receptor A2 (EPHa2), estrogen receptor, Fc receptor-like 5 (FCRL5;Fc receptor homolog 5, also known as FCRH5, fetal acetylcholine receptor (fetal AchR), folate-binding protein (FBP), folate receptor alpha, ganglioside GD2, O-acetylated GD2 (OGD2), ganglioside GD3, glycoprotein 100 (gp100), glypican-3 (GPC3), G protein-coupled receptor 5D (GPCR5D), Her2 / neu (receptor tyrosine kinase erb-B2), Her3 (erb-B3), Her4 (erb-B4), erbB dimer, human high molecular weight-melanoma associated antigen (HMW-MAA), hepatitis B surface antigen, human leukocyte antigen A1 (HLA-A1), human leukocyte antigen A2 (HLA-A2), Ig kappa, Ig lambda, IL-22 receptor alpha (IL-22Rα), IL-13 receptor alpha 2 (IL-13Rα2), kinase insert domain receptor (kdr), L1 cell adhesion molecule (L1-CAM), CE7 epitope of L1-CAM, leucine rich repeat containing 8 family member A (LRRC8A), Lewis Y, melanoma associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, MAGE-A10, mesothelin (MSLN), c-Met, murine cytomegalovirus (CMV), mucin 1 (MUC1), MUC16, natural killer group 2 member D (NKG2D) ligand, Melan A (MART-1), neural cell adhesion molecule (NCAM), tumor fetal antigen, melanoma preferentially expressed antigen (PRAME), progesterone receptor, prostate specific antigen, prostate stem cell antigen (PSCA), prostate specific membrane antigen (PSMA), ROR1, survivin, TACI, trophoblast glycoprotein (TPBG; also known as 5T4), tumor associated glycoprotein 72 (TAG72), tyrosinase related protein 1 (TRP1; also known as TYRP1 or gp75), tyrosinase related protein 2 (TRP2; also known as dopachrome tautomerase, dopachrome delta-isomerase, or DCT), vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor 2 (VEGFR2), Wilms tumor 1 (WT-1), a pathogen-specific antigen or a pathogen-expressed antigen, any of the methods of the present invention from 1059 to 1082; [The present invention 1084] The method of the present invention 1051, the present invention 1082, or the present invention 1083, wherein the B-cell malignancy is lymphoma. [The present invention 1085] The method of the present invention 1084, wherein the lymphoma is non-Hodgkin lymphoma (NHL). [The present invention 1086] The method of the present invention 1085, wherein the NHL is aggressive NHL, diffuse large B-cell lymphoma (DLBCL), DLBCL-NOS, optionally transformed low-grade; EBV-positive DLBCL-NOS; T cell / histiocyte-rich large B-cell lymphoma; primary mediastinal large B-cell lymphoma (PMBCL); follicular lymphoma (FL), optionally follicular lymphoma grade 3B (FL3B); and / or high-grade B-cell lymphoma with rearrangement of MYC and BCL2 and / or BCL6 having a DLBCL histological pattern (double / triple hit). [The present invention 1087] The method according to any one of the present inventions 1001 to 1086, wherein the subject is identified as having or has a status of 1 or less according to the Eastern Cooperative Oncology Group Performance Status (ECOG). [The present invention 1088] The method according to any one of the present inventions 1059 to 1087, wherein the target antigen is CD20, CD19, CD22, ROR1, CD45, CD21, CD5, CD33, Ig kappa, Ig lambda, CD79a, CD79b, or CD30. [The present invention 1089] The method according to any one of the present inventions 1059 to 1088, wherein the target antigen is CD19. [The present invention 1090] The method according to any one of the present inventions 1059 to 1087, wherein the target antigen is not CD20, CD19, CD22, ROR1, CD45, CD21, CD5, CD33, Ig kappa, Ig lambda, CD79a, CD79b, or CD30. [The present invention 1091] The method according to any one of the present inventions 1059 to 1081, wherein the cancer is multiple myeloma. [The present invention 1092] The method according to any one of aspects 1059 to 1091 of the present invention, wherein the target antigen is BCMA, G protein-coupled receptor class C group 5 member D (GPRC5D), CD38 (cyclic ADP ribose hydrolase), CD138 (syndecan-1, syndecan, SYN-1), CS-1 (CS1, CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24), BAFF-R, TACI, or FcRH5. [Aspect 1093 of the present invention] The method according to any one of aspects 1059 to 1092 of the present invention, wherein the target antigen is BCMA. [Aspect 1094 of the present invention] The method according to any one of aspects 1020 to 1093 of the present invention, wherein the administration of the compound continues for a period of 3 months or about 3 months or more than 3 months after the start of the administration of the T cell therapy. [Aspect 1095 of the present invention] The method according to aspect 1074 of the present invention, wherein the effective amount is 4 mg or less or about 4 mg or less per day. [Aspect 1096 of the present invention] The method according to aspect 1074 of the present invention, wherein the effective amount is from 1.0 mg or about 1.0 mg to 4 mg or about 4 mg. [Aspect 1097 of the present invention] The method according to aspect 1074 of the present invention, wherein the effective amount is 3 mg or less or about 3 mg or less per day. [Aspect 1098 of the present invention] The method according to aspects 1074 and 1097 of the present invention, wherein the effective amount is from 1.0 mg or about 1.0 mg to 3 mg or about 3 mg. [Aspect 1099 of the present invention] The method according to aspect 1074 of the present invention, wherein the effective amount is 2.5 mg or less or about 2.5 mg or less per day. [Aspect 1100 of the present invention] For each week of the cycling regimen, or for at least one week of the cycling regimen, the administration of the compound includes administration of the compound on each of 5 days or less consecutive days of the week, followed by a rest period during which no compound is administered for the remainder of the week. The method according to any one of aspects 1074 and 1095 to 1099 of the present invention. [Aspect 1101 of the present invention] The method of the present invention 1100, wherein the continuous 5 days or less is a continuous 3 days per week and a rest period of 4 days during which the compound is not administered thereafter. [The present invention 1102] The method of the present invention 1100, wherein the continuous 5 days or less is a continuous 4 days per week and a rest period of 3 days during which the compound is not administered thereafter. [The present invention 1103] The method of the present invention 1100, wherein the continuous 5 days or less is a continuous 5 days per week and a rest period of 2 days during which the compound is not administered thereafter. [The present invention 1104] The method according to any one of the present inventions 1020 to 1103, wherein the administration continues over a period of 4 months or about 4 months or more than 4 months after the start of the administration of the T cell therapy. [The present invention 1105] The method according to any one of the present inventions 1020 to 1104, wherein the administration continues over a period of 5 months or about 5 months or more than 5 months after the start of the administration of the T cell therapy. [The present invention 1106] The method according to any one of the present inventions 1020 to 1105, wherein the administration continues over a period of 6 months or about 6 months or more than 6 months after the start of the administration of the T cell therapy. [The present invention 1107] The method according to any one of the present inventions 1074 and 1095 to 1106, wherein the administration of the compound per day is in an amount of 3 mg or about 3 mg. [The present invention 1108] The method according to any one of the present inventions 1074 and 1095 to 1106, wherein the administration of the compound per day is in an amount of 2.5 mg or about 2.5 mg. [The present invention 1109] The method according to any one of the present inventions 1074 and 1095 to 1106, wherein the administration of the compound per day is in an amount of 2 mg or about 2 mg. [The present invention 1110] The method according to any one of the present inventions 1074 and 1095 to 1106, wherein the administration of the compound per day is in an amount of 1.5 mg or about 1.5 mg. [The present invention 1111] Any method of the present invention 1074 and any of 1095 - 1106, wherein the administration of the compound per day is in an amount of 1 mg or about 1 mg per day. [The present invention 1112] Any method of the present invention 1020 - 1111, wherein if the subject shows a complete response (CR) after treatment at the end of the period, the administration of the compound is terminated at the end of the period. [The present invention 1113] Any method of the present invention 1020 - 1112, wherein if the cancer is progressing or has recurred following remission after treatment at the end of the period, the administration of the compound is terminated at the end of the period. [The present invention 1114] Any method of the present invention 1020 - 1113, wherein the administration of the compound continues over a period ranging from 3 months or 3 months or about 3 months to 6 months or 6 months. [The present invention 1115] Any method of the present invention 1020 - 1114, wherein the administration of the compound continues over a period of 3 months or about 3 months after the start of the administration of T - cell therapy. [The present invention 1116] Any method of the present invention 1020 - 1114, wherein if the subject has achieved a complete response (CR) after treatment 3 months or about 3 months prior, or if the cancer is progressing or has recurred following remission after treatment, the administration of the compound continues over a period of 3 months or about 3 months after the start of the administration of T - cell therapy. [The present invention 1117] Any method of the present invention 1116, wherein if the subject has achieved a complete response (CR) in 3 months, the administration of the compound continues over a period of 3 months or about 3 months after the start of the administration of T - cell therapy. [The present invention 1118] Any method of the present invention 1020 - 1114, wherein the administration of the compound continues over a period of 6 months or about 6 months after the start of the administration of T - cell therapy. [The present invention 1119] If the subject has achieved a complete response (CR) after treatment 6 months or approximately 6 months prior, or if the cancer has progressed or recurred following remission after treatment, the administration of the compound continues for a period of 6 months or approximately 6 months following the start of administration of the T cell therapy, any method of the present invention from 1020 to 1118. [The present invention 1120] If the subject has achieved a complete response (CR) at 6 months, the period is 6 months or approximately 6 months following the start of administration of the T cell therapy, the method of the present invention 1119. [The present invention 1121] Even if the subject has achieved a complete response (CR) at a point prior to the end of the period, the administration continues over the duration of the continuation period, any method of the present invention from 1020 to 1120. [The present invention 1122] Any method of the present invention from 1020 to 1121, wherein the subject achieves a complete response (CR) during and prior to the end of the administration period. [The present invention 1123] If, at the end of the period, the subject exhibits a partial response (PR) or stable disease (SD), further comprising continuing the administration after the end of the period, any method of the present invention from 1020 to 1111, 1114, 1115, 1119, 1121, and 1122. [The present invention 1124] If, at 6 months or approximately 6 months, the subject exhibits a partial response (PR) or stable disease (SD) after treatment, the administration continues for more than 6 months, any method of the present invention from 1020 to 1123. [The present invention 1125] The method of the present invention 1123 or the method of the present invention 1124, wherein the administration continues until the subject achieves a complete response (CR) after treatment or until the cancer progresses or recurs following remission after treatment. [The present invention 1126] The administration of the compound is initiated at or after the point at which the peak or maximum level of the cells of the T cell therapy becomes detectable in the subject's blood, any method of the present invention from 1020 to 1125. [The present invention 1127] Any method according to any one of the present inventions 1020 to 1126, wherein the administration of the compound is initiated about 14 to about 35 days after the initiation of the administration of the T cell therapy. [The present invention 1128] Any method according to any one of the present inventions 1020 to 1127, wherein the administration of the compound is initiated about 21 to about 35 days after the initiation of the administration of the T cell therapy. [The present invention 1129] Any method according to any one of the present inventions 1020 to 1128, wherein the administration of the compound is initiated about 21 to about 28 days after the initiation of the administration of the T cell therapy. [The present invention 1130] Any method according to any one of the present inventions 1020 to 1129, wherein the administration of the compound is initiated 21 days or about 21 days, 22 days or about 22 days, 23 days or about 23 days, 24 days or about 24 days, 25 days or about 25 days, 26 days or about 26 days, 27 days or about 27 days, or 28 days or about 28 days after the initiation of the administration of the T cell therapy. [The present invention 1131] Any method according to any one of the present inventions 1020 to 1130, wherein the administration of the compound is initiated 28 days or about 28 days after the initiation of the administration of the T cell therapy. [The present invention 1132] Any method according to any one of the present inventions 1020 to 1131, wherein at the start of the administration of the compound, the subject does not exhibit severe toxicity after the administration of the T cell therapy. [The present invention 1133] The severe toxicity is severe cytokine release syndrome (CRS), optionally grade 3 or higher, long-term grade 3 or higher, or grade 4 or 5 CRS; and / or The severe toxicity is severe neurotoxicity, optionally grade 3 or higher, long-term grade 3 or higher, or grade 4 or 5 neurotoxicity, The method of the present invention 1132. [The present invention 1134] Any method according to any one of the present inventions 1020 to 1133, wherein if the subject exhibits toxicity, optionally hematotoxicity, after the administration of the compound, the administration of the compound is stopped and / or the administration is modified. [The present invention 1135] The method of the present invention 1134, wherein the toxicity is selected from severe neutropenia, optionally febrile neutropenia, and persistent grade 3 or higher neutropenia. [The present invention 1136] The method of the present invention 1134 or 1135, wherein the administration of the compound is resumed after the subject no longer exhibits toxicity. [The present invention 1137] The method of the present invention 1136, wherein the administration is modified after the resumption of the administration of the compound. [The present invention 1138] The method according to any one of the present inventions 1134 to 1137, wherein the modified administration includes administering a reduced amount of the compound and / or reducing the frequency of administration of the compound. [The present invention 1139] The method according to any one of the present inventions 1134 to 1138, wherein the modified administration includes administering a reduced amount of the compound. [The present invention 1140] The method of the present invention 1139, wherein the dose of the compound is reduced, and the reduced amount is from 1 mg or about 1 mg to 2 mg or about 2 mg per day for no more than 5 days per week. [The present invention 1141] The method according to any one of the present inventions 1001 to 1067 and 1075 to 1139, wherein the compound is a pharmaceutically acceptable salt of (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione or comprises the same. [The present invention 1142] The method according to any one of the present inventions 1001 to 1067 and 1075 to 1139, wherein the compound is a hydrate of (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione or comprises the same. [The present invention 1143] A method according to any one of the methods of the present invention 1001 to 1067 and 1075 to 1139, wherein the compound is a solvate of (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione or comprises the same. [The present invention 1144] A method according to any one of the methods of the present invention 1001 to 1067 and 1075 to 1139, wherein the compound is (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione or comprises the same. [The present invention 1145] A method according to any one of the methods of the present invention 1001 to 1074 and 1080 to 1140, wherein the compound is a solvate of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione or comprises the same. [The present invention 1146] A method according to any one of the methods of the present invention 1001 to 1074 and 1080 to 1140, wherein the compound is a hydrate of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione or comprises the same. [The present invention 1147] A method according to any one of the methods of the present invention 1001 to 1074 and 1080 to 1140, wherein the compound is a pharmaceutically acceptable salt of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione or comprises the same. [The present invention 1148] A method according to any one of the methods of the present invention 1001 to 1074 and 1080 to 1140, wherein the compound is 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione or comprises the same. [The present invention 1149] A method according to any one of the methods of the present invention 1020 to 1148, wherein the compound is administered orally. [The present invention 1150] The administration of the compound is Reverse the exhausted phenotype in recombinant receptor-expressing T cells in a subject; Prevent, suppress, or delay the onset of the exhausted phenotype in recombinant receptor-expressing T cells in a subject; Or, reduce the level or degree of the exhausted phenotype in recombinant receptor-expressing T cells in a subject; or Reduce the percentage of the total number of recombinant receptor-expressing T cells in a subject that have an exhausted phenotype, Any method of the invention from 1020 to 1149. [The invention 1151] The start of administration of the compound is carried out subsequent to the administration of the T cell therapy, and after the administration or the start thereof, the subject exhibits a restoration or rescue of the antigen-specific or tumor-specific activity or function of the recombinant receptor-expressing T cells in the subject, and optionally, the restoration, rescue, and / or the start of administration of the compound is at a time point after the recombinant receptor-expressing T cells in the subject or in the subject's blood have exhibited an exhausted phenotype. Any method of the invention from 1003 to 1149. [The invention 1152] The administration of the compound is (a) After exposure of T cells to an antigen or an antigen receptor-specific agent, result in an increase in the antigen-specific or antigen receptor-driven activity of naive or non-exhausted T cells in a subject optionally comprising the T cells expressing the recombinant receptor as compared to in the absence of the administration of the compound; or (b) After exposure of T cells to an antigen or an antigen receptor-specific agent, prevent, suppress, or delay the onset of the exhausted phenotype in naive or non-exhausted T cells in a subject optionally comprising the T cells expressing the recombinant receptor as compared to in the absence of the administration of the compound; or (c) In a subject, reverse the exhausted phenotype in exhausted T cells optionally comprising the T cells expressing the recombinant receptor as compared to in the absence of the administration to the subject Comprising administration in an effective amount, frequency, and / or duration for any method of the invention from 1003 to 1149. [The present invention 1153] Administration of the compound is (i) resulting in the increase in the activity and (ii) preventing, suppressing, or delaying the onset of the exhaustion phenotype and / or reversing the exhaustion phenotype including administration in an effective amount, frequency, and / or duration for the method of the present invention 1152. [The present invention 1154] The method of the present invention 1152 or 1153, wherein the T cells in the subject include T cells expressing the recombinant receptor and / or the antigen is a target antigen. [The present invention 1155] An exhaustion phenotype related to a T cell or a population of T cells is an increase in the level or degree of surface expression or the percentage of a population of T cells showing surface expression of one or more exhaustion markers, optionally two, three, four, five, or six exhaustion markers, on one or more T cells, compared to a reference T cell population under the same conditions; or a decrease in the level or degree of activity exhibited by the T cell or population of T cells upon exposure to an antigen or an antigen receptor-specific agent, compared to a reference T cell population under the same conditions including the method according to any one of the present inventions 1150 to 1154. [The present invention 1156] The method of the present invention 1155, wherein the increase in the level, degree, or percentage is 1.2-fold or about 1.2-fold, 1.5-fold or about 1.5-fold, 2.0-fold or about 2.0-fold, 3-fold or about 3-fold, 4-fold or about 4-fold, 5-fold or about 5-fold, 6-fold or about 6-fold, 7-fold or about 7-fold, 8-fold or about 8-fold, 9-fold or about 9-fold, 10-fold or about 10-fold, or greater than that. [The present invention 1157] The method of the present invention 1155, wherein the decrease in said level, degree, or percentage is greater than 1.2-fold or about 1.2-fold, 1.5-fold or about 1.5-fold, 2.0-fold or about 2.0-fold, 3-fold or about 3-fold, 4-fold or about 4-fold, 5-fold or about 5-fold, 6-fold or about 6-fold, 7-fold or about 7-fold, 8-fold or about 8-fold, 9-fold or about 9-fold, 10-fold or about 10-fold, or more. [The present invention 1158] The method according to any one of the present inventions 1155-1157, wherein the reference T cell population is optionally a population of T cells known to have a non-depleted phenotype, from the same subject from which one or more T cells having a depleted phenotype are derived, or of the same species as the subject, or a population of naive T cells, or a population of central memory T cells, or a population of stem central memory T cells. [The present invention 1159] (a) The reference T cell population is a population adapted to the subject comprising bulk T cells isolated from the blood of a subject from which one or more T cells having a depleted phenotype are derived, and optionally, the bulk T cells do not express a recombinant receptor and / or (b) The reference T cell population is obtained from a subject from which one or more T cells having a depleted phenotype are derived, prior to administration of a dose of T cells expressing a recombinant receptor. The method according to any one of the present inventions 1155-1158. [The present invention 1160] The method according to any one of the present inventions 1155-1158, wherein the reference T cell population is a composition comprising a sample of a T cell therapy, or a pharmaceutical composition comprising T cells expressing a recombinant receptor, prior to its administration to a subject, and optionally, the composition is a cryopreserved sample. [The present invention 1161] The method according to any one of the present inventions 1155-1160, wherein the one or more depletion markers are inhibitory receptors. [The present invention 1162] Any method of the present invention from 1155 to 1161, wherein the one or more consumable markers are selected from PD-1, CTLA-4, TIM-3, LAG-3, BTLA, 2B4, CD160, CD39, VISTA, and TIGIT. [The present invention 1163] Any method of the present invention from 1155 to 1162, wherein the activity is one or more of proliferation, cytotoxicity, or production of one or a combination of inflammatory cytokines, and optionally, one or a combination of the cytokines is selected from the group consisting of IL-2, IFN-gamma, and TNF-alpha. [The present invention 1164] Any method of the present invention from 1155 to 1163, wherein the exposure to the antigen or antigen receptor-specific agent includes incubation with the antigen or antigen receptor-specific agent, optionally, an agent that binds to a recombinant receptor, and the antigen is optionally a target antigen. [The present invention 1165] The method of the present invention 1164, wherein the antigen or antigen receptor-specific agent includes antigen-expressing target cells, optionally, cells of the disease, disorder, or condition. [The present invention 1166] Any method of the present invention from 1002 and 1011 to 1165, wherein the target antigen is a human antigen. [The present invention 1167] Any method of the present invention from 1001 to 1166, wherein the subject is human. [The present invention 1168] Any method of the present invention from 1001 to 1167, wherein the recombinant antigen receptor is a chimeric antigen receptor that specifically binds to a target antigen. [The present invention 1169] The method of the present invention 1016 or the present invention 1168, wherein the chimeric antigen receptor (CAR) includes an extracellular antigen recognition domain that specifically binds to a target antigen and an intracellular signaling domain that includes an ITAM. [The present invention 1170] The method of the present invention 1169, wherein the intracellular signaling domain comprises a CD3-zeta (CD3ζ) chain, optionally the signaling domain of a human CD3-zeta chain. [The present invention 1171] The method of the present invention 1169 or 1170, wherein the chimeric antigen receptor (CAR) further comprises a co-stimulatory signaling region. [The present invention 1172] The method of the present invention 1171, wherein the co-stimulatory signaling region comprises CD28 or 4-1BB, optionally the signaling domain of a human CD28 or a human 4-1BB. [The present invention 1173] The method of the present invention 1171 or 1172, wherein the co-stimulatory domain is or comprises the signaling domain of human 4-1BB. [The present invention 1174] The CAR comprises a scFv specific for a target antigen; a transmembrane domain; optionally, a cytoplasmic signaling domain derived from a co-stimulatory molecule which is 4-1BB, optionally human 4-1BB or comprises the same; and optionally, a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule which is a CD3 zeta signaling domain, optionally a human CD3 zeta signaling domain or comprises the same; and optionally, the CAR further comprises a spacer between the transmembrane domain and the scFv; The CAR comprises, in order, a scFv specific for a target antigen; a transmembrane domain; optionally, a cytoplasmic signaling domain derived from a co-stimulatory molecule which is a 4-1BB signaling domain, optionally a human 4-1BB signaling domain or comprises the same; and optionally, a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule which is a CD3 zeta signaling domain; or The CAR is, in order, an scFv specific for a target antigen; a spacer; a transmembrane domain, optionally a cytoplasmic signaling domain derived from a costimulatory molecule which is a 4-1BB signaling domain, and optionally a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule which is or includes a CD3 zeta signaling domain. Any method of the present invention 1016 and 1168 to 1173. [The present invention 1175] The dose of the genetically engineered T cells is 1×10 5 ~5×10 8 or about 1×10 5 ~5×10 8 of total CAR-expressing T cells, 1×10 6 ~2.5×10 8 or about 1×10 6 ~2.5×10 8 of total CAR-expressing T cells, 5×10 6 ~1×10 8 or about 5×10 6 ~1×10 8 of total CAR-expressing T cells, 1×10 7 ~2.5×10 8 or about 1×10 7 ~2.5×10 8 of total CAR-expressing T cells, 5×10 7 ~1×10 8 or about 5×10 7 ~1×10 8 of total CAR-expressing T cells (including both end values), any method of the present invention 1021 to 1174. [The present invention 1176] The dose of the genetically engineered T cells is at least 1×10 5 or at least about 1×10 5 of CAR-expressing cells, at least 2.5×10 5 or at least about 2.5×10 5 of CAR-expressing cells, at least 5×10 5 or at least about 5×10 5 of CAR-expressing cells, at least 1×10 6 or at least about 1×10 6CAR-expressing cells of at least 2.5×10 6 or at least about 2.5×10 6 CAR-expressing cells of at least 5×10 6 or at least about 5×10 6 CAR-expressing cells of at least 1×10 7 or at least about 1×10 7 CAR-expressing cells of at least 2.5×10 7 or at least about 2.5×10 7 CAR-expressing cells of at least 5×10 7 or at least about 5×10 7 CAR-expressing cells of at least 1×10 8 or at least about 1×10 8 CAR-expressing cells of at least 2.5×10 8 or at least about 2.5×10 8 CAR-expressing cells, or at least 5×10 8 or at least about 5×10 8 Any method of the present invention from 1021 to 1175, comprising CAR-expressing cells. [Invention 1177] The dose of genetically engineered T cells is 5×10 7 or about 5×10 7 Any method of the present invention from 1021 to 1176, comprising total CAR-expressing T cells. [Invention 1178] The dose of genetically engineered T cells is 1×10 8 or about 1×10 8 Any method of the present invention from 1021 to 1177, comprising CAR-expressing cells. [Invention 1179] Any method of the present invention from 1021 to 1178, wherein the dose of cells is administered parenterally, optionally intravenously. [Invention 1180] Any method of the present invention from 1021 to 1179, wherein the T cells are primary T cells obtained from a subject. [Invention 1181] Any method of the present invention from 1021 to 1180, wherein the T cells are autologous to the subject. [The present invention 1182] Any method of the present invention 1021-1180, wherein the T cells are allogeneic to the subject. [The present invention 1183] Any method of the present invention 1021-1182, wherein the dose of genetically engineered T cells comprises CD4+ T cells expressing a CAR and CD8+ T cells expressing a CAR, and the administration of the dose comprises administering a plurality of separate compositions, the plurality of separate compositions comprising a first composition comprising one of CD4+ T cells and CD8+ T cells and a second composition comprising the other of CD4+ T cells or CD8+ T cells. [The present invention 1184] Any method of the present invention 1021-1183, wherein prior to said administration, the subject has been preconditioned with a lymphodepleting therapy comprising administration of fludarabine and / or cyclophosphamide. [The present invention 1185] Any method of the present invention 1021-1184, further comprising administering to the subject a lymphodepleting therapy comprising administration of fludarabine and / or cyclophosphamide immediately prior to said administration. [The present invention 1186] Said lymphodepleting therapy comprises daily administration of cyclophosphamide at about 200-400 mg / m 2 , optionally 300 mg / m 2 or about 300 mg / m 2 (including both end values), and / or fludarabine at about 20-40 mg / m 2 , optionally 30 mg / m 2 for 2-4 days, optionally 3 days, or said lymphodepleting therapy comprises administration of cyclophosphamide at about 500 mg / m 2 , according to the method of the present invention 1184 or the present invention 1185. [The present invention 1187] Said lymphodepleting therapy comprises daily administration of cyclophosphamide at 300 mg / m 2 or about 300 mg / m 2 and fludarabine at about 30 mg / m 2 for 3 days; and / or The lymphodepletion therapy is 500 mg / m 2 or about 500 mg / m 2 of cyclophosphamide and about 30 mg / m 2 of fludarabine, including daily administration for 3 days, any method of the present invention from 1184 to 1186. [The present invention 1188] At least 35%, at least 40%, or at least 50% of the subjects treated according to the method achieve a complete response (CR) that is persistent or persistent in at least 60, 70, 80, 90, or 95% of the subjects who achieve CR over 6 months or more or 9 months or more; and / or At least 60, 70, 80, 90, or 95% of the subjects who achieve CR by 6 months remain in response, remain in CR, and / or survive or survive without aversion over a period longer than 3 months or more and / or 6 months or more and / or 9 months or more; and / or At least 50%, at least 60%, or at least 70% of the subjects treated according to the method achieve an objective response (OR), optionally the OR is persistent over 6 months or more or 9 months or more, or is persistent in at least 60, 70, 80, 90, or 95% of the subjects who achieve OR; and / or At least 60, 70, 80, 90, or 95% of the subjects who achieve OR by 6 months remain in response or survive over a period longer than 3 months or more and / or 6 months or more. any method of the present invention from 1020 to 1187. [The present invention 1189] (a) T cell therapy comprising a dose of T cells expressing a recombinant antigen receptor that binds to a target antigen; and (b) Thalidomide analogs; thalidomide derivatives; compounds that interact with and / or bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of Ikaros (IKZF1); inhibitors of Aiolos (IKZF3); and compounds that enhance or promote ubiquitination and / or depletion and / or degradation of Ikaros (IKZF1) and / or Aiolos (IKZF3), immunomodulatory compounds selected from the group consisting of; and (c) Instructions for administering the compound and / or the T cell therapy according to any of the methods of the present invention from 1001 to 1187 A kit comprising.

Brief Description of Drawings

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Mode for Carrying Out the Invention

[0080] Detailed Description Provided herein are combination therapies comprising administration of an immunotherapy, including T cell function or activity such as T cell therapy, and an immunomodulatory compound such as a structural or functional analog or derivative of thalidomide and / or an inhibitor of an E3-ubiquitin ligase. In some aspects, the provided methods enhance or modulate the proliferation and / or activity of T cell activity associated with administration of an immunotherapy or an immunotherapeutic agent (e.g., a composition comprising cells (e.g., CAR-expressing T cells) for adoptive cell therapy, such as T cell therapy). In some embodiments, the combination therapy comprises administration of an immunomodulatory compound such as a structural or functional analog of thalidomide and / or an inhibitor of an E3-ubiquitin ligase and administration of a T cell therapy (e.g., a composition comprising cells (e.g., CAR-expressing T cells) for adoptive cell therapy, such as T cell therapy).

[0081] T cell-based therapies, such as adoptive T cell therapy (including adoptive T cell therapy comprising administration of cells expressing a chimeric receptor specific for a disease or disorder of interest, such as a chimeric antigen receptor (CAR) and / or other recombinant antigen receptors, as well as other adoptive immune cell therapies and adoptive T cell therapies), can be effective in the treatment of cancer and other diseases and disorders. Engineered expression of a recombinant receptor, such as a chimeric antigen receptor (CAR), on the surface of T cells enables redirection of T cell specificity. In clinical trials, CAR-T cells, such as anti-CD19 CAR-T cells, have resulted in durable complete responses in both leukemia and lymphoma patients (Porter et al. (2015) Sci Transl Med., 7:303ra139; Kochenderfer (2015) J. Clin. Oncol., 33:540-9; Lee et al. (2015) Lancet, 385:517-28; Maude et al. (2014) N Engl J Med, 371:1507-17).

[0082] In certain situations, the available approaches to adoptive cell therapy may not always be fully satisfactory. For example, in certain cases, the persistence of CAR T cells can be detected in many subjects with lymphoma, but in subjects with NHL, fewer complete responses (CRs) have been observed compared to subjects with ALL. More specifically, overall response rates as high as 80% (CR rates of 47% - 60%) have been reported after CAR T cell infusion, but the responses in some are transient, and subjects have been shown to relapse in the presence of persistent CAR T cells (Neelapu, 58th Annual Meeting of the American Society of Hematology (ASH): 2016; San Diego, CA, USA. Abstract No. LBA - 6.2016; Abramson, Blood. 2016 Dec 01;128(22):4192). Another study reported a long - term CR rate of 40% (Schuster, Ann Hematol. 2016 Oct;95(11):1805 - 10).

[0083] In some scenarios, the explanation for this is the immunological depletion of circulating CAR-expressing T cells and / or changes in the T lymphocyte population. In some situations, optimal efficacy may depend on the ability of the administered cells to migrate to, localize in, and successfully enter the appropriate sites, tumors, and their environment within the subject that recognize and bind to the target, e.g., the target antigen. In some situations, optimal efficacy involves avoiding or reducing the immunosuppressive state in the local microenvironment of the disease, differentiating, migrating, or reprogramming to a particular phenotypic state (e.g., a long-lived memory state, a less differentiated state, and an effector state) that exhibits various effector functions including activated, increased cytotoxic killing and secretion of various factors such as cytokines, persisting over time, providing an effective and robust recall response upon clearance and re-exposure to the target ligand or antigen, and avoiding or reducing depletion, anergy, peripheral tolerance, terminal differentiation, and / or differentiation to a suppressed state.

[0084] In some embodiments, the exposure and persistence of the engineered cells decreases or wanes after administration to the subject. However, in some cases, it has been observed that an increase in the subject's exposure to the cells expressing the administered recombinant receptor (e.g., an increase in cell number or duration over time) can improve the efficacy and therapeutic outcome in adoptive cell therapy. Preliminary analyses conducted after administration of CAR-expressing T cells targeting different CD19s to subjects with various CD19-expressing cancers in multiple clinical trials revealed a correlation between a greater and / or longer extent of exposure to the CAR-expressing cells and treatment outcome. Such outcomes included patient survival and remission, even in individuals with a high or significant tumor burden.

[0085] In some embodiments, after exposure to long-term stimuli or antigens and / or exposure under conditions in the tumor microenvironment, T cells may become functionally reduced over time and / or exhibit characteristics associated with a depleted state. In some aspects, this reduces the persistence and efficacy of T cells against antigens and limits their ability to be effective. There is a need for methods for improving the efficacy and function of CAR T cells, particularly for minimizing, reducing, preventing, or reversing the functionally reduced or depleted state.

[0086] The methods provided include administering a T cell therapy (e.g., an adoptive cell therapy, a composition comprising cells (e.g., CAR-expressing T cells) for T cell therapy, etc.) and an immunomodulatory compound such as a structural or functional analog of thalidomide and / or an inhibitor of an E3-ubiquitin ligase, e.g., lenalidomide, compound 1, or compound 2. In some embodiments, the immunomodulatory compound for use in the methods and uses provided is an E3 ligase regulatory compound that is an inhibitor of an E3 ubiquitin ligase. In some embodiments, the immunomodulatory compound for use in the methods and uses provided is lenalidomide. In some embodiments, the immunomodulatory compound for use in the methods and uses provided is compound 1 (3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione). In some embodiments, the immunomodulatory compound for use in the methods and uses provided is compound 2 ((S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione).

[0087] Lenalidomide, which has the structural formula 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, is an immunomodulatory drug recently approved for the treatment of multiple myeloma (MM) and mantle cell lymphoma (MCL) and is being clinically tested in the treatment of diffuse large B-cell lymphoma of activated B-cell immunophenotype. In some cases, lenalidomide increases the ubiquitination of Ikaros and Aiolos transcription factors, which in turn leads to changes in the expression of various receptors on the surface of tumor cells, by at least partially modulating the activity of the E3 ubiquitin ligase cereblon (CRBN), thereby increasing the anti-tumor immune response (see, for example, Otahal et al. (2016) Oncoimmunology., April; 5(4): e1115940).

[0088] Compound 1, which has the structural formula 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures, is an immunomodulatory drug that is a multifaceted small molecule capable of directly attenuating primary tumor growth, modulating the immunosuppressive tumor microenvironment, and promoting a more robust anti-tumor inflammatory response. Compound 1 has been evaluated as a single-agent treatment for targeting tumors in B-cell lymphoid malignancies, exerting anti-proliferative activity against B cells.

[0089] The structural formula (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or racemic mixture thereof of Compound 2 is also a cereblon (CRBN) E3 ligase modulatory compound that modulates CRBN, which induces the ubiquitination of the transcription factors Ikaros and Aiolos. In some aspects, ubiquitination increases their proteasome-dependent degradation. Compound 2 binds to CRBN more potently than lenalidomide and pomalidomide and is more efficient in the degradation of Ikaros and Aiolos. As shown herein, Compound 2 is also 10- to 20-fold more potent than Compound 1 in the degradation of Ikaros and Aiolos. Compound 2 has a direct anti-proliferative effect on lymphoma cells. As shown herein, Compound 2 also enhances T cell function.

[0090] Immunomodulatory drugs such as compound 1, compound 2, and lenalidomide have been shown to directly affect the survival of malignant lymphocytes through the degradation of Ikaros family transcription factors. The molecular target of such compounds has been identified as the protein cereblon (CRBN), which is a substrate receptor of the Cullin 4 RING E3 ubiquitin ligase complex. Binding to the hydrophobic tri-tryptophan pocket within CRBN promotes the recruitment, ubiquitination, and subsequent proteasomal degradation of several protein substrates, including aiolos (IKZF3) and Ikaros (IKZF1). (Fischer, Nature. 2014 Aug; 512, 49-53; Chamberlain, Nat Struct Mol Biol. 2014 Sep;21(9):803-9; Gandhi, Br J Haematol. 2014 Mar;164(6):811-21; Lu, Science. 2014 Jan 17;343(6168):305-9; and Kronke, Oncoimmunology, 2014; 3(7): e941742.) Ikaros is expressed at the immature stage of myeloid differentiation and controls early neutrophil differentiation (Dumortier et al. (2003) Blood 101:2219). Thus, in some cases, depletion of Ikaros, for example, by administration of an immunomodulatory compound, such as compound 1, to a subject can result in neutropenia in some instances. To mitigate neutropenia while maintaining antitumor activity against B cell lymphoma, a dose of 4 mg of compound 1 administered for 5 days (5 / 7 days) followed by a 2-day rest period has been found to be the maximum tolerated dose (MTD) for the treatment of subjects with DLBCL (Carpio et al. (2015) Blood, 126:1594). See also International Patent Application Publication No. WO2017096024.

[0091] E3 ligase regulatory compounds such as Compound 1 exert a co-stimulatory effect on immune cells such as T cells and NK cells in addition to their cell-autonomous activity against malignant B cells. This activity has also been shown to occur through the CRBN-mediated degradation of Aiolos and Ikaros, which are negative regulators of activation molecules and cytokines such as interleukin-2 (IL-2) expression. (Gandhi, Br J Haematol. 2014 Mar;164(6):811-21, Kronke, Oncoimmunology, 2014; 3(7): e941742.)

[0092] The methods provided are based on the observation that immunomodulatory compounds such as structural or functional analogs or derivatives of thalidomide and / or inhibitors of E3 ubiquitin ligases, such as lenalidomide, Compound 1, or Compound 2 as described, improve T cell function, including the ability of T cells to produce one or more cytokines, cytotoxicity, expansion, proliferation, and functions related to persistence. In some aspects, the methods provided enhance or modulate the expansion and / or activity of T cell activity associated with the administration of T cell therapies (e.g., CAR-expressing T cells). Such methods and uses have been found to provide or achieve improved or greater T cell function and thereby improved anti-tumor efficacy.

[0093] Such immunomodulatory compounds, such as lenalidomide, Compound 1, or Compound 2, in addition to enhancing T cell function, also exhibit the effect of reversing, delaying, or preventing T cell exhaustion, including by increasing T cell signaling and / or altering one or more genes that are differentially regulated after chronic (long-term) stimulation, as found herein. Thus, in some cases, agents that increase or enhance T cell activity may drive cells into a depleted state, but the activity of such immunomodulatory compounds, such as lenalidomide, Compound 1, or Compound 2, to enhance T cell activity is found herein to be dissociable from T cell exhaustion. In some embodiments, the provided methods, including administration of such immunomodulatory compounds, such as lenalidomide, Compound 1, or Compound 2, can enhance the activity of naive T cells and delay, limit, reduce, suppress, or prevent exhaustion.

[0094] Furthermore, observations herein show that immunomodulatory compounds, such as lenalidomide or Compound 1, exhibit the activity of rescuing T cells from T cell exhaustion, for example, by restoring or partially restoring one or more T cell activities after the cells have exhibited characteristics of exhaustion. Notably, results herein show that exposure of T cells that are chronically stimulated and exhibit characteristics of exhausted T cells to the immunomodulatory compounds described herein, such as Compound 1, can restore or partially restore their activity. These results are not observed, in some cases, with interleukin 2 (IL-2), a downstream regulator induced by such immunomodulatory compounds. The observations herein support that the provided methods can also achieve an improved or more persistent response compared to certain alternative methods, for example, in a particular group of subjects being treated.

[0095] These observations were made using a chronic stimulation assay that renders CAR T cells hypofunctional (e.g., reduced cytolysis and IL-2 secretion). Using this model, CAR T cells were examined to assess the effect of immunomodulatory compounds that inhibit E3 ligases, such as lenalidomide, compound 1, or compound 2, on CAR T cell function when present during (concomitant) or after (rescue) exposure to conditions leading to hypofunction and exhaustion. The findings provided herein demonstrate that, upon antigen re-challenge, concomitant treatment of CAR T cells under such conditions reverses the activities and phenotypes, including the gene signature, associated with CAR T cell hypofunction and preserves more effector function. Similarly, the results indicate that immunomodulatory compounds that inhibit E3 ligases, such as lenalidomide, compound 1, or compound 2, were able to rescue or restore T cell functions, including cytokine production and cytolytic activity, in exhausted T cells. Furthermore, the results were seen with different target antigens and different CARs.

[0096] In some embodiments, the effects on T cell exhaustion, such as those observed with immunomodulatory compounds such as lenalidomide or compound 1, are not observed or induced by IL-2. In some embodiments, such effects, such as the ability to reduce, prevent, or delay T cell exhaustion or to rescue or restore T cell activity in exhausted T cells, are not induced by physiologically relevant amounts or therapeutically effective amounts of IL-2. In some embodiments, the effects induced by immunomodulatory compounds, such as lenalidomide or compound 1, such as the ability to reduce, prevent, or delay T cell exhaustion or to rescue or restore T cell activity in exhausted T cells, are greater than or induced by more than 1.2-fold, 2.0-fold, 3-fold, 4.0-fold, 5.0-fold, 6.0-fold, 7.0-fold, 10.0-fold, or more than that seen or induced by IL-2, such as physiologically relevant amounts or therapeutically effective amounts of IL-2, or about 1.2-fold, 2.0-fold, 3-fold, 4.0-fold, 5.0-fold, 6.0-fold, 7.0-fold, 10.0-fold, or more.

[0097] The observations provided herein also demonstrate that immunomodulatory compounds that inhibit E3 ligase exhibit the activity of increasing effector cytokine production by CAR T cells while simultaneously slowing their proliferation rate. This result is not due to the effect of the compound on T cell viability. This effect on proliferation was observed at various concentrations and was found to be due to the accumulation of T cells in the G1 phase. The decoupling of effector cytokine production from this proliferation rate may be clinically beneficial, for example, by limiting T cell differentiation in vivo, which can limit efficacy.

[0098] The findings provided show that in methods involving T cells, such as those including adoptive T cell therapy administration, the combination therapy of immunomodulatory compounds such as structural or functional analogs or derivatives of thalidomide and / or inhibitors of E3 ubiquitin ligase, for example, lenalidomide, compound 1, or compound 2, can achieve improvement in the function of T cell therapy, for example, by enhancing T cell activity and reducing, preventing, or delaying T cell exhaustion, or rescuing cells from T cell exhaustion. In some embodiments, the combination of cell therapy (e.g., administration of engineered T cells) and an immunomodulatory compound, such as lenalidomide or compound 1, improves one or more functions and / or effects of T cell therapy, such as persistence, augmentation, cytotoxicity, and / or therapeutic outcome, such as the ability to kill or reduce the burden of tumors or other diseases or target cells.

[0099] In certain aspects, immunomodulatory compounds such as structural or functional analogs or derivatives of thalidomide and / or inhibitors of E3 ubiquitin ligase, e.g., lenalidomide, Compound 1, or Compound 2, are found herein to promote the continued function and / or survival of cells of T cell therapy (e.g., CAR-T cells) after activation, including after encounter with an antigen. In some aspects, lenalidomide, Compound 1, or Compound 2 increases the ability of such T cells to persist or function for a long period of time, e.g., by preventing exhaustion or cell death. In certain embodiments, an immunomodulatory compound that is an inhibitor of an E3 ligase, e.g., lenalidomide, Compound 2, or combination therapy with Compound 2, can provide a useful therapeutic approach for enhancing and prolonging the activity of CAR T cells across B cell malignancies by modulating the tumor microenvironment by improving the persistent anti-tumor function of CAR T cells. Optionally, the compound can also have a direct anti-tumor effect on lymphoma cells. In some embodiments, such improvement results in a combination therapy that shows an improved overall response, e.g., a reduction in tumor burden, and / or an increase in survival period, compared to a subject treated with monotherapy comprising administration of T cell therapy (e.g., CAR-T cells) or an immunomodulatory compound (e.g., lenalidomide, Compound 1, or Compound 2) alone. In some aspects, the methods provided increase the overall response and / or survival period by 1.5-fold, 2.0-fold, 3.0-fold, 4.0-fold, 5.0-fold, 10-fold or more, or greater than 1.5-fold, 2.0-fold, 3.0-fold, 4.0-fold, 5.0-fold, 10-fold or more, compared to alternative treatments, e.g., compared to monotherapy comprising administration of T cell therapy (e.g., CAR-T cells) or an immunomodulatory compound (e.g., lenalidomide or Compound 1) alone.

[0100] The provided method includes administering compound 1 in an effective amount that exhibits a T cell regulatory effect. It has been found herein that a specific dosage of an exemplary immunomodulatory compound as described, such as lenalidomide or compound 1, increases or enhances the T cell function of T cell therapies, such as CAR-T cell therapy. In some cases, overly high dosages can have a negative impact on T cell function. As shown herein, long-term treatment with compound 1 at physiologically relevant concentrations (10 or 100 nM) can increase the long-term proliferative capacity of CAR-expressing T cells, while higher concentrations, such as 500 mM or about 500 mM, can be detrimental to the performance of the long-term product. In some embodiments, the dosage of compound 1 administered is from 1 mg or about 1 mg to about 10 mg, such as from 1 mg or about 1 mg to about 5 mg. The dosage can be administered daily during the course of the treatment or cycling regimen.

[0101] Similar results were seen with the immunomodulatory drug lenalidomide, although its T cell potency activity was lower than that of compound 1. In CAR-expressing T cells, Ikaros expression decreased in a concentration-dependent manner in the presence of lenalidomide or compound 1 and had similar maximum half-maximal effective concentration (EC50) values, although the magnitude of Ikaros loss was greater after compound 1 treatment. In certain embodiments, a dosage of compound 1 of 40-150 nM (corresponding to an approximately 1 mg dosage level) results in 50% Ikaros degradation in T cells (such as CAR-expressing T cells). Furthermore, in vitro studies evaluating the effect of compound 1 on antigen-dependent cytokine production by CD19-directed CAR-expressing T cells demonstrated increased levels of IFNγ and IL-2 compared to vehicle control or equimolar concentrations of lenalidomide. Thus, administration of compound 1 by the provided method can increase the activity of CAR-expressing cells for treating cancer by enhancing and / or restoring T cell function and the activity of engineered T cells, and in some aspects, may also exhibit its cell-autonomous anti-neoplastic effect.

[0102] In certain embodiments, Compound 2 can be used in any of the provided methods. As described, the findings show that Compound 2 is 10 to 20 times more potent than Compound 1 and is thus also more potent than Compound 2. In some embodiments, the provided method includes administering Compound 2 in an effective amount that exhibits a T cell regulatory effect. In some embodiments, the effective amount is 10 to 20 less than the amount of Compound 1 for the same or similar effect. In some embodiments, the dosage of Compound 2 administered is from 0.1 mg or about 0.1 mg to about 1 mg, for example, from 0.3 mg or about 0.3 mg to about 0.6 mg. The dosage can be administered daily during the course of the treatment or cycling regimen.

[0103] In some embodiments, the combination with an immunomodulatory compound improves one or more outcomes or functional attributes without affecting one or more side effects or unwanted changes in T cells, e.g., without reducing the ability of cells to secrete, increase, and / or sustain one or more desired cytokines, such as those measured in an in vitro assay, that are activated, compared to such cells cultured under otherwise identical conditions but in the absence of the immunomodulatory compound. Thus, in some embodiments, generally provided are methods and combinations that result in an improvement in T cell function or phenotype, e.g., native T cell function and / or native T cell phenotype, without impairing one or more other desired properties of the function, e.g., CAR-T cell function.

[0104] In some embodiments, the provided method can enhance T cell therapy, such as CAR-T cell therapy, which can improve the outcome of treatment in some aspects. In some embodiments, the method is in a subject in which the cells of the T cell therapy show weak growth, are depleted, show reduced persistence or decreased persistence, and / or in a cancer that is resistant or refractory to other therapies, an invasive or high-risk cancer, and / or in a subject having a cancer that may have or is likely to have a relatively low response rate to CAR-T cell therapy administered without an immunomodulatory compound as compared to another type of cancer or compared to the administration of a different CAR-T cell therapy, and is particularly advantageous.

[0105] In some embodiments, the provided method is used when T cell therapy (e.g., CAR T cells) may or is likely to exhibit characteristics of exhaustion. In some embodiments, the exhausted phenotype becomes apparent after T cells that had reached peak expansion begin to decline in number in the subject's blood. In some embodiments, the method of exposing or contacting T cells of the T cell therapy (CAR T cells) with an immunomodulatory compound that inhibits an E3 ligase, such as lenalidomide, Compound 1, or Compound 2, is performed when the T cells show an increase in a hypofunctional or exhausted state as compared to just prior to exposure of the T cells to the antigen (baseline), or when the cells are exposed to the antigen but continue to proliferate and have not yet reached peak expansion. In some embodiments, the increase in the hypofunctional or exhausted state can be determined by an increase in the expression of exhaustion markers as compared to an earlier initial time point. In some embodiments, the increase in the hypofunctional or exhausted state, such as an increase in the expression of exhaustion markers, is at a time after administration of T cell therapy (e.g., CAR T cells) to a subject having a disease or condition associated with the antigen targeted by the T cell therapy. T cells, such as T cells in peripheral blood after administration to the subject, can be monitored for markers of T cell activation or exhaustion, such as PD-1, TIM-3, and LAG-3.

[0106] In some situations, the provided method can overcome, for example, the lack of persistence and / or exhaustion of T cells, such as less than 10 μL, for example less than 5 μL or less than 1 μL of such cells or its CD8+ or CD3+ subset being detectable in the blood of a subject at about days 12-15 or about 12-15 days after the start of administration of T cell therapy, by enhancing, increasing or strengthening T cell therapy. In some embodiments, a subject receiving T cell therapy, such as administration of CAR-T cells, is monitored for the presence, absence or level of the T cells of the therapy in the subject, such as in a biological sample of the subject, such as in the blood of the subject. In some embodiments, immunomodulatory compounds such as structural or functional analogs or derivatives of thalidomide and / or inhibitors of E3 ubiquitin ligase, such as lenalidomide, Compound 1 or Compound 2, are administered to a subject receiving T cell therapy (such as CAR-T cells) in which such cells are growing weakly and / or in which strong or robust expansion of CAR-T cells in the subject typically occurs at a time point when, in a plurality of subjects administered the same T cell therapy (such as the same CAR-T cells) in some cases, such cells are below a threshold level in a sample of the subject, such as a blood sample. In some situations, immunomodulatory compounds such as structural or functional analogs or derivatives of thalidomide and / or inhibitors of E3 ubiquitin ligase, such as lenalidomide, Compound 1 or Compound 2, are administered at about days 12-15 or about 12-15 days after the start of administration of T cell therapy when less than 10 μL, for example less than 5 μL or less than 1 μL of such cells or its CD8+ or CD3+ subset is detectable in the blood.

[0107] In certain aspects, the provided methods can enhance, increase, or potentiate T cell therapy in a subject in whom peak responses to T cell therapy have been observed, but in which the response, such as the presence of T cells and / or reduction in tumor burden, is decreasing or is no longer detectable. In some aspects, immunomodulatory compounds such as structural or functional analogs or derivatives of thalidomide and / or inhibitors of E3 ubiquitin ligases, such as lenalidomide, Compound 1, or Compound 2, are administered to a subject when (i) the peak or maximal level of cells of the T cell therapy becomes detectable in the subject's blood; (ii) the number of detectable cells of the T cell therapy in the blood becomes undetectable or is reduced, optionally reduced compared to a prior time point after administration of the T cell therapy, after becoming detectable in the blood; (iii) the number of detectable cells of the T cell therapy in the blood is reduced by 1.5-fold or more than 1.5-fold, 2.0-fold or more than 2.0-fold, 3.0-fold or more than 3.0-fold, 4.0-fold or more than 4.0-fold, 5.0-fold or more than 5.0-fold, 10-fold or more than 10-fold, or more, from the peak or maximal number of detectable cells of the T cell therapy in the subject's blood after the start of administration of the T cell therapy; (iv) at a time point after the peak or maximal level of cells of the T cell therapy becomes detectable in the subject's blood, the number of detectable T cells or cells derived therefrom in blood from the subject is less than 10%, less than 5%, less than 1%, or less than 0.1% of the total peripheral blood mononuclear cells (PBMCs) in the subject's blood; (v) the subject exhibits disease progression following treatment with T cell therapy and / or relapses following remission; and / or (iv) the subject is administered within one week, such as within 1 day, 2 days, or 3 days, after showing an increased tumor burden compared to the tumor burden at a time point before or after administration of the T cells and before the start of administration of the immunomodulatory compound.

[0108] In some embodiments, the method is for treating a disease or condition, such as a B cell malignancy or a hematological malignancy, in particular, the response to treatment with a T cell therapy alone (e.g., a composition comprising cells for adoptive cell therapy (e.g., T cell therapy) such as CAR-expressing T cells), such as a complete response, is low compared to other T cell therapies or treatments for other diseases or malignancies (e.g., less than 60% or about 60% or less, less than 50% or about 50% or less or less than 45% or about 45% or less of subjects so treated have a CR), and / or the disease, condition or malignancy is not responsive to treatment with an immunomodulatory compound such as a structural or functional analog or derivative of thalidomide and / or an inhibitor of an E3 ubiquitin ligase, such as lenalidomide, compound 1 or compound 2 alone, and can be used to treat such diseases, conditions or malignancies.

[0109] In some embodiments, the combination therapies provided herein are for use in a subject having cancer who has relapsed following remission after treatment with a T cell therapy (e.g., a composition comprising cells for adoptive cell therapy, such as CAR-expressing T cells), after the initiation of administration of the T cell therapy. In some embodiments, an immunomodulatory compound such as a structural or functional analog or derivative of thalidomide and / or an inhibitor of an E3 ubiquitin ligase, such as lenalidomide, Compound 1 or Compound 2, is administered to a subject who has relapsed following such remission. In some embodiments, the combination therapies provided herein are for use in a subject having a disease or condition, such as cancer, wherein the amount of the immunomodulatory compound administered is insufficient to improve, reduce or prevent the disease or condition or its symptoms or outcome, e.g., insufficient to improve, reduce or prevent the disease or condition or its symptoms or outcome in the subject, when administered as a single agent and / or in the absence of administration of a T cell therapy. In some embodiments, the method thereby reduces or improves the symptoms or outcome or burden of the disease or condition to an extent that exceeds the combination of (i) the degree of reduction or improvement achieved by administration of the immunomodulatory agent alone, optionally averaged in a population of subjects having the disease or condition, and (ii) the degree of reduction or improvement by administration of the T cell therapy alone, optionally averaged in a population of subjects having the disease or condition. In some embodiments, the method reduces or improves such symptoms, outcome or burden of the disease, e.g., by more than 1.5-fold or about 1.5-fold, more than 2.0-fold or about 2.0-fold, more than 3.0-fold or about 3.0-fold, more than 4.0-fold or about 4.0-fold, more than 5.0-fold or about 5.0-fold, more than 6.0-fold or about 6.0-fold, more than 7.0-fold or about 7.0-fold, more than 8.0-fold or about 8.0-fold, more than 9.0-fold or about 9.0-fold, more than 10.0-fold or about 10.0-fold, more than 20.0-fold or about 20.0-fold, more than 30.0-fold or about 30.0-fold, more than 40.0-fold or about 40.0-fold, more than 50.0-fold or about 50.0-fold or more, as compared to an average population of subjects having the disease or condition.

[0110] In some embodiments, the combination therapy provided is used in conjunction with the treatment of certain diseases or conditions, such as cancer, where it is difficult to achieve optimal stimulation of recombinant antigen receptors, such as CAR-T cells, and / or where such stimulation is not consistently observed. In some embodiments, suboptimal stimulation may result in in vivo, for example, low or inaccessible levels of disease antigen on or in tumors. In some embodiments, certain cancers, such as NHLs, such as high-risk or aggressive NHLs, such as DLBCL, and / or chronic lymphocytic leukemia (CLL), may be associated with defects or reductions in native T cell function that are in some cases affected by the disease itself. For example, the pathogenesis of many cancers, such as CLL and NHLs, such as DLBCL, may be associated with immunodeficiency that promotes tumor growth and immune evasion, such as by T cell immunosuppression being driven by one or more factors in the tumor microenvironment. In some cases, alleviating such native T cell defects obtained from the cancer of such patients in conjunction with adoptive cell therapy can also provide a stronger response to adoptive T cell therapy, such as CAR-T cell therapy. In some cases, suboptimal stimulation may be due to differences in the expression levels of CARs on engineered T cells administered to a subject. In any of such embodiments, administration of an immunomodulatory compound, such as lenalidomide, Compound 1 or Compound 2, which is a structural or functional analog or derivative of thalidomide and / or an inhibitor of an E3 ubiquitin ligase, can enhance such T cell stimulation or activity in vivo in a subject.

[0111] In some embodiments of the provided methods, it is possible to improve or increase or make greater one or more properties of the administered genetically engineered cells as compared to the cells of the reference composition (e.g., enhanced or longer expansion and / or persistence of such administered cells in a subject and / or increased or greater recall response when restimulated with an antigen, etc.). In some embodiments, the increase is at least 1.2-fold, at least 1.5-fold, at least 2-fold, up to 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, or at least 10-fold increase in such property or characteristic as compared to the same property or characteristic when the reference cell composition is administered. In some embodiments, an increase in one or more of such properties or characteristics can be observed or present within 7 days, within 14 days, within 21 days, within 1 month, within 2 months, within 3 months, within 4 months, within 5 months, within 6 months, or within 12 months after administration of the genetically engineered cells and after initiation of administration of an immunomodulatory compound (e.g., a structural or functional analog or derivative of thalidomide and / or an inhibitor of an E3 ubiquitin ligase, such as lenalidomide or compound 1).

[0112] In some embodiments, the reference cell composition can be a composition of T cells derived from the blood of a subject without or suspected of having cancer, or an isolated, produced, produced, incubated and / or administered population of T cells obtained under the same or substantially the same conditions except that it has not been incubated or administered in the presence of an immunomodulatory compound. In some embodiments, the reference cell composition contains genetically engineered cells that are substantially the same, including the expression of the same recombinant receptor (e.g., CAR). In some aspects, such T cells are treated identically or substantially identically, e.g., made in the same way, formulated in the same way, and administered at the same or nearly the same dosage and other similar factors.

[0113] In some embodiments, provided are methods that result in increased persistence of genetically engineered cells and / or better efficacy in a subject to which the cells are administered. In some embodiments, the persistence of genetically engineered cells (e.g., CAR-expressing T cells, etc.) in a subject is increased compared to the persistence that would be achieved by alternative methods (e.g., methods involving administration of a reference cell composition, such as T cell therapy administration without administration of an immunomodulatory compound). In some embodiments, the persistence is increased by at least 1.5-fold or about at least 1.5-fold, at least 2-fold or about at least 2-fold, at least 3-fold or about at least 3-fold, at least 4-fold or about at least 4-fold, at least 5-fold or about at least 5-fold, at least 6-fold or about at least 6-fold, at least 7-fold or about at least 7-fold, at least 8-fold or about at least 8-fold, at least 9-fold or about at least 9-fold, at least 10-fold or about at least 10-fold, at least 20-fold or about at least 20-fold, at least 30-fold or about at least 30-fold, at least 50-fold or about at least 50-fold, at least 60-fold or about at least 60-fold, at least 70-fold or about at least 70-fold, at least 80-fold or about at least 80-fold, at least 90-fold or about at least 90-fold, at least 100-fold or about at least 100-fold, or more.

[0114] In some embodiments, the degree or extent of persistence of the administered cells can be detected or quantified after administration to a subject. For example, in some instances, quantitative PCR (qPCR) is used to evaluate the amount of cells expressing a recombinant receptor (e.g., CAR-expressing cells) in the subject's blood or serum or organ or tissue (e.g., the diseased site). In some instances, persistence is quantified as the copy number of DNA encoding the receptor (e.g., CAR) or plasmid per microgram of DNA, or as the number of receptor-expressing cells (e.g., CAR-expressing cells) per microliter of sample (e.g., blood or serum), or relative to the total number of peripheral blood mononuclear cells (PBMCs) or leukocytes or T cells in a microliter of sample. In some embodiments, a flow cytometry assay can also be performed to detect cells expressing the receptor, generally using an antibody specific for the receptor. Cell-based assays can also be used to detect the number or proportion of functional cells (e.g., cells capable of binding to diseased or pathological cells and / or neutralizing diseased or pathological cells and / or inducing a response (e.g., a cytotoxic response, etc.) to diseased or pathological cells or expressing an antigen recognized by the receptor). In any such embodiment, the degree or level of expression of another marker associated with the recombinant receptor (e.g., CAR-expressing cells) can be used to distinguish the administered cells from endogenous cells in the subject.

[0115] Also, for example, methods for engineering, preparing, and making cells, compositions containing cells and / or immunomodulatory compounds, and kits and devices containing cells and / or inhibitors, as well as kits and devices for using, manufacturing, and administering cells and / or immunomodulatory compounds, are provided, such as according to the provided combination therapies.

[0116] All publications referred to in this application, including patent documents, scientific papers, and databases, are hereby incorporated by reference in their entirety for all purposes as if each individual publication were individually incorporated by reference. If the definitions set forth herein conflict with or otherwise do not match the definitions set forth in patents, patent applications, published patent applications, and other publications incorporated by reference herein, the definitions set forth herein shall control over the definitions incorporated by reference herein.

[0117] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0118] I. Combination Therapy Provided herein are methods for combination therapies for treating a disease or disorder, such as cancer or a proliferative disease, comprising administering to a subject a combination therapy that includes 1) an immunomodulatory compound, such as lenalidomide, or Compound 1 and Compound 2, which are structural or functional analogs or derivatives of thalidomide and / or inhibitors of E3 ubiquitin ligase, and 2) a T cell therapy, such as a chimeric antigen receptor (CAR)-expressing cell, such as a T cell. In certain embodiments, the immunomodulatory compound is an inhibitor of an E3 ubiquitin ligase. In some embodiments, the T cell therapy is an adoptive immunocyte therapy comprising T cells that specifically recognize and / or target an antigen associated with a disease or disorder, such as cancer or a proliferative disease. Also provided are combinations and articles of manufacture, such as kits, containing a composition comprising a T cell therapy and / or a composition comprising an immunomodulatory compound, and the use of such compositions and combinations for treating or preventing diseases, conditions, and disorders, including cancer.

[0119] In some embodiments, such a method can include administering an immunomodulatory compound, such as lenalidomide, Compound 1, or Compound 2, which is a structural or functional analog or derivative of thalidomide and / or an inhibitor of an E3 ubiquitin ligase, before, simultaneously with, during, over the course of (including once and / or periodically over the course of), and / or subsequent to the administration of T cell therapy (e.g., CAR-expressing T cells), such as the initiation of the administration. In some embodiments, the administration can include sequential or intermittent administration of the immunomodulatory compound and the T cell therapy.

[0120] In some embodiments, the cell therapy is adoptive cell therapy. In some embodiments, the cell therapy is tumor-infiltrating lymphocyte (TIL) therapy, transgenic TCR therapy, or recombinant receptor-expressing cell therapy (optionally T cell therapy), which is optionally chimeric antigen receptor (CAR)-expressing cell therapy, or includes the same. In some embodiments, the therapy is a therapy in which B cells are targeted. In some embodiments, the therapy targets B cell maturation antigen (BCMA). In some embodiments, the therapy targets CD19. In some embodiments, the cells and the dosing regimen for administering the cells can include any of those described under "Administration of T Cell Therapy" in Subsection A below.

[0121] In some embodiments, the immunomodulatory compound enhances T cell function. In some embodiments, the immunomodulatory compound promotes anti-myeloma activity. In some embodiments, the immunomodulatory compound modifies the suppressive microenvironment.

[0122] In some embodiments, the immunomodulatory compound is a structural or functional analog or derivative of thalidomide. In some embodiments, the immunomodulatory compound is an inhibitor of an E3 ubiquitin ligase. In some embodiments, the immunomodulatory compound is lenalidomide or a compound having the same or similar properties as lenalidomide, including analogs or derivatives of lenalidomide, stereoisomers thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds or polymorphs thereof. In some embodiments, the immunomodulatory compound is compound 1 as described or a compound having the same or similar properties as compound 1, including analogs or derivatives of compound 1, stereoisomers thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds or polymorphs thereof. In some embodiments, the immunomodulatory compound is compound 1 as described or a compound having the same or similar properties as compound 1, including analogs or derivatives of compound 1, stereoisomers thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds or polymorphs thereof. In some embodiments, the dosing regimen for administering the immunomodulatory compound can include any as described under "Administration of Immunomodulatory Compounds" in Subsection B below.

[0123] In some embodiments, T cell therapy (e.g., CAR-expressing T cells) and an immunomodulatory compound are provided as a pharmaceutical composition for administration to a subject. In some embodiments, the pharmaceutical composition contains a therapeutically effective amount of one or both of the agents (e.g., T cells for adoptive cell therapy and an immunomodulatory compound as described) for combination therapy. In some embodiments, the agents are formulated for administration in separate pharmaceutical compositions. In some embodiments, any of the pharmaceutical compositions provided herein can be formulated in a dosage form appropriate for each route of administration.

[0124] In some embodiments, the combination therapy involves administering a T cell therapy comprising engineered cells, such as CAR-T cell therapy, etc., and an immunomodulatory compound, and is thus administered to a subject or patient having or at risk of having a disease or condition to be treated (e.g., cancer), such as cancer. In some aspects, the method provides for the treatment of a disease or condition, e.g., improvement of one or more symptoms of the disease or condition, such as reducing tumor burden in a cancer that expresses an antigen recognized by an immunotherapy or immunotherapeutic agent, e.g., an antigen recognized by engineered T cells.

[0125] In some embodiments, the disease or condition to be treated is one in which antigen expression is associated with and / or involved in the etiology of the disease, condition, or disorder, e.g., causes, exacerbates, or otherwise is involved in such a disease, condition, or disorder. Exemplary diseases and conditions can include those associated with malignant tumors or cell transformation (e.g., cancer), autoimmune or inflammatory diseases, or infectious diseases (e.g., infectious diseases caused by bacterial pathogens, viral pathogens, or other pathogens). Exemplary antigens can include any of the antigens described herein, including those associated with the various diseases and conditions that can be treated. In certain embodiments, a recombinant receptor expressed on the surface of the engineered cells of the combination therapy, including a chimeric antigen receptor or transgenic TCR, specifically binds to an antigen associated with the disease or condition.

[0126] In some embodiments, the disease or condition is a tumor (e.g., a solid tumor, etc.), lymphoma, leukemia, hematologic malignancy, metastatic tumor, or other cancer or tumor type.

[0127] In some embodiments, the cancer or proliferative disorder is a B cell malignancy or a hematological malignancy. In some embodiments, the cancer or proliferative disorder is lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), or chronic lymphocytic leukemia (CLL). In some embodiments, the cancer is CLL. In some embodiments, the method can be used to treat multiple myeloma, lymphoma or leukemia. In some embodiments, the method can be used to treat non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), diffuse large B cell lymphoma (DLBCL), acute myeloid leukemia (AML), or multiple myeloma (e.g., multiple myeloma (MM)). In some embodiments, the method can be used to treat MM or DBCBL.

[0128] In some embodiments, the antigen associated with the disease or disorder is selected from the group consisting of ROR1, and B cell maturation antigen (BCMA), Her2, L1-CAM, CD19, CD20, CD22, mesothelin, CEA, hepatitis B surface antigen, anti-folate receptor, CD23, CD24, CD30, CD33, CD38, CD44, EGFR, EGP-2, EGP-4, EphA2, ErbB2, 3 or 4, erbB dimer, EGFR vIII, FBP, FCRL5, FCRH5, fetal acetylcholine e receptor, GD2, GD3, HMW-MAA, IL-22R-alpha, IL-13R-alpha2, kdr, kappa light chain, Lewis Y, L1-cell adhesion molecule (L1-CAM), melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, melanoma-predominant expression antigen (PRAME), survivin, EGP2, EGP40, TAG72, B7-H6, IL-13 receptor a2 (IL-13Ra2), CA9, GD3, HMW-MAA, CD171, G250 / CAIX, HLA-AI MAGE Al, HLA-A2 NY-ESO-1, PSCA, folate receptor-a, CD44v6, CD44v7 / 8, avb6 integrin, 8H9, NCAM, VEGF receptor, 5T4, fetal AchR, NKG2D ligand, CD44v6, dual antigen, and antigen associated with universal tag, cancer testicular antigen, mesothelin, MUC1, MUC16, PSCA, NKG2D ligand, NY-ESO-1, MART-1, gp100, G protein-coupled receptor 5D (GPCR5D), tumor fetal antigen, ROR1, TAG72, VEGF-R2, cancer fetal antigen (CEA), prostate-specific antigen, PSMA, Her2 / neu, estrogen receptor, progesterone receptor, ephrin B2, CD123, c-Met, GD-2, O-acetylated GD2 (OGD2), CE7, Wilms tumor 1 (WT-1), cyclin, cyclin A2, CCL-1, CD138, and pathogen-specific antigen. In some embodiments, the antigen is associated with a universal tag or is a universal tag.

[0129] In some embodiments, the cancer or proliferative disorder expresses BCMA. In some embodiments, the provided methods use recombinant receptor-expressing T cells (e.g., CAR-T cells) that target BCMA.

[0130] In some embodiments, the cancer or proliferative disorder expresses CD19. In some embodiments, the provided methods use recombinant receptor-expressing T cells (e.g., CAR-T cells) that target CD19.

[0131] In some embodiments, the methods can be used to treat non-blood cancers (e.g., solid tumors, etc.). In some embodiments, the methods can be used to treat cancers of the bladder, lung, brain, melanoma (e.g., small cell lung, melanoma), breast, cervix, ovary, colorectal, pancreas, endometrium, esophagus, kidney, liver, prostate, skin, thyroid, or uterus. In some embodiments, the cancer or proliferative disorder is cancer, and is pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, pancreatic cancer, rectal cancer, thyroid cancer, uterine cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain tumor, bone cancer, or soft tissue sarcoma.

[0132] In some embodiments, the disease or condition is an infectious disease or condition, such as, but not limited to, viral infections, retroviral infections, bacterial infections, and protozoal infections, immunodeficiency, cytomegalovirus (CMV), Epstein-Barr virus (EBV), adenovirus, BK polyomavirus, etc. In some embodiments, the disease or condition is an autoimmune or inflammatory disease or condition, such as, but not limited to, arthritis (e.g., rheumatoid arthritis (RA)), type I diabetes, systemic lupus erythematosus (SLE), inflammatory bowel disease, psoriasis, scleroderma, autoimmune thyroid disease, Graves' disease, Crohn's disease, multiple sclerosis, asthma, and / or diseases or conditions associated with transplantation.

[0133] For the prevention or treatment of a disease, the appropriate dosage of an immunomodulatory compound (e.g., lenalidomide, compound 1 or compound 2) and / or immunotherapy (e.g., T cell therapy (e.g., CAR-expressing T cells)) may depend on the type of disease to be treated, the specific immunomodulatory compound, the cells and / or the recombinant receptor expressed on the surface of the cells, the severity and course of the disease, the route of administration, whether the immunomodulatory compound and / or T cell therapy is administered for prophylactic or therapeutic purposes, previous treatments, the dosing frequency, the clinical history of the subject and the response to the cells, as well as the judgment of the attending physician. The compositions and cells are preferably administered to a patient in some embodiments once or over a series of treatments. Exemplary dosing regimens and schedules for the provided combination therapies are described.

[0134] In some embodiments, the T cell therapy and the immunomodulatory compound are administered as part of a further combination treatment that can be administered simultaneously with or sequentially to another therapeutic intervention, in any order. In some situations, the T cell therapy, e.g., engineered T cells (e.g., CAR-expressing T cells, etc.), is co-administered with another treatment that is sufficiently close in time such that the T cell therapy enhances the effect of one or more further therapeutic agents, or co-administration is performed in the reverse manner. In some embodiments, the cells are administered prior to the one or more further therapeutic agents. In some embodiments, the T cell therapy, e.g., engineered T cells (e.g., CAR-expressing T cells, etc.), is administered after the one or more further therapeutic agents. In some embodiments, the combination therapy method further comprises lymphodepleting therapy (e.g., administration of a chemotherapeutic agent, etc.). In some embodiments, the combination therapy further comprises administering another therapeutic agent (e.g., an anti-cancer agent, a checkpoint inhibitor or another immunomodulatory agent, etc.). Use includes the use of the combination therapy in such methods and treatments, as well as the use of such compositions in the preparation of medicaments for practicing such combination therapy methods. In some embodiments, the methods and uses thereby treat a disease or condition or disorder (e.g., cancer or a proliferative disease, etc.) in a subject.

[0135] Before, during, or after administration of immunotherapy (e.g., T cell therapy, e.g., CAR-T cell therapy, etc.) and / or immunomodulatory compounds, the biological activity of the T cell therapy, e.g., the biological activity of the engineered cell population, is measured in some aspects, e.g., by any of several known methods. Parameters for evaluation include, for example, the ability of the engineered cells to destroy target cells, the persistence of T cell activity, and other metrics, such as those measured using any suitable method known in the art, e.g., assays further described in Section III below. In some aspects, the biological activity of the cells (e.g., T cells administered for T cell-based therapy) is measured by assaying cytotoxic cell killing, expression and / or secretion of one or more cytokines, proliferation, or expansive proliferation (e.g., when restimulated with an antigen). In some contexts, the biological activity is measured by evaluating disease burden and / or clinical outcome (e.g., a decrease in tumor mass or tumor cell mass, etc.). In some aspects, the administration of one or both of the agents of the combination therapy, and / or any repeated administration of the therapy, can be determined based on the results of an assay before, during, the course of, or after administration of one or both of the agents of the combination therapy.

[0136] In some aspects, the combined effect of an immunomodulatory compound in combination with cell therapy can be synergistic compared to treatment with the immunomodulatory compound alone or monotherapy with cell therapy alone. For example, in some aspects, the methods provided herein result in an increase or improvement in the desired therapeutic effect, e.g., an increase or improvement in the reduction or suppression of one or more symptoms associated with cancer.

[0137] In some embodiments, the immunomodulatory compound enhances the expansion or proliferation of engineered T cells (e.g., CAR T cells, etc.). In some embodiments, the enhancement in expansion or proliferation is observed in vivo when administered to a subject. In some embodiments, the increase in the number of engineered T cells (e.g., CAR-T cells) is more than 1.2-fold or about 1.2-fold, more than 1.5-fold or about 1.5-fold, more than 2.0-fold or about 2.0-fold, more than 3.0-fold or about 3.0-fold, more than 4.0-fold or about 4.0-fold, more than 5.0-fold or about 5.0-fold, more than 6.0-fold or about 6.0-fold, more than 7.0-fold or about 7.0-fold, more than 8.0-fold or about 8.0-fold, more than 9.0-fold or about 9.0-fold, more than 10.0-fold or about 10.0-fold, or greater.

[0138] A. Performance of T cell therapy In some embodiments of the methods, compositions, combinations, kits and uses provided herein, the combination therapy includes administering to a subject an immune cell therapy such as T cell therapy (e.g., CAR-expressing T cells). The performance of such therapy can be initiated before, after, or simultaneously with the administration of one or more immunomodulatory compounds, as described.

[0139] In some embodiments, the cell therapy is or includes the administration of immune cells, such as T cells or NK cells, that target a molecule expressed on the surface of a lesion such as a tumor or cancer. In some embodiments, the immune cells express a T cell receptor (TCR) or other antigen-binding receptor. In some embodiments, the immune cells express a recombinant receptor such as a transgenic TCR or chimeric antigen receptor (CAR). In some embodiments, the cells are autologous to the subject. In some embodiments, the cells are allogeneic to the subject.

[0140] In some aspects, T cell therapy is or includes T cell therapy involving genetically engineered cells such as tumor infiltrating lymphocyte (TIL) therapy, transgenic TCR therapy, or recombinant receptor-expressing cell therapy. In some embodiments, the recombinant receptor specifically binds to a ligand that is associated with a disease or condition, such as one that is associated with or expressed on the cells of a tumor or cancer. In some embodiments, T cell therapy includes administering T cells engineered to express a chimeric antigen receptor (CAR).

[0141] In some embodiments, the provided cells express and / or are engineered to express a receptor such as a recombinant receptor that includes a ligand binding domain or a binding fragment thereof, as well as a T cell receptor (TCR) and its components, and / or a functional non-TCR antigen receptor such as a chimeric antigen receptor (CAR). In some embodiments, the recombinant receptor includes an extracellular ligand binding domain that specifically binds to an antigen. In some embodiments, the recombinant receptor is a CAR that includes an extracellular antigen recognition domain that specifically binds to an antigen. In some embodiments, a ligand such as an antigen is a protein expressed on the surface of a cell. In some embodiments, the CAR is a TCR-like CAR and the antigen is a processed peptide antigen such as a peptide antigen of an intracellular protein, which is recognized on the cell surface in association with a major histocompatibility complex (MHC) molecule, like a TCR.

[0142] Engineered cells containing recombinant receptors, including some of those described in Section II below. Exemplary recombinant receptors include CARs and recombinant TCRs, and methods for engineering and introducing receptors into cells are described, for example, in WO 2000 / 014257, WO 2013 / 126726, WO 2012 / 129514, WO 2014 / 031687, WO 2013 / 166321, WO 2013 / 071154, WO 2013 / 123061, WO 2016 / 0046724, WO 2016 / 014789, WO 2016 / 090320, WO 2016 / 094304, WO 2017 / 025038, WO 2017 / 173256, US 2002 / 0131960, US 2013 / 287748, US 2013 / 0149337, US 6,451,995, US 7,446,190, US 8,252,592, US 8,339,645, US 8,398,282, US 7,446,179, US 6,410,319, US 7,070,995, US 7,265,209, US 7,354,762, US 7,446,191, US 8,324,353, US 8,479,118, and US 9,765,342, and EP 2537416, and / or those described by Sadelain et al., Cancer Discov., 3(4):388-398 (2013); Davila et al., PLoS ONE 8(4):e61338 (2013); Turtle et al., Curr. Opin. Immunol., 24(5):633-39 (2012); Wu et al., Cancer, 18(2):160-75 (2012). In some aspects, the genetically engineered antigen receptors include those described in US 7,446,190 and WO 2014 / 055668A1.

[0143] In some embodiments, the antigen is αvβ6 integrin (avb6 integrin), B cell maturation antigen (BCMA), B7-H3, B7-H6, carbonic anhydrase 9 (CA9, also known as CAIX or G250), cancer / testis antigen, cancer / testis antigen 1B (CTAG, also known as NY-ESO-1 and LAGE-2), carcinoembryonic antigen (CEA), cyclin, cyclin A2, C-C motif chemokine ligand 1 (CCL-1), CD19, CD20, CD22, CD23, CD24, CD30, CD33, CD38, CD44, CD44v6, CD44v7 / 8, CD123, CD133, CD138, CD171, chondroitin sulfate proteoglycan 4 (CSPG4), epidermal growth factor protein (EGFR), truncated epidermal growth factor protein (tEGFR), epidermal growth factor receptor variant type III (EGFR vIII), epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), ephrin B2, ephrin receptor A2 (EPHa2), estrogen receptor, Fc receptor-like 5 (FCRL5; also known as Fc receptor homolog 5 or FCRH5), fetal acetylcholine receptor (fetal AchR), folate-binding protein (FBP), folate receptor alpha, ganglioside GD2, O-acetylated GD2 (OGD2), ganglioside GD3, glycoprotein 100 (gp100), glypican-3 (GPC3), G protein-coupled receptor 5D (GPCR5D), Her2 / neu (receptor tyrosine kinase erb-B2), Her3 (erb-B3), Her4 (erb-B4), erbB dimer, human high-molecular weight-melanoma associated antigen (HMW-MAA), hepatitis B surface antigen, human leukocyte antigen A1 (HLA-A1), human leukocyte antigen A2 (HLA-A2), IL-22 receptor alpha (IL-22Rα), IL-13 receptor alpha 2 (IL-13Rα2), kinase insert domain receptor (kdr), kappa light chain, L1 cell adhesion molecule (L1-CAM), CE7 epitope of L1-CAM, leucine-rich repeat-containing 8 family member A (LRRC8A), Lewis Y, melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, MAGE-A10, mesothelin (MSLN), c-Met, murine cytomegalovirus (CMV),Mucin 1 (MUC1), MUC16, Natural Killer group 2 member D (NKG2D) ligand, Melan A (MART-1), Neural Cell Adhesion Molecule (NCAM), Tumor fetal antigen, Melanoma preferentially expressed antigen (PRAME), Progesterone receptor, Prostate specific antigen, Prostate stem cell antigen (PSCA), Prostate specific membrane antigen (PSMA), Receptor-type tyrosine kinase-like orphan receptor 1 (ROR1), Survivin, Trophoblast glycoprotein (TPBG, also known as 5T4), Tumor-associated glycoprotein 72 (TAG72), Tyrosinase-related protein 1 (TRP1, also known as TYRP1 or gp75), Tyrosinase-related protein 2 (TRP2, dopachrome tautomerase, dopachrome delta-isomerase or DCT), Vascular endothelial growth factor receptor (VEGFR), Vascular endothelial growth factor receptor 2 (VEGFR2), Wilms tumor 1 (WT-1), pathogen-specific antigen or pathogen-expressed antigen, or an antigen associated with a universal tag, and / or a biotinylated molecule, and / or a molecule expressed by or comprising HIV, HCV, HBV or other pathogen. The antigen targeted by the receptor includes, in some embodiments, an antigen associated with B cell malignancies such as any number of known B cell markers. In some embodiments, the antigen is or includes CD20, CD19, CD22, ROR1, CD45, CD21, CD5, CD33, Ig kappa, Ig lambda, CD79a, CD79b or CD30.,

[0144] In some embodiments, the antigen is or includes a pathogen-specific antigen or pathogen-expressed antigen. In some embodiments, the antigen is a viral antigen (e.g., a viral antigen derived from HIV, HCV, HBV, etc.), a bacterial antigen, and / or a parasitic antigen.

[0145] In some embodiments, the combination therapy comprises administering to a subject cells, such as T cells, that express a recombinant receptor that specifically recognizes and / or targets an antigen associated with cancer and / or present on a universal tag.In some embodiments, the antigen recognized or targeted by T cells is ROR1, B cell maturation antigen (BCMA), carbonic anhydrase 9 (CAIX), tEGFR, Her2 / neu (receptor tyrosine kinase erbB2), L1-CAM, CD19, CD20, CD22, mesothelin, CEA, and hepatitis B surface antigen, anti-folate receptor, CD23, CD24, CD30, CD33, CD38, CD44, EGFR, epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), EPHa2, erb-B2, erb-B3, erb-B4, erbB dimer, EGFR vIII, folate binding protein (FBP), FCRL5, FCRH5, fetal acetylcholine receptor, GD2, GD3, HMW-MAA, IL-22R-alpha, IL-13R-alpha2, kinase insert domain receptor (kdr), kappa light chain, Lewis Y, L1-cell adhesion molecule (L1-CAM), melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, melanoma-predominantly expressed antigen (PRAME), survivin, TAG72, B7-H6, IL-13 receptor alpha2 (IL-13Ra2), CA9, GD3, HMW-MAA, CD171, G250 / CAIX, HLA-AI MAGE Al, HLA-A2, PSCA, folate receptor-a, CD44v6, CD44v7 / 8, avb6 integrin, 8H9, NCAM, VEGF receptor, 5T4, fetal AchR, NKG2D ligand, CD44v6, dual antigen, cancer testis antigen, mesothelin, murine CMV, mucin 1 (MUC1), MUC16, PSCA, NKG2D, NY-ESO-1, MART-1, gp100, G protein-coupled receptor 5D (GPCR5D), tumor fetal antigen, ROR1, TAG72, VEGF-R2, cancer fetal antigen (CEA), Her2 / neu, estrogen receptor, progesterone receptor, ephrin B2, CD123, c-Met, GD-2, O-acetylated GD2 (OGD2), CE7, Wilms tumor 1 (WT-1), cyclin, cyclin A2, CCL-1, CD138, optionally any of the foregoing human antigens; a pathogen-specific antigen.

[0146] Methods of administering engineered cells for adoptive cell therapy are known and can be used in connection with the provided methods and compositions. For example, methods of adoptive T cell therapy are described, e.g., in U.S. Patent Application Publication No. 2003 / 0170238 to Gruenberg et al.; U.S. Patent No. 4,690,915 to Rosenberg; Rosenberg (2011) Nat Rev Clin Oncol. 8(10):577-85). See, e.g., Themeli et al., (2013) Nat Biotechnol. 31(10):928-933; Tsukahara et al., (2013) Biochem Biophys Res Commun 438(1):84-9; Davila et al., (2013) PLoS ONE 8(4):e61338.

[0147] In some embodiments, cell therapy, e.g., adoptive T cell therapy, is performed by autologous transplantation, where the cells are isolated from and / or otherwise prepared from a sample from or of a subject who is or will be undergoing the cell therapy. Thus, in some aspects, the cells are derived from a subject in need of treatment, e.g., a patient, and are administered to the same subject after isolation and processing.

[0148] In some embodiments, cell therapy, e.g., adoptive T cell therapy, is performed by allogeneic transplantation, where the cells are isolated from and / or otherwise prepared from a subject other than the subject who is or will ultimately be undergoing the cell therapy, e.g., a first subject. In such embodiments, the cells are then administered to a different subject of the same species, e.g., a second subject. In some embodiments, the first and second subjects are genetically identical. In some embodiments, the first and second subjects are genetically similar. In some embodiments, the second subject expresses the same HLA class or supertype as the first subject.

[0149] In certain embodiments, individual populations of cells, or cell subtypes, are administered to a subject in the range of about 1 million to about 100 billion cells and / or at such a cell amount per kilogram of body weight, for example, in the range of 1 million to about 50 billion cells (e.g., about 5 million cells, about 25 million cells, about 500 million cells, about 1 billion cells, about 5 billion cells, about 20 billion cells, about 30 billion cells, about 40 billion cells, or a range defined by any two of the foregoing values), for example, in the range of about 10 million to about 100 billion cells (e.g., about 20 million cells, about 30 million cells, about 40 million cells, about 60 million cells, about 70 million cells, about 80 million cells, about 90 million cells, about 10 billion cells, about 25 billion cells, about 50 billion cells, about 75 billion cells, about 90 billion cells, or a range defined by any two of the foregoing values), and in some cases in the range of about 100 million to about 50 billion cells (e.g., about 120 million cells, about 250 million cells, about 350 million cells, about 450 million cells, about 650 million cells, about 8 billion cells, about 9 billion cells, about 30 billion cells, about 30 billion cells, about 45 billion cells), or at any value between these ranges, and / or administered to the subject per kilogram of body weight. The dosage may vary depending on the disease or disorder and / or attributes specific to the patient and / or other treatments.

[0150] In some embodiments, for example, when the subject is human, the dose is about 1×10 8 less than total recombinant receptor (e.g., CAR) expressing cells, T cells or peripheral blood mononuclear cells (PBMCs), for example, about 1×10 6 to 1×10 8 such cells (e.g., generally 2×10 6 , 5×10 6 , 1×10 7 , 5×10 7 , or 1×10 8 such cells), or in the range between any two of the foregoing values.

[0151] The cells can be administered by any suitable means. The cells are administered in a dosing regimen to achieve a therapeutic effect such as a reduction in tumor burden. The dosing and administration may in part depend on the dosing schedule of the immunomodulatory compound, which may be administered before, after, and / or simultaneously with the initiation of the T cell therapy. Various dosing schedules for T cell therapy include, but are not limited to, single or multiple administrations over various time points, bolus administration, and pulsed infusion.

[0152] 1. Compositions and Formulations In some embodiments, the dose of cells for a T cell therapy, such as a T cell therapy comprising cells engineered with a recombinant antigen receptor, e.g., a CAR or a TCR, is provided as a composition or formulation, such as a pharmaceutical composition or formulation. Such compositions can be used according to the provided methods in the prevention or treatment of diseases, conditions, and disorders, etc.

[0153] In some embodiments, T cell therapies such as engineered T cells (e.g., CAR T cells) are formulated with a pharmaceutically acceptable carrier. In some aspects, the choice of carrier is determined in part by a particular cell or agent, and / or by the method of administration. Accordingly, a variety of suitable formulations exist. For example, the pharmaceutical composition may contain a preservative. Suitable preservatives may include, for example, methylparaben, propylparaben, sodium benzoate, and benzalkonium chloride. In some aspects, a mixture of two or more preservatives is used. The preservative or mixture thereof is typically present in an amount from about 0.0001 wt% to about 2 wt% of the total composition. Carriers are described, for example, in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980). Pharmaceutically acceptable carriers are generally non-toxic to the recipient at the dosages and concentrations employed and include, but are not limited to: buffers such as phosphates, citrates and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as alkyl parabens like octadecyl dimethyl benzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol, methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants such as polyethylene glycol (PEG).

[0154] In some aspects, a buffering agent is included in the composition. Suitable buffering agents include, for example, citric acid, sodium citrate, phosphoric acid, potassium phosphate, and various other acids and salts. In some aspects, a mixture of two or more buffering agents is used. The buffering agent or mixture thereof is typically present in an amount from about 0.001 wt% to about 4 wt% of the total composition. Methods for preparing administrable pharmaceutical compositions are known. Exemplary methods are described in more detail, for example, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins; 21st ed. (May 1, 2005).

[0155] The formulation may contain an aqueous solution. The formulation or composition may also contain a plurality of active ingredients useful for a particular indication, disease, or condition to be prevented or treated with a cell or agent, provided that the respective activities do not adversely affect each other. Such active ingredients are appropriately present in combination in an amount effective for the intended purpose. Thus, in some embodiments, the pharmaceutical composition further comprises a chemotherapeutic agent, such as asparaginase, busulfan, carboplatin, cisplatin, daunorubicin, doxorubicin, fluorouracil, gemcitabine, hydroxyurea, methotrexate, paclitaxel, rituximab, vinblastine, vincristine, and other pharmaceutically active agents or drugs of this kind.

[0156] In some aspects, the pharmaceutical composition contains an amount of cells effective to treat or prevent a disease or condition, such as a therapeutically effective amount or a prophylactically effective amount. In some aspects, the effectiveness of the treatment or prevention is monitored by regular evaluation of the subject being treated. For repeated administration over several days or more, depending on the condition, the treatment is repeated until the desired suppression of the symptoms of the disease occurs. However, other dosing regimens may be useful and may be determined. The desired dosage can be delivered by a single bolus administration of the composition, by multiple bolus administrations of the composition, or by continuous infusion administration of the composition.

[0157] The cells can be administered using standard administration techniques, formulations, and / or devices. Formulations and devices such as syringes and vials are provided for the storage and administration of the compositions. With respect to the cells, the administration can be autologous or allogeneic. For example, immunoresponsive cells or precursors can be obtained from one subject and administered to the same subject or a different, compatible subject. Immunoresponsive cells derived from peripheral blood or their progeny (e.g., in vivo, ex vivo, or in vitro derived) can be administered by catheter administration, systemic infusion, local infusion, intravenous injection, or local infusion including parenteral administration. When administering a therapeutic composition (e.g., a pharmaceutical composition comprising genetically modified immunoresponsive cells), the therapeutic composition is generally formulated in a unit-dose injection form (solution, suspension, emulsion).

[0158] Formulations include those for oral administration, intravenous administration, intraperitoneal administration, subcutaneous administration, pulmonary administration, transdermal administration, intramuscular administration, intranasal administration, oral administration, sublingual administration, or suppository administration. In some embodiments, the agent or cell population is administered parenterally. As used herein, the term "parenteral" includes intravenous administration, intramuscular administration, subcutaneous administration, rectal administration, vaginal administration, and intraperitoneal administration. In some embodiments, the agent or cell population is administered to a subject using peripheral systemic delivery by intravenous, intraperitoneal, or subcutaneous injection.

[0159] In some embodiments, the composition is provided as a sterile liquid formulation, such as an isotonic aqueous solution, suspension, emulsion, dispersion, or viscous composition, that can be buffered to a selected pH in several aspects. Liquid formulations are generally easier to prepare than gels, other viscous compositions, and solid compositions. Further, liquid compositions are somewhat more convenient to administer, particularly by injection. On the other hand, viscous compositions can be formulated within an appropriate viscosity range to provide a longer contact period with a particular tissue. The liquid or viscous composition can include a carrier, which can be a solvent or dispersion medium including, for example, water, saline, phosphate buffered saline, polyols (such as glycerol, propylene glycol, liquid polyethylene glycol), and suitable mixtures thereof.

[0160] Sterile injectable solutions can be prepared by incorporating the cells in a solvent such as a suitable carrier, diluent, or excipient, such as a mixture with sterile water, saline, glucose, dextrose, etc. The composition can also be lyophilized. The composition can contain auxiliary substances such as wetting agents, dispersing agents or emulsifying agents (such as methylcellulose), pH buffering agents, gelling or thickening additives, preservatives, flavoring agents, coloring agents, etc., depending on the desired route of administration and formulation. In some aspects, appropriate formulations can be prepared with reference to standard texts.

[0161] Various additives can be added to enhance the stability and sterility of the composition, including antibacterial preservatives, antioxidants, chelating agents, and buffering agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, etc. Sustained absorption of injectable pharmaceutical forms can be brought about by the use of agents that delay absorption, such as aluminum monostearate and gelatin.

[0162] Formulations used for in vivo administration are generally sterile. Sterility can be readily achieved, for example, by filtration through sterile filtration membranes.

[0163] For the prevention or treatment of a disease, an appropriate dosage can depend on the type of disease being treated, the type of one or more agents, the type of cell or recombinant receptor, the severity and course of the disease, whether the agent or cell is administered for prophylactic or therapeutic purposes, past therapies, the medical history of the subject and response to the agent or cell, as well as the discretion of the attending physician. The composition may, in some embodiments, be appropriately administered to the subject either once or over a series of treatments.

[0164] In some cases, cell therapy is administered as a single pharmaceutical composition containing the cells. In some embodiments, a given dose is administered by a single bolus injection of the cell or agent. In some embodiments, a given dose is administered by, for example, multiple bolus injections of the cell or agent over a period of up to 3 days, or by continuous infusion of the cell or agent.

[0165] 2. Administration Schedule and Administration In some embodiments, a dose of cells is administered to the subject according to the methods of combination therapy provided. In some embodiments, the size or timing of the dose is determined in relation to a particular disease or condition in the subject. The size or timing of the dose for a particular disease may be determined empirically, taking into account the explanations provided.

[0166] In certain embodiments, individual populations of cells, or cell subtypes, are administered to a subject in the range of about 100,000 to about 100 billion cells and / or in an amount of cells per kilogram of the subject's body weight, such as 100,000 to about 50 billion cells (e.g., about 5 million cells, about 25 million cells, about 500 million cells, about 1 billion cells, about 5 billion cells, about 20 billion cells, about 30 billion cells, about 40 billion cells, or a range defined by any two of said values), 1 million to about 50 billion cells (e.g., about 5 million cells, about 25 million cells, about 500 million cells, about 1 billion cells, about 5 billion cells, about 20 billion cells, about 30 billion cells, about 40 billion cells, or a range defined by any two of said values), such as about 10 million to about 100 billion cells (e.g., about 20 million cells, about 30 million cells, about 40 million cells, about 60 million cells, about 70 million cells, about 80 million cells, about 90 million cells, about 10 billion cells, about 25 billion cells, about 50 billion cells, about 75 billion cells, about 90 billion cells, or a range defined by any two of said values), and in some cases, about 100 million to about 50 billion cells (e.g., about 120 million cells, about 250 million cells, about 350 million cells, about 450 million cells, about 650 million cells, about 800 million cells, about 900 million cells, about 3 billion cells, about 30 billion cells, about 45 billion cells), or any value between these ranges and / or in an amount of cells per kilogram of the subject's body weight. The dosage can vary depending on the disease or disorder and / or patient and / or other treatment-specific attributes. In some embodiments, such values refer to the number of recombinant receptor-expressing cells, and in other embodiments, they refer to the number of T cells or PBMCs or total cells administered.

[0167] In some embodiments, the cell therapy involves a cell count of 1×10 5 or more and 1×10 8 or less or about 1×10 5 or more and 1×10 8The following total recombinant receptor-expressing cells, total T cells or total peripheral blood mononuclear cells (PBMCs), 5×10 5 or more 1×10 7 or less or about 5×10 5 or more 1×10 7 The following total recombinant receptor-expressing cells, total T cells or total peripheral blood mononuclear cells (PBMCs), or 1×10 6 or more 1×10 7 or less or about 1×10 6 or more 1×10 7 Administration of a dose comprising the following total recombinant receptor-expressing cells, total T cells or total peripheral blood mononuclear cells (PBMCs) is included. In some embodiments, the cell therapy is at least 1×10 5 or about at least 1×10 5 total recombinant receptor-expressing cells, total T cells or total peripheral blood mononuclear cells (PBMCs), e.g., at least 1×10 6 or about at least 1×10 6 , at least 1×10 7 or about at least 1×10 7 , at least 1×10 8 or about at least 1×10 8 and includes administration of a cell dose comprising such cells.

[0168] In some embodiments, e.g., when the subject is human, the dose is less than about 5×10 8 total recombinant receptor (e.g., CAR) -expressing cells, T cells or peripheral blood mononuclear cells (PBMCs), e.g., about 1×10 6 to 5×10 8 such cells, e.g., 2×10 6 , 5×10 6 , 1×10 7 , 5×10 7 , 1×10 8 or 5×10 8 such total cells, or ranges between any two of the aforementioned numerical values are included.

[0169] In some embodiments, the number relates to the total number of CD3+ or CD8+ cells, and in some cases also recombinant receptor-expressing (e.g., CAR+) cells. In some embodiments, the cell therapy is at a cell count of 1×10 5 or more to 1×10 8 or less or about 1×10 5 or more to 1×10 8 or less of total CD3+ or CD8+ T cells or CD3+ or CD8+ recombinant receptor-expressing cells, 5×10 5 or more to 1×10 7 or less or about 5×10 5 or more to 1×10 7 or less of total CD3+ or CD8+ T cells or CD3+ or CD8+ recombinant receptor-expressing cells, or 1×10 6 or more to 1×10 7 or less or about 1×10 6 or more to 1×10 7 or less of total CD3+ or CD8+ T cells or CD3+ or CD8+ recombinant receptor-expressing cells, and includes administration of a dose comprising such cells. In some embodiments, the cell therapy is at a cell count of 1×10 5 or more to 1×10 8 or less or about 1×10 5 or more to 1×10 8 or less of total CD3+ / CAR+ or CD8+ / CAR+ cells, 5×10 5 or more to 1×10 7 or less or about 5×10 5 or more to 1×10 7 or less of total CD3+ / CAR+ or CD8+ / CAR+ cells, or 1×10 6 or more to 1×10 7 or less or about 1×10 6 or more to 1×10 7 or less of total CD3+ / CAR+ or CD8+ / CAR+ cells, and includes administration of a dose comprising such cells.

[0170] In some embodiments, the dose of genetically engineered cells is 1×10 5 to 5×10 8 or about 1×10 5 to 5×10 8 of total CAR-expressing T cells, 1×105 ~2.5×10 8 or approximately 1×10 5 ~2.5×10 8 total CAR-expressing T cells of 1×10 5 ~1×10 8 or approximately 1×10 5 ~1×10 8 total CAR-expressing T cells of 1×10 5 ~5×10 7 or approximately 1×10 5 ~5×10 7 total CAR-expressing T cells of 1×10 5 ~2.5×10 7 or approximately 1×10 5 ~2.5×10 7 total CAR-expressing T cells of 1×10 5 ~1×10 7 or approximately 1×10 5 ~1×10 7 total CAR-expressing T cells of 1×10 5 ~5×10 6 or approximately 1×10 5 ~5×10 6 total CAR-expressing T cells of 1×10 5 ~2.5×10 6 or approximately 1×10 5 ~2.5×10 6 total CAR-expressing T cells of 1×10 5 ~1×10 6 or approximately 1×10 5 ~1×10 6 total CAR-expressing T cells of 1×10 6 ~5×10 8 or approximately 1×10 6 ~5×10 8 total CAR-expressing T cells of 1×10 6 ~2.5×10 8 or approximately 1×10 6 ~2.5×10 8 total CAR-expressing T cells of 1×10 6 ~1×10 8 or approximately 1×10 6 ~1×10 8 total CAR-expressing T cells of 1×10 6 ~5×10 7 or approximately 1×106 ~5×10 7 of total CAR-expressing T cells, 1×10 6 ~2.5×10 7 or approximately 1×10 6 ~2.5×10 7 of total CAR-expressing T cells, 1×10 6 ~1×10 7 or approximately 1×10 6 ~1×10 7 of total CAR-expressing T cells, 1×10 6 ~5×10 6 or approximately 1×10 6 ~5×10 6 of total CAR-expressing T cells, 1×10 6 ~2.5×10 6 or approximately 1×10 6 ~2.5×10 6 of total CAR-expressing T cells, 2.5×10 6 ~5×10 8 or approximately 2.5×10 6 ~5×10 8 of total CAR-expressing T cells, 2.5×10 6 ~2.5×10 8 or approximately 2.5×10 6 ~2.5×10 8 of total CAR-expressing T cells, 2.5×10 6 ~1×10 8 or approximately 2.5×10 6 ~1×10 8 of total CAR-expressing T cells, 2.5×10 6 ~5×10 7 or approximately 2.5×10 6 ~5×10 7 of total CAR-expressing T cells, 2.5×10 6 ~2.5×10 7 or approximately 2.5×10 6 ~2.5×10 7 of total CAR-expressing T cells, 2.5×10 6 ~1×10 7 or approximately 2.5×10 6 ~1×10 7 of total CAR-expressing T cells, 2.5×10 6 ~5×10 6 or approximately 2.5×10 6~5×10 6 of total CAR-expressing T cells, 5×10 6 ~5×10 8 or approximately 5×10 6 ~5×10 8 of total CAR-expressing T cells, 5×10 6 ~2.5×10 8 or approximately 5×10 6 ~2.5×10 8 of total CAR-expressing T cells, 5×10 6 ~1×10 8 or approximately 5×10 6 ~1×10 8 of total CAR-expressing T cells, 5×10 6 ~5×10 7 or approximately 5×10 6 ~5×10 7 of total CAR-expressing T cells, 5×10 6 ~2.5×10 7 or approximately 5×10 6 ~2.5×10 7 of total CAR-expressing T cells, 5×10 6 ~1×10 7 or approximately 5×10 6 ~1×10 7 of total CAR-expressing T cells, 1×10 7 ~5×10 8 or approximately 1×10 7 ~5×10 8 of total CAR-expressing T cells, 1×10 7 ~2.5×10 8 or approximately 1×10 7 ~2.5×10 8 of total CAR-expressing T cells, 1×10 7 ~1×10 8 or approximately 1×10 7 ~1×10 8 of total CAR-expressing T cells, 1×10 7 ~5×10 7 or approximately 1×10 7 ~5×10 7 of total CAR-expressing T cells, 1×10 7 ~2.5×10 7 or approximately 1×10 7 ~2.5×10 7 of total CAR-expressing T cells, 2.5×107 ~5×10 8 or approximately 2.5×10 7 ~5×10 8 total CAR-expressing T cells, 2.5×10 7 ~2.5×10 8 or approximately 2.5×10 7 ~2.5×10 8 total CAR-expressing T cells, 2.5×10 7 ~1×10 8 or approximately 2.5×10 7 ~1×10 8 total CAR-expressing T cells, 2.5×10 7 ~5×10 7 or approximately 2.5×10 7 ~5×10 7 total CAR-expressing T cells, 5×10 7 ~5×10 8 or approximately 5×10 7 ~5×10 8 total CAR-expressing T cells, 5×10 7 ~2.5×10 8 or approximately 5×10 7 ~2.5×10 8 total CAR-expressing T cells, 5×10 7 ~1×10 8 or approximately 5×10 7 ~1×10 8 total CAR-expressing T cells, 1×10 8 ~5×10 8 or approximately 1×10 8 ~5×10 8 total CAR-expressing T cells, 1×10 8 ~2.5×10 8 or approximately 1×10 8 ~2.5×10 8 total CAR-expressing T cells, or 2.5×10 8 ~5×10 8 or approximately 2.5×10 8 ~5×10 8 including total CAR-expressing T cells.

[0171] In some embodiments, the dose of the genetically engineered cells is at least 1×10 5 or at least approximately 1×105 CAR-expressing cells of, at least 2.5×10 5 or at least about 2.5×10 5 CAR-expressing cells of, at least 5×10 5 or at least about 5×10 5 CAR-expressing cells of, at least 1×10 6 or at least about 1×10 6 CAR-expressing cells of, at least 2.5×10 6 or at least about 2.5×10 6 CAR-expressing cells of, at least 5×10 6 or at least about 5×10 6 CAR-expressing cells of, at least 1×10 7 or at least about 1×10 7 CAR-expressing cells of, at least 2.5×10 7 or at least about 2.5×10 7 CAR-expressing cells of, at least 5×10 7 or at least about 5×10 7 CAR-expressing cells of, at least 1×10 8 or at least about 1×10 8 CAR-expressing cells of, at least 2.5×10 8 or at least about 2.5×10 8 CAR-expressing cells, or at least 5×10 8 or at least about 5×10 8 including CAR-expressing cells.

[0172] In some embodiments, the cell therapy is a total of recombinant receptor-expressing cells, total T cells or total peripheral blood mononuclear cells (PBMCs) of 1×10 5 or more and 5×10 8 or less or about 1×10 5 or more and 5×10 8 or less of total recombinant receptor-expressing cells, total T cells or total peripheral blood mononuclear cells (PBMCs), 5×10 5 or more and 1×10 7 or less or about 5×10 5 or more and 1×10 7 or less of total recombinant receptor-expressing cells, total T cells or total peripheral blood mononuclear cells (PBMCs), or 1×10 6 or more and 1×107 The following or about 1×10 6 or more 1×10 7 The administration of a dose comprising the following total recombinant receptor-expressing cells, total T cells or total peripheral blood mononuclear cells (PBMC). In some embodiments, the cell therapy is at least 1×10 5 or at least about 1×10 5 total recombinant receptor-expressing cells, total T cells or total peripheral blood mononuclear cells (PBMC), e.g., at least 1×10 6 or about at least 1×10 6 , at least 1×10 7 or at least about 1×10 7 , at least 1×10 8 or at least about 1×10 8 The administration of a cell dose comprising such cells. In some embodiments, the number relates to the total number of CD3+ or CD8+ cells, and in some cases also recombinant receptor-expressing (e.g., CAR+) cells. In some embodiments, the cell therapy is from 1×10 5 or more to 5×10 8 or about 1×10 5 or more to 5×10 8 total CD3+ or CD8+ total T cells or CD3+ or CD8+ recombinant receptor-expressing cells, 5×10 5 or more to 1×10 7 or about 5×10 5 or more to 1×10 7 or about 5×10 6 or more to 1×10 7 or about 1×10 6 or more to 1×10 7 or about 1×10 5 or more to 5×10 8 or about 1×10 5 or more to 5×10 8 total CD3+ / CAR+ or CD8+ / CAR+ cells, 5×105 1×10 or more 7 5×10 or less or about 5×10 5 1×10 or more 7 Total CD3+ / CAR+ or CD8+ / CAR+ cells of 5×10 or less, or 1×10 6 1×10 or more 7 1×10 or less or about 1×10 6 1×10 or more 7 Administration of a dose containing total CD3+ / CAR+ or CD8+ / CAR+ cells of 1×10 or less is included.

[0173] In some embodiments, the dose of T cells includes CD4+ T cells, CD8+ T cells, or both CD4+ and CD8+ T cells.

[0174] In some embodiments, for example, when the subject is human, the CD8+ T cells in the dose, including when in a dose containing both CD4+ and CD8+ T cells, are about 1×10 6 cells to 1×10 8 cells and include a total of recombinant receptor (e.g., CAR) expressing CD8+ cells, for example, about 5×10 6 cells to 1×10 8 cells, such cells, generally 1×10 7 cells, 2.5×10 7 cells, 5×10 7 cells, 7.5×10 7 cells, 1×10 8 cells, or 5×10 8 cells, or include a range between any two of the aforementioned values. In some embodiments, multiple doses are administered to the patient, and each of these doses, or the total dose, can be within the range of any of the aforementioned values. In some embodiments, the dose of cells is 1×10 7 cells to 0.75×10 8 cells or about 1×10 7 cells to about 0.75×10 8 cells of total recombinant receptor expressing CD8+ T cells, 1×10 7 cells to 2.5×10 7 cells or about 1×10 7 cells to about 2.5×107 individual total recombinant receptor-expressing CD8+ T cells, 1×10 7 cells to 0.75×10 8 cells or approximately 1×10 7 cells to approximately 0.75×10 8 cells of total recombinant receptor-expressing CD8+ T cells. In some embodiments, the cell dose is 1×10 7 cells or approximately 1×10 7 cells, 2.5×10 7 cells or approximately 2.5×10 7 cells, 5×10 7 cells or approximately 5×10 7 cells, 7.5×10 7 cells or approximately 7.5×10 7 cells, 1×10 8 cells or approximately 1×10 8 cells, or 5×10 8 cells or approximately 5×10 8 cells of total recombinant receptor-expressing CD8+ T cells.

[0175] In some embodiments, the dose of cells (e.g., recombinant receptor-expressing T cells) is administered to the subject as a single dose, or administered only once within a period of 2 weeks, 1 month, 3 months, 6 months, 1 year or more.

[0176] In some embodiments, the cell therapy is at least the following value or at least approximately the following value or the following value or approximately the following value per kg of the subject's body weight: 0.1×10 6 cells / kg, 0.2×10 6 cells / kg, 0.3×10 6 cells / kg, 0.4×10 6 cells / kg, 0.5×10 6 cells / kg, 1×10 6 cells / kg, 2.0×10 6 cells / kg, 3×10 6 cells / kg, or 5×10 6 cells / kg and comprises administration of a dose containing the number of cells.

[0177] In some embodiments, the cell therapy comprises administration of a dose containing a number of cells that is, for each kg of the subject's body weight, 0.1×10 6 cells / kg to 1.0×10 7 cells / kg or approximately said value, 0.5×10 6 cells / kg to 5×10 6 cells / kg or approximately said value, 0.5×10 6 cells / kg to 3×10 6 cells / kg or approximately said value, 0.5×10 6 cells / kg to 2×10 6 cells / kg or approximately said value, 0.5×10 6 cells / kg to 1×10 6 cells / kg or approximately said value, 1.0×10 6 cells / kg to 5×10 6 cells / kg or approximately said value, 1.0×10 6 cells / kg to 3×10 6 cells / kg or approximately said value, about 1.0×10 6 cells / kg to 2×10 6 cells / kg or approximately said value, 2.0×10 6 cells / kg to 5×10 6 cells / kg or approximately said value, 2.0×10 6 cells / kg to 3×10 6 cells / kg or approximately said value, or 3.0×10 6 cells / kg to 5×10 6 cells / kg or approximately said value.

[0178] In some embodiments, the cell dose is 2×10 5 cells / kg to 2×10 6 cells / kg or approximately said value, e.g., 4×10 5 cells / kg to 1×10 6 cells / kg or approximately said value, or 6×10 5 cells / kg to 8×10 5 cells / kg or approximately said value. In some embodiments, the cell dose is (cells / kg) 2×10 per kg of the subject's body weight 5cells or less (e.g., antigen-expressing cells such as CAR-expressing cells), e.g., 3×10 5 cells / kg or less or approximately the value or less, 4×10 5 cells / kg or less or approximately the value or less, 5×10 5 cells / kg or less or approximately the value or less, 6×10 5 cells / kg or less or approximately the value or less, 7×10 5 cells / kg or less or approximately the value or less, 8×10 5 cells / kg or less or approximately the value or less, 9×10 5 cells / kg or less or approximately the value or less, 1×10 6 cells / kg or less or approximately the value or less, or 2×10 6 cells / kg or less or approximately the value or less. In some embodiments, the cell dose is 2×10 5 cells (e.g., antigen-expressing cells such as CAR-expressing cells) per kilogram of the subject's body weight (cells / kg) or about 2×10 5 cells, or at least 2×10 5 cells or at least approximately 2×10 5 cells, e.g., the following values or approximately the following values or at least the following values or at least approximately the following values: 3×10 5 cells / kg, 4×10 5 cells / kg, 5×10 5 cells / kg, 6×10 5 cells / kg, 7×10 5 cells / kg, 8×10 5 cells / kg, 9×10 5 cells / kg, 1×10 6 cells / kg, or 2×10 6 cells / kg.

[0179] In connection with adoptive cell therapy, administration of a given "dose" of cells encompasses administration of a given amount or number of cells as a single composition and / or as a single uninterrupted administration (e.g., as a single injection or continuous infusion), and also encompasses administration of a given amount or number of cells as divided doses provided in multiple individual compositions or infusions over a specified period (within 3 days). Thus, in some situations, a dose is a single or continuous administration of a specified number of cells given or initiated at one point in time. However, in some situations, a dose is administered by multiple injections or infusions over a period within 3 days (e.g., once daily over 3 days or 2 days), or by multiple infusions over a 1-day period.

[0180] Thus, in some aspects, the cells of the dose are administered in a single pharmaceutical composition. In some embodiments, the cells of the dose are administered in multiple compositions that together contain the cells of the dose.

[0181] The term "divided dose" refers to a dose that is divided to be administered over more than 1 day. This type of administration is encompassed by the methods of the invention and is considered to be a single dose. In some embodiments, the divided dose of cells is administered over a period within 3 days in multiple compositions that together contain the cells of the dose.

[0182] Thus, a dose of cells can be administered as a divided dose. For example, in some embodiments, a dose can be administered to a subject over 2 or 3 days. Exemplary methods for divided administration include administering 25% of the dose on day 1 and the remaining 75% of the dose on day 2. In other embodiments, 33% of the dose can be administered on day 1 and the remaining 67% on day 2. In some aspects, 10% of the dose is administered on day 1, 30% of the dose on day 2, and 60% of the dose on day 3. In some embodiments, the divided dose does not exceed 3 days.

[0183] In some embodiments, a dose of cells is generally an amount sufficient to be effective in reducing disease burden.

[0184] In some embodiments, the cells are administered at a desired dosage, which in some instances includes a desired dose or number of cells or cell types and / or a desired ratio of cell types. Thus, in some embodiments, the dosage of cells is based on the total number of cells (or number per kg of body weight) and the desired ratio of individual populations or subtypes, such as the CD4+ to CD8+ ratio. In some embodiments, the dosage of cells is based on the desired total number of cells (or number per kg of body weight) in an individual population or individual cell type. In some embodiments, the dosage is based on a combination of features such as the desired number of total cells, the desired ratio, and the desired total number of cells in an individual population.

[0185] In some embodiments, CD8 + and CD4 + Populations or subtypes of cells, such as CD8 and CD4 T cells, are administered within or within the tolerance of the desired dosage of total cells, such as the desired dosage of cells. In some embodiments, the desired dosage is the desired number of cells or the desired number of cells per unit body weight of the subject to which the cells are administered, such as cells / kg. In some instances, the desired dosage is at or above the minimum number of cells or the minimum number of cells per unit body weight. In some instances, of the total cells administered at the desired dosage, individual populations or subtypes are present at or near the desired production ratio (such as the CD4 + to CD8 + ratio, etc.), for example within a certain tolerance or error of such a ratio.

[0186] In some embodiments, the cells are the desired dosage of CD4 + cells and / or the desired dosage of CD8 +It is administered at or within the tolerance of the desired dose of one or more individual populations or subtypes of cells, such as cells. In some aspects, the desired dose is the desired number of cells of a subtype or population, or the desired number of such cells per unit body weight of the subject to which the cells are administered, such as cells / kg. In some aspects, the desired dose is at or above the minimum number of cells of a population or subtype, or at or above the minimum number of cells of a population or subtype per unit body weight.

[0187] Thus, in some embodiments, the dosage is based on the desired fixed dose and desired ratio of total cells, and / or on the desired fixed dose of one or more of the individual subtypes or subpopulations, such as each. Thus, in some embodiments, the dosage is based on the desired fixed or minimum dose of T cells and CD4 + versus CD8 + cells, and / or on the desired ratio of CD4 + and / or CD8 + cells, and / or on the desired fixed or minimum dose of CD4 and / or CD8 cells.

[0188] In some embodiments, the cells are administered at or within the tolerance of the desired production ratio of a plurality of cell populations or subtypes, such as CD4 + and CD8 + cells or subtypes. In some aspects, the desired ratio can be a specific ratio or a range of ratios. For example, in some embodiments, the desired ratio (e.g., CD4 + versus CD8 +The ratio of cells) is 5:1 to 5:1 or about 5:1 to about 5:1 (or greater than about 1:5 and less than about 5:1), or 1:3 to 3:1 or about 1:3 to about 3:1 (or greater than about 1:3 and less than about 3:1), for example 2:1 to 1:5 or about 2:1 to about 1:5 (or greater than about 1:5 and less than about 2:1, for example 5:1, 4.5:1, 4:1, 3.5:1, 3:1, 2.5:1, 2:1, 1.9:1, 1.8:1, 1.7:1, 1.6:1, 1.5:1, 1.4:1, 1.3:1, 1.2:1, 1.1:1, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, or 1:5, or approximately the said ratio. In some aspects, the tolerance is within about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50% of the desired ratio, including any value between these ranges.

[0189] In certain embodiments, the number and / or concentration of cells refers to the number of recombinant receptor (e.g., CAR) expressing cells. In other embodiments, the number and / or concentration of cells refers to the number or concentration of all cells, T cells, or peripheral blood mononuclear cells (PBMCs) being administered.

[0190] In some aspects, the size of the dose is determined based on one or more criteria such as the subject's response to previous treatments, e.g., chemotherapy, the disease burden in the subject, e.g., the amount, volume, size, or degree, extent or type of metastases of a tumor, the disease stage, and / or the toxic outcome, e.g., the likelihood or incidence of a subject developing CRS, macrophage activation syndrome, tumor lysis syndrome, neurotoxicity, and / or the host immune response to the cells and / or recombinant receptor being administered.

[0191] In some embodiments, administering an immunomodulatory compound in combination with cells can significantly enhance the expansion or proliferation of the cells, and thus, a smaller dose of cells can be administered to a subject. In some cases, the provided method allows a smaller dose of such cells to be administered to achieve a treatment with the same or better efficacy as the dose in a method in which cell therapy is administered without the administration of an immunomodulatory compound, for example, at a dose that is at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, or 10-fold less than the dose in a method in which cell therapy is administered without the administration of an immunomodulatory compound, such as lenalidomide or Compound 1.

[0192] In some embodiments, for example, the dose is between 5.0×10 6 ~2.25×10 7 or about between 5.0×10 6 ~2.25×10 7 ; between 5.0×10 6 ~2.0×10 7 or about between 5.0×10 6 ~2.0×10 7 ; between 5.0×10 6 ~1.5×10 7 or about between 5.0×10 6 ~1.5×10 7 ; between 5.0×10 6 ~1.0×10 7 or about between 5.0×10 6 ~1.0×10 7 ; between 5.0×10 6 ~7.5×10 6 or about between 5.0×10 6 ~7.5×10 6 ; between 7.5×10 6 ~2.25×10 7 or about between 7.5×10 6 ~2.25×10 7 ; between 7.5×10 6 ~2.0×10 7 or about between 7.5×10 6 ~2.0×10 7 ; between 7.5×106 ~1.5×10 7 between or about 7.5×10 6 ~1.5×10 7 between, 7.5×10 6 ~1.0×10 7 between or about 7.5×10 6 ~1.0×10 7 between, 1.0×10 7 ~2.25×10 7 between or about 1.0×10 7 ~2.25×10 7 between, 1.0×10 7 ~2.0×10 7 between or about 1.0×10 7 ~2.0×10 7 between, 1.0×10 7 ~1.5×10 7 between or about 1.0×10 7 ~1.5×10 7 between, 1.5×10 7 ~2.25×10 7 between or about 1.5×10 7 ~2.25×10 7 between, 1.5×10 7 ~2.0×10 7 between or about 1.5×10 7 ~2.0×10 7 between, 2.0×10 7 ~2.25×10 7 between or about 2.0×10 7 ~2.25×10 7 contains between. In some embodiments, the dose of cells is at least 5×10 6 or at least about 5×10 6 , at least 6×10 6 or at least about 6×10 6 , at least 7×10 6 or at least about 7×10 6 , at least 8×10 6 or at least about 8×10 6 , at least 9×10 6 or at least about 9×10 6 , at least 10×10 6 or at least about 10×106 ~about 15×10 6 contains recombinant receptor-expressing cells, such as CD8+ recombinant receptor-expressing cells, with a cell count between. In some embodiments, such a dose, e.g., such a target cell count, refers to the total recombinant receptor-expressing cells in the administered composition.

[0193] In some embodiments, for example, a lower dose contains less than about 5×10 6 cells, recombinant receptor (e.g., CAR)-expressing cells, T cells and / or PBMCs per kilogram of the subject's body weight, e.g., less than about 4.5×10 6 cells, less than about 4×10 6 cells, less than about 3.5×10 6 cells, less than about 3×10 6 cells, less than about 2.5×10 6 cells, less than about 2×10 6 cells, less than about 1.5×10 6 cells, less than about 1×10 6 cells, less than about 5×10 5 cells, less than about 2.5×10 5 cells, or less than about 1×10 5 cells, etc. In some embodiments, a lower dose contains less than about 1×10 5 cells, less than about 2×10 5 cells, less than about 5×10 5 cells, or less than about 1×10 6 cells, or contains a value within the range between any two of the aforementioned values. In some embodiments, such a value indicates the number of recombinant receptor-expressing cells. In other embodiments, such a value indicates the number of T cells or PBMCs or total cells administered.

[0194] In some embodiments, the subject receives multiple doses of the cells, such as two or more doses or multiple consecutive doses. In some embodiments, two doses are administered to the subject. In some embodiments, the subject receives consecutive doses, for example, the second dose is administered approximately 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days after the first dose. In some embodiments, the multiple consecutive doses are administered following the first dose such that one or more additional doses are administered following the administration of those consecutive doses. In some aspects, the number of cells administered to the subject during the additional dose is the same as or similar to the first dose and / or the consecutive doses. In some embodiments, the one or more additional doses are greater than the prior dose. In some embodiments, one or more subsequent doses of the cells can be administered to the subject. In some embodiments, the subsequent dose of the cells is administered after 7 days or about 7 days after the start of administration of the first cell dose, after 14 days or about 14 days after, after 21 days or about 21 days after, after 28 days or about 28 days after, or after 35 days or about 35 days after. The subsequent dose of the cells can be greater than, approximately the same as, or less than the first dose. In some embodiments, administration of the T cell therapy, such as administration of the first and / or second cell doses, can be repeated.

[0195] In some embodiments, the start of administration of the cell therapy, such as the first dose of the cell dose or the fractional dose of the cell, is administered before (prior to) the administration of the immunomodulatory compound, such as lenalidomide, compound 1, or compound 2, concurrently with the administration, or after (subsequent to or following) the administration.

[0196] In some embodiments, the dose of cells, or a subsequent dose of cells, is administered according to a method of combination therapy in parallel with the initiation of administration of an immunomodulatory compound. In some embodiments, the dose of cells, or a subsequent dose of cells, is administered according to a method of combination therapy on the same day as the initiation of administration of the immunomodulatory compound. In some embodiments, the dose of cells, or a subsequent dose of cells, is administered according to a method of combination therapy within 1 day, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, or within 7 days of the initiation of administration of the immunomodulatory compound.

[0197] In some embodiments, the dose of cells, or a subsequent dose of cells, is administered prior to or prior to initiating the administration of an immunomodulatory compound by the provided combination therapy. In some embodiments, the dose of cells is at least 1 hour or at least about 1 hour, at least 2 hours or at least about 2 hours, at least 3 hours or at least about 3 hours, at least 6 hours or at least about 6 hours, at least 12 hours or at least about 12 hours, at least 1 day or at least about 1 day, at least 2 days or at least about 2 days, at least 3 days or at least about 3 days, at least 4 days or at least about 4 days, at least 5 days or at least about 5 days, at least 6 days or at least about 6 days, at least 7 days or at least about 7 days, at least 12 days or at least about 12 days, at least 14 days or at least about 14 days, at least 15 days or at least about 15 days, at least 21 days or at least about 21 days, at least 28 days or at least about 28 days, at least 30 days or at least about 30 days, at least 35 days or at least about 35 days, at least 42 days or at least about 42 days, at least 60 days or at least about 60 days, or at least 90 days or at least about 90 days before administering the immunomodulatory compound by the provided combination therapy.

[0198] In some embodiments, administration of an immunomodulatory compound (e.g., lenalidomide or Compound 1) by the provided combination therapy is when the previous administration of immunotherapy (e.g., T cell therapy, e.g., CAR-T cell therapy, etc.) is likely to be associated with or related to decreased functionality of T cells as compared to the functionality of T cells at the time immediately prior to the initiation of immunotherapy (e.g., T cell therapy, e.g., CAR-T cell therapy, etc.) or at a prior time point after initiation of T cell therapy. In some embodiments, the method involves evaluating a sample from a subject for one or more functions of T cells (e.g., cell expansion or persistence) ...

Claims

1. 1. A method for rescuing T cell activity, comprising: The method comprises exposing a plurality of T cells having an exhausted phenotype to an effective amount of an immunomodulatory compound selected from the group consisting of: a thalidomide analog; a thalidomide derivative; a compound that interacts with and / or binds to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; an inhibitor of Ikaros (IKZF1); an inhibitor of Aiolos (IKZF3); and a compound that enhances or promotes ubiquitination, depletion, and / or degradation of Ikaros (IKZF1) and / or Aiolos (IKZF3).

2. The method of claim 1, wherein the one or more T cells comprise a T cell that expresses a recombinant receptor that specifically binds to a target antigen.

3. 1. A method for increasing T cell activity or potency, and for preventing or inhibiting, reducing or delaying the onset of T cell exhaustion, comprising: exposing a plurality of T cells to an effective amount of an immunomodulatory compound selected from the group consisting of: a thalidomide analog; a thalidomide derivative; a compound that interacts with and / or binds to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; an inhibitor of Ikaros (IKZF1); an inhibitor of Aiolos (IKZF3); and a compound that enhances or promotes ubiquitination, depletion, and / or degradation of Ikaros (IKZF1) and / or Aiolos (IKZF3); at least a portion of the exposing step is performed during conditions that induce or are capable of inducing an exhausted phenotype in the plurality of T cells in the absence of the compound. The method.

4. 1. A method for reducing or delaying the onset of T cell exhaustion, comprising: exposing a plurality of T cells to an effective amount of an immunomodulatory compound selected from the group consisting of: a thalidomide analog; a thalidomide derivative; a compound that interacts with and / or binds to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; an inhibitor of Ikaros (IKZF1); an inhibitor of Aiolos (IKZF3); and a compound that enhances or promotes ubiquitination, depletion, and / or degradation of Ikaros (IKZF1) and / or Aiolos (IKZF3); at least a portion of the exposing step is performed during conditions that induce or are capable of inducing an exhausted phenotype in the plurality of T cells in the absence of the compound. The method.

5. 5. The method of claim 3 or claim 4, wherein the conditions comprise T cell stimulatory conditions comprising exposure to at least one T cell stimulant capable of stimulating a signal in a plurality of T cells, the signal optionally comprising a primary signal and / or a costimulatory signal.

6. The method of claim 5, wherein the condition comprises sustained, repeated, extended, or prolonged exposure to at least one T cell stimulant.

7. 7. The method of claim 5 or claim 6, wherein the at least one T cell stimulator comprises a polyclonal agent, an antigen that is specifically recognized by a receptor expressed on multiple T cells, or an agent that is bound by an antigen receptor expressed by multiple T cells.

8. The method of any one of claims 5 to 7, wherein the at least one T cell stimulant comprises an anti-CD3 antibody.

9. 9. The method of claim 8, wherein the at least one T cell stimulatory agent further comprises an agent that specifically binds to a T cell costimulatory molecule, optionally wherein the T cell costimulatory molecule is CD28, CD137 (4-1-BB), OX40, CD40L, or ICOS.

10. 10. The method of claim 9, wherein the at least one T cell stimulator comprises an anti-CD28 antibody.

11. The method of any one of claims 3 to 10, wherein one or more of the plurality of T cells express a recombinant antigen receptor that binds to a target antigen.

12. The method of claim 11 , wherein the at least one T cell stimulator binds to a recombinant antigen receptor.

13. 13. The method of claim 12, wherein the at least one T cell stimulator is or comprises an anti-idiotypic antibody specific for a recombinant antigen receptor.

14. 13. The method of claim 12, wherein the at least one T cell stimulator is or comprises a target antigen or a portion thereof that is recognized by or bound by a recombinant antigen receptor, and / or the condition comprises exposure to a target antigen.

15. The method according to any one of claims 12 to 14, wherein the recombinant antigen receptor is a recombinant T cell receptor (TCR).

16. The method of any one of claims 12 to 14, wherein the recombinant antigen receptor is a chimeric antigen receptor (CAR).

17. The method of any one of claims 1 to 16, wherein the one or more T cells are primary human T cells, optionally derived from the subject.

18. The method of any one of claims 1 to 17, wherein the exposing step is performed ex vivo.

19. The method of any one of claims 1 to 17, wherein the exposing step is carried out in vivo.

20. 20. The method of claim 19, wherein the exposing step comprises administering the compound to a subject, and optionally, the T cells are derived from a subject and the administration of the compound is to the subject.

21. 21. The method of claim 20, wherein said exposing comprises said administering of said compound, and prior to the exposing step, said subject has been administered a composition comprising a plurality of T cells directed against the subject for treating a disease or condition, and optionally, the target antigen is associated with the disease or condition.

22. 22. The method of any one of claims 19-21, wherein the exposing step comprises administering the plurality of T cells to a subject, and optionally, when the T cells are derived from a subject, administering the compound to the subject.

23. the exposing comprises administering the plurality of T cells to the subject to treat a disease or condition, and optionally the target antigen is associated with a disease or condition, and the subject has been administered the compound prior to the exposing step; or the exposing comprises administering to the subject the plurality of T cells to treat a disease or condition, optionally wherein the target antigen is associated with a disease or condition and comprises administering to the subject the compound.

23. The method of claim 22.

24. 1. A method of treatment comprising administering to a subject an immunomodulatory compound, the immunomodulatory compound is selected from the group consisting of: a thalidomide analog; a thalidomide derivative; a compound that interacts with and / or binds to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; an inhibitor of Ikaros (IKZF1); an inhibitor of Aiolos (IKZF3); and a compound that enhances or promotes the ubiquitination, depletion, and / or degradation of Ikaros (IKZF1) and / or Aiolos (IKZF3); (a) the subject has been administered a T cell therapy comprising a dose of T cells expressing a recombinant antigen receptor that binds to a target antigen prior to administration of the compound; or (b) prior to or at the time of administration of the compound, the subject or a blood sample from the subject contains, or is confirmed to contain, one or more T cells that express a recombinant antigen receptor; Upon administration of the compound, one or more of the recombinant receptor-expressing T cells in the subject have an exhausted phenotype. The method.

25. 25. The method of claim 24, wherein upon administration of the compound, one or more exhausted phenotypes of recombinant receptor-expressing T cells, or markers or parameters indicative thereof, are detected or measured in the subject or in a biological sample derived from the subject.

26. 26. The method of claim 24 or claim 25, wherein at least or at least about 10%, at least or at least about 20%, at least or at least about 30%, at least or at least about 40%, or at least or at least about 50% of the total recombinant receptor-expressing T cells in a biological sample from the subject have an exhausted phenotype.

27. 27. The method of any one of claims 24-26, wherein greater than or about 10%, greater than or about 20%, greater than or about 30%, greater than or about 40%, or greater than or about 50% of the recombinant receptor-expressing T cells in a biological sample from the subject have an exhausted phenotype compared to the percentage of recombinant receptor-expressing cells in a comparable biological sample at a previous time point that have an exhausted phenotype.

28. (a) selecting a subject as a candidate for administration of an immunomodulatory compound, the selected subject having depleted recombinant receptor-expressing T cells; and (b) administering to the subject an immunomodulatory compound, wherein the immunomodulatory compound is selected from the group consisting of: a thalidomide analog; a thalidomide derivative; a compound that interacts with and / or binds to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; an inhibitor of Ikaros (IKZF1); an inhibitor of Aiolos (IKZF3); and a compound that enhances or promotes ubiquitination, depletion, and / or degradation of Ikaros (IKZF1) and / or Aiolos (IKZF3). A method of treatment comprising:

29. a tissue, tumor, biological fluid, or biological sample from or derived from said selected subject; One or more T cells that express a recombinant antigen receptor that binds to a target antigen and have an exhausted phenotype.

30. The method of claim 28, comprising:

30. 30. The method of claim 29, wherein the tissue, tumor, biological fluid, or biological sample comprises a plurality of T cells expressing a recombinant antigen receptor that binds to a target antigen, and wherein at least or at least about 10%, at least or at least about 20%, at least or at least about 30%, at least or at least about 40%, at least or at least about 50%, at least or at least about 60%, at least or at least about 70%, or at least or at least about 80% of the T cells in the tissue, biological fluid, tumor, or sample that express the recombinant receptor have an exhausted phenotype.

31. the tissue, tumor, biological fluid, or biological sample comprises a plurality of T cells that express a recombinant antigen receptor that binds to a target antigen; or more than about 10% more, or more than about 20% more, or more than about 30% more, or more than about 40% more, or more than about 50% more, or more than 2-fold more, or more than 3-fold more, or more than 5-fold more, or more than 10-fold more, of the T cells in a tissue, tumor, fluid, or sample of or from a selected subject that express a recombinant antigen receptor have the exhausted phenotype compared to the percentage or number of T cells expressing the recombinant receptor that had the exhausted phenotype in a fluid, tissue, tumor, or sample from the subject at an earlier time point or in a comparable fluid, tissue, tumor, or sample.

31. The method of claim 29 or claim 30.

32. 31. The method of claim 27 or claim 30, wherein prior to administration of the compound, the subject has been administered a plurality of T cells expressing a recombinant receptor, and the earlier time point is the time immediately prior to administration of the plurality of T cells expressing a recombinant antigen receptor to the subject.

33. 31. The method of claim 27 or claim 30, wherein prior to administration of the compound, the subject has been administered a plurality of T cells expressing a recombinant receptor, and the earlier time point is after administration of the T cells and prior to said selection.

34. The previous time point was following administration of the recombinant receptor-expressing T cells to the selected subject, and at or before the peak or maximum level of the recombinant receptor-expressing T cells becomes detectable in the blood of the subject; Within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days or more prior to said decision or selection 34. The method of claim 27, claim 30 or claim 33, wherein

35. The subject had a disease or condition at the time of administration of the T cell therapy; or the subject has a disease or condition at the time of administration of the T cell therapy and at the time of administration of the compound; The method of any one of claims 24 to 34.

36. The method of any one of claims 20-35, wherein at the time of administration of the T cell therapy, the subject has a disease or condition, and at the time of administration of the compound, the disease or condition has recurred or progressed, or is considered non-responsive to the compound, in the subject following administration of the T cell therapy.

37. An exhaustion phenotype for a T cell or population of T cells, an increase in the level or degree of surface expression on one or more T cells, or the percentage of said T population that exhibits surface expression, of one or more exhaustion markers, optionally two, three, four, five, or six exhaustion markers, compared to a reference T cell population under the same conditions; or A decrease in the level or degree of activity exhibited by the T cell or population of T cells upon exposure to an antigen or antigen receptor-specific agent, as compared to a reference T cell population under the same conditions. The method of any one of claims 1 to 36, comprising:

38. 38. The method of claim 37, wherein said increase in level, degree, or percentage is greater than or equal to 1.2-fold, 1.5-fold or about 1.5-fold, 2.0-fold or about 2.0-fold, 3-fold or about 3-fold, 4-fold or about 4-fold, 5-fold or about 5-fold, 6-fold or about 6-fold, 7-fold or about 7-fold, 8-fold or about 8-fold, 9-fold or about 9-fold, 10-fold or about 10-fold, or more.

39. 38. The method of claim 37, wherein said level, degree, or percentage decrease is greater than or equal to 1.2-fold, 1.5-fold, or about 1.5-fold, 2.0-fold, or about 2.0-fold, 3-fold, or about 3-fold, 4-fold, or about 4-fold, 5-fold, or about 5-fold, 6-fold, or about 6-fold, 7-fold, or about 7-fold, 8-fold, or about 8-fold, 9-fold, or about 9-fold, 10-fold, or more.

40. The method of any one of claims 37 to 39, wherein said reference T cell population is a population of T cells known to have a non-exhausted phenotype, optionally from the same subject from which the one or more T cells with an exhausted phenotype are derived, or of the same species as the subject, a population of naive T cells, a population of central memory T cells, or a population of stem central memory T cells.

41. (a) the reference T cell population is a subject-matched population comprising bulk T cells isolated from the blood of the subject from which one or more T cells having an exhausted phenotype are derived, optionally wherein the bulk T cells do not express a recombinant receptor; and / or (b) the reference T cell population is obtained from a subject from which one or more T cells having an exhausted phenotype were derived prior to receiving a dose of T cells expressing a recombinant receptor; The method of any one of claims 37 to 40.

42. 41. The method of any one of claims 37 to 40, wherein said reference T cell population is a composition comprising a sample of a T cell therapy prior to its administration to a subject, or a pharmaceutical composition comprising T cells expressing a recombinant receptor, optionally wherein said composition is a cryopreserved sample.

43. The method of any one of claims 37 to 42, wherein one or more of said one or more exhaustion markers is an inhibitory receptor.

44. The method of any one of claims 37-43, wherein one or more of said one or more exhaustion markers are selected from among PD-1, CTLA-4, TIM-3, LAG-3, BTLA, 2B4, CD160, CD39, VISTA, and TIGIT.

45. 45. The method of any one of claims 37-44, wherein said activity is one or more of proliferation, cytotoxicity, or production of one or a combination of inflammatory cytokines, optionally wherein the one or a combination of cytokines is selected from the group consisting of IL-2, IFN-gamma, and TNF-alpha.

46. 46. ​​The method of any one of claims 37 to 45, wherein the exposure to an antigen or antigen receptor-specific agent comprises incubation with an antigen or antigen receptor-specific agent, optionally an agent that binds to a recombinant receptor, the antigen being optionally a target antigen.

47. 47. The method of claim 46, wherein the antigen or antigen receptor specific agent comprises an antigen-expressing target cell, optionally a cell of the disease, disorder, or condition.

48. 50. The method of any one of claims 2 and 11-47, wherein the target antigen is associated with, specific for, and / or expressed on cells or tissues of a disease, disorder, or condition.

49. The method of any one of claims 2 and 11 to 48, wherein the target antigen is a tumor antigen.

50. The target antigen may be αvβ6 integrin (avb6 integrin), B-cell maturation antigen (BCMA), BAFF-R, B7-H3, B7-H6, carbonic anhydrase 9 (CA9; also known as CAIX or G250), cancer testis antigen, cancer / testis antigen 1B (CTAG; also known as NY-ESO-1 and LAGE-2), carcinoembryonic antigen (CEA), cyclin, cyclin A2, CC motif chemokine ligand 1 (CCL-1), CD19, CD20, CD22, CD23, CD24, CD30, CD33, CD38, CD44, CD44v6, CD44v7 / 8, CD123, CD133, CD138, CD171, CS-1, chondroitin sulfate proteoglycan 4 (CSPG4), epidermal growth factor protein (EGFR), truncated epidermal growth factor protein (tEGFR), epidermal growth factor receptor type III mutant (EGFR vIII), epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), ephrin B2, ephrin receptor A2 (EPHa2), estrogen receptor, Fc receptor-like 5 (FCRL5;Fc receptor homolog 5 or FCRH5), fetal acetylcholine receptor (fetal AchR), folate binding protein (FBP), folate receptor alpha, ganglioside GD2, O-acetylated GD2 (OGD2), ganglioside GD3, glycoprotein 100 (gp100), glypican-3 (GPC3), G protein-coupled receptor 5D (GPCR5D), Her2 / neu (receptor tyrosine kinase erb-B2), Her3 (erb -B3), Her4 (erb-B4), erbB dimer, human high molecular weight melanoma-associated antigen (HMW-MAA), hepatitis B surface antigen, human leukocyte antigen A1 (HLA-A1), human leukocyte antigen A2 (HLA-A2), IL-22 receptor alpha (IL-22Rα), IL-13 receptor alpha 2 (IL-13Rα2), kinase insert domain receptor (kdr), kappa light chain, L1 cell adhesion molecule (L1-CAM), CE7 epitope of L1-CAM, leucine L-rich repeat-containing 8 family member A (LRRC8A), Lewis Y, melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, MAGE-A10, mesothelin (MSLN), c-Met, murine cytomegalovirus (CMV), mucin 1 (MUC1), MUC16, natural killer group 2 member D (NKG2D) ligand, melan-A (MART-1), neural cell adhesion molecule (NCAM), oncofetal antigen, preferentially expressed antigen in melanoma (PRAME), progesterone receptor, prostate-specific antigen, prostate stem cell antigen (PSCA), prostate-specific membrane antigen (PSMA), receptor tyrosine kinase-like orphan receptor 1 (ROR1), survivin, TACI, trophoblast glycoprotein (TPBG; also known as 5T4), tumor-associated glycoprotein 72 (TAG72), tyrosinase-related protein 1 (TRP1; also known as TYRP1 or gp75), tyrosinase-related protein 2 (TRP2;The method of any one of claims 2 and 11 to 48, wherein the antigen is selected from among dopachrome tautomerase, also known as dopachrome delta-isomerase, or DCT), vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor 2 (VEGFR2), Wilms' tumor 1 (WT-1), a pathogen-specific or pathogen-expressed antigen, or an antigen associated with a universal tag, and / or a biotinylated molecule, and / or a molecule expressed by HIV, HCV, HBV or other pathogens;

51. 43. The method of any one of claims 1 to 42, wherein the disease or condition is a B cell malignancy or a B cell derived malignancy.

52. 52. The method of any one of claims 2 and 11 to 51, wherein the target antigen is CD20, CD19, CD22, ROR1, CD45, CD21, CD5, CD33, Igkappa, Iglamda, CD79a, CD79b, or CD30.

53. The method of any one of claims 2 and 11 to 52, wherein the target antigen is CD19.

54. 52. The method of any one of claims 1 to 51, wherein the disease or condition is multiple myeloma.

55. 55. The method of any one of claims 2 and 11 to 51 and 54, wherein the target antigen is BCMA, G protein-coupled receptor class C group 5 member D (GPRC5D), CD38 (cyclic ADP ribose hydrolase), CD138 (syndecan-1, syndecan, SYN-1), CS-1 (CS1, CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24), BAFF-R, TACI, or FcRH5.

56. The method of any one of claims 2 and 11 to 51 and 55, wherein the target antigen is BCMA.

57. The method of any one of claims 26, 27, and 29 to 56, wherein the biological sample is a blood sample.

58. The method of any one of claims 26, 27 and 29 to 56, wherein the biological sample is a tumor sample, optionally a tumor biopsy sample.

59. (a) administering a T cell therapy to a subject having cancer, the T cell therapy comprising a dose of T cells expressing a recombinant antigen receptor that binds to a target antigen; and (b) an immunomodulatory compound selected from the group consisting of a thalidomide analog; a thalidomide derivative; a compound that interacts with and / or binds to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; an inhibitor of Ikaros (IKZF1); an inhibitor of Aiolos (IKZF3); and a compound that enhances or promotes ubiquitination and / or depletion and / or degradation of Ikaros (IKZF1) and / or Aiolos (IKZF3), (1) after exposure of T cells to an antigen or to an antigen receptor-specific agent, results in increased antigen-specific or antigen receptor-driven activity of naive or non-exhausted T cells in a subject optionally comprising T cells expressing the recombinant receptor, compared to the absence of said administration of the compound; or (2) preventing, suppressing, or delaying the onset of an exhaustion phenotype in T cells of naive or non-exhausted T cells in a subject optionally comprising T cells expressing the recombinant receptor following exposure of the T cells to an antigen or to an antigen receptor-specific agent, compared to the absence of said administration of the compound; or (3) reversing an exhausted phenotype in exhausted T cells, optionally including T cells that express the recombinant receptor, in a subject compared to the absence of said administration in said subject. administering to the subject in an amount, duration, and / or frequency effective to A method of treatment comprising:

60. The amount, duration, and / or frequency are (i) resulting in an increase in said antigen-specific or antigen receptor-driven activity; and (ii) preventing, inhibiting or delaying the onset of said wasting phenotype and / or reversing said wasting phenotype 60. The method of claim 59, wherein the method is effective for:

61. The amount, duration, and / or frequency are (i) resulting in an increase in said antigen-specific or antigen receptor-driven activity; and (ii) preventing, inhibiting, or delaying the onset of the wasting phenotype; 61. The method of claim 59 or claim 60, which is effective for:

62. The amount, duration, and / or frequency are (i) resulting in an increase in said antigen-specific or antigen receptor-driven activity; and (ii) preventing, inhibiting, or delaying the onset of the wasting phenotype, and reversing the wasting phenotype; 61. The method of claim 59 or claim 60, which is effective for:

63. (a) administering a T cell therapy to a subject having cancer, the T cell therapy comprising a dose of T cells expressing a recombinant antigen receptor that binds to a target antigen; and (b) an immunomodulatory compound selected from the group consisting of a thalidomide analog; a thalidomide derivative; a compound that interacts with and / or binds to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; an inhibitor of Ikaros (IKZF1); an inhibitor of Aiolos (IKZF3); and a compound that enhances or promotes ubiquitination and / or depletion and / or degradation of Ikaros (IKZF1) and / or Aiolos (IKZF3), (1) after exposure of T cells to an antigen or to an antigen receptor-specific agent, results in increased antigen-specific or antigen receptor-driven activity of naive or non-exhausted T cells in a subject optionally comprising T cells expressing the recombinant receptor, compared to the absence of said administration of the compound; or (2) preventing, suppressing, or delaying the onset of an exhaustion phenotype in T cells of naive or non-exhausted T cells in a subject optionally comprising T cells expressing the recombinant receptor following exposure of the T cells to an antigen or to an antigen receptor-specific agent, compared to the absence of said administration of the compound; or (3) reversing an exhausted phenotype in exhausted T cells, optionally including T cells that express the recombinant receptor, in a subject compared to the absence of said administration in said subject. administering to the subject in an amount, duration, and / or frequency effective to A method of treatment comprising:

64. The amount, duration, and / or frequency are (i) resulting in an increase in said antigen-specific or antigen receptor-driven activity; and (ii) preventing, inhibiting or delaying the onset of said wasting phenotype and / or reversing said wasting phenotype 64. The method of claim 63, wherein the method is effective for:

65. The amount, duration, and / or frequency are (i) resulting in an increase in said antigen-specific or antigen receptor-driven activity; and (ii) preventing, inhibiting, or delaying the onset of the wasting phenotype; 65. The method of claim 63 or claim 64, which is effective for:

66. The amount, duration, and / or frequency are (i) resulting in an increase in said antigen-specific or antigen receptor-driven activity; and (ii) preventing, inhibiting, or delaying the onset of the wasting phenotype, and reversing the wasting phenotype; 65. The method of claim 63 or claim 64, which is effective for:

67. The method of any one of claims 1 to 66, wherein the compound depletes or degrades Ikaros (IKZF1).

68. The compound has the following structure: or a pharma- ceutically acceptable salt thereof, During the ceremony, One of X and Y is -C(O)-, and the other of X and Y is -C(O)- or -CH 2 - and (1) R 1 , R 2 , R 3 , and R 4 each is independently halo, alkyl of 1 to 4 carbon atoms, or alkoxy or 1 to 4 carbon atoms; (2) R 1 , R 3 , R 4 , and R 5 One of them is -NHR a and R 1 , R 2 , R 3 , and R 4 the remainder are hydrogen, where R a is hydrogen or alkyl of 1 to 8 carbon atoms; R 5 is hydrogen or alkyl of 1 to 8 carbon atoms, benzyl, or halo; provided that X and Y are -C(O)-, and (i) R 1 , R 2 , R 3 , and R 4 is fluoro; or (ii) R 1 , R 2 , R 3 , and R 4 If one of is amino, then R 5 is other than hydrogen, 68. The method of any one of claims 1 to 67.

69. The compound has the following structure: or a pharma- ceutically acceptable salt thereof, In the formula, one of X and Y is -C(O)-, and the other of X and Y is -C(O)- or -CH 2 - and R 5 is hydrogen or lower alkyl; 69. The method of any one of claims 1 to 68.

70. The compound has the following structure: or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.

71. 71. The method of any one of claims 1 to 70, wherein the compound is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione.

72. The compound has the following structure: or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.

73. 73. The method of any one of claims 1 to 67 and 72, wherein the compound is 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

74. 74. The method of any one of claims 20-73, wherein the immunomodulatory compound is administered in an effective amount of between or about 1 mg to 50 mg per day, between or about 1 mg to 25 mg per day, between or about 1 mg to 25 mg per day, between or about 1 mg to 10 mg per day, between or about 1 mg to 5 mg per day, between or about 1 mg to 5 mg per day, between or about 5 mg to 50 mg per day, between or about 5 mg to 25 mg per day, between or about 5 mg to 25 mg per day, between or about 5 mg to 10 mg per day, optionally wherein the administration is daily for a sustained period in the cycling regimen.

75. The compound has the following structure: or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, Z is C=O or CH 2 and R 11 -Z 1 -R 13 and R 12 is H or (C 1 -C 6 ) alkyl; Z 1 is a 6-10 membered aryl, heteroaryl, or heterocycle, each of which is optionally substituted with one or more halogens; or a bond; R 13 teeth, -(CH 2 ) n -aryl, -O-(CH 2 ) n -aryl, or -(CH 2 ) n -O-aryl, wherein aryl is optionally substituted with one or more of the following: 1 -C 6 ) alkyl; itself optionally substituted with one or more halogens; (C 1 -C 6 )alkoxy, itself substituted with one or more halogens; oxo; amino; carboxyl; cyano; hydroxyl; halogen; deuterium; one or more (C 1 -C 6 ) alkyl, (C 1 -C 6 ) 6-10 membered aryl or heteroaryl optionally substituted with alkoxy or halogen; -CONH 2 ; or -COO-(C 1 -C 6 ) alkyl, wherein the alkyl may be substituted with one or more halogens; -(CH 2 ) n -Heterocycle, -O-(CH 2 ) n -heterocycle, or -(CH 2 ) n -O-heterocycle, wherein the heterocycle is optionally substituted with one or more of the following: 1 -C 6 ) alkyl, itself optionally substituted with one or more halogens; 1 -C 6 )alkoxy, itself substituted with one or more halogens; oxo; amino; carboxyl; cyano; hydroxyl; halogen; deuterium; one or more (C 1 -C 6 ) alkyl, (C 1 -C 6 ) 6-10 membered aryl or heteroaryl optionally substituted with alkoxy or halogen; -CONH 2 ; or -COO-(C 1 -C 6 ) alkyl, wherein the alkyl may be substituted with one or more halogens; or -(CH 2 ) n -heteroaryl, -O-(CH 2 ) n -heteroaryl, or -(CH 2 ) n -O-heteroaryl, wherein heteroaryl is optionally substituted with one or more of the following: 1 -C 6 ) alkyl, itself optionally substituted with one or more halogens; 1 -C 6 )alkoxy, itself substituted with one or more halogens; oxo; amino; carboxyl; cyano; hydroxyl; halogen; deuterium; one or more (C 1 -C 6 ) alkyl, (C 1 -C 6 ) 6-10 membered aryl or heteroaryl optionally substituted with alkoxy or halogen; -CONH 2 ; or -COO-(C 1 -C 6 ) alkyl, wherein the alkyl may be substituted with one or more halogens. and n is 0, 1, 2, or 3; 68. The method of any one of claims 1 to 67.

76. The compound is or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

77. The compound is 77. The method of any one of claims 1-67, 75, and 76, wherein the compound is a Form A crystalline form of the hydrochloride salt of 78. The method of claim 77, wherein the XRPD pattern of a crystalline form A of the hydrochloride salt of is characterized by XRPD peaks located at or near 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or all of the following positions: 9.69, 12.82, 15.09, 15.94, 16.76, 17.65, 19.44, 19.80, 2230, 22.47, 22.95, 23.02, 24.29, 24.48, 24.70, 26.27, 26.77, 27.60, 29.43, 29.72, and 32.91 degrees 2θ.

79. 80. The method of any one of claims 20-67 and 75-78, wherein the immunomodulatory compound is administered at or about 0.1 mg to 1 mg per day, at or about 0.1 mg to 0.6 mg per day, at or about 0.1 mg to 0.6 mg per day, at or about 0.1 mg to 0.3 mg per day, optionally wherein the administration is daily for a period in a cycling regimen.

80. The method of any one of claims 20-79, wherein administration of the compound is initiated subsequent to the initiation of administration of T cell therapy.

81. 81. The method of any one of claims 59-80, wherein the cancer is a B cell malignancy, a B cell derived malignancy, a non-hematologic cancer, or a solid tumor.

82. 82. The method of any one of claims 59-81, wherein the target antigen is a tumor antigen, and optionally the target antigen is associated with, specific for, and / or expressed on a cancer cell or tissue.

83. The target antigen may be B cell maturation antigen (BCMA), αvβ6 integrin (avb6 integrin), BAFF-R, B7-H3, B7-H6, carbonic anhydrase 9 (CA9; also known as CAIX or G250), cancer testis antigen, cancer / testis antigen 1B (CTAG; also known as NY-ESO-1 and LAGE-2), carcinoembryonic antigen (CEA), cyclin, cyclin A2, CC motif chemokine ligand 1 (CCL-1 ), CD5, CD19, CD20, CD21, CD22, CD23, CD24, CD30, CD38, CD44, CD44v6, CD44v7 / 8, CD45, CD79a, CD79b, CD123, CD133, CD138, CD171, CS-1, chondroitin sulfate proteoglycan 4 (CSPG4), epidermal growth factor protein (EGFR), truncated epidermal growth factor protein (tEGFR), epidermal growth factor receptor type III mutated (EGFR vIII), epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), ephrin B2, ephrin receptor A2 (EPHa2), estrogen receptor, Fc receptor-like 5 (FCRL5;also known as Fc receptor homolog 5 or FCRH5), fetal acetylcholine receptor (fetal AchR), folate-binding protein (FBP), folate receptor alpha, ganglioside GD2, O-acetylated GD2 (OGD2), ganglioside GD3, glycoprotein 100 (gp100), glypican-3 (GPC3), G protein-coupled receptor 5D (GPCR5D), Her2 / neu (receptor tyrosine kinase erb-B2), Her3 (erb-B3), Her4 (erb-B4), erbB dimer, human high molecular weight Melanoma-associated antigen (HMW-MAA), Hepatitis B surface antigen, Human leukocyte antigen A1 (HLA-A1), Human leukocyte antigen A2 (HLA-A2), Ig kappa, Ig lambda, IL-22 receptor alpha (IL-22Rα), IL-13 receptor alpha 2 (IL-13Rα2), Kinase insert domain receptor (kdr), L1 cell adhesion molecule (L1-CAM), CE7 epitope of L1-CAM, Leucine-rich repeat containing 8 family member A (LRRC8A), Lewis Y, Melanoma-associated antigen (MAGE)-A1, MAGE-A3, M AGE-A6, MAGE-A10, mesothelin (MSLN), c-Met, murine cytomegalovirus (CMV), mucin 1 (MUC1), MUC16, natural killer group 2 member D (NKG2D) ligand, melan-A (MART-1), neural cell adhesion molecule (NCAM), oncofetal antigen, preferentially expressed antigen in melanoma (PRAME), progesterone receptor, prostate-specific antigen, prostate stem cell antigen (PSCA), prostate-specific membrane antigen (PSMA), ROR1, survivin, TACI, trophoblast glycoprotein (TPBG; also known as 5T4) 83. The method of any one of claims 59 to 82, wherein the antigen is selected from the group consisting of a tyrosinase-related protein 1 (TRP1; also known as TYRP1 or gp75), a tumor associated glycoprotein 72 (TAG72), a tyrosinase-related protein 1 (TRP1; also known as TYRP1 or gp75), a tyrosinase-related protein 2 (TRP2; also known as dopachrome tautomerase, dopachrome delta-isomerase, or DCT), a vascular endothelial growth factor receptor (VEGFR), a vascular endothelial growth factor receptor 2 (VEGFR2), Wilms' tumor 1 (WT-1), a pathogen-specific antigen, or a pathogen-expressed antigen;

84. The method of claim 51, claim 82, or claim 83, wherein the B cell malignancy is lymphoma.

85. 85. The method of claim 84, wherein the lymphoma is non-Hodgkin's lymphoma (NHL).

86. The method of claim 85, wherein the NHL comprises aggressive NHL, diffuse large B-cell lymphoma (DLBCL), DLBCL-NOS, optionally transformed low-grade; EBV-positive DLBCL-NOS; T-cell / histiocyte-rich large B-cell lymphoma; primary mediastinal large B-cell lymphoma (PMBCL); follicular lymphoma (FL), optionally follicular lymphoma grade 3B (FL3B); and / or high-grade B-cell lymphoma with MYC and BCL2 and / or BCL6 rearrangements with DLBCL histology (double / triple hit).

87. 87. The method of any one of claims 1-86, wherein the subject is identified or has been identified as having an Eastern Cooperative Oncology Group Performance Status (ECOG) of 1 or less.

88. 88. The method of any one of claims 59 to 87, wherein the target antigen is CD20, CD19, CD22, ROR1, CD45, CD21, CD5, CD33, Igkappa, Iglamda, CD79a, CD79b, or CD30.

89. The method of any one of claims 59 to 88, wherein the target antigen is CD19.

90. 88. The method of any one of claims 59-87, wherein the target antigen is not CD20, CD19, CD22, ROR1, CD45, CD21, CD5, CD33, Igkappa, Iglamda, CD79a, CD79b, or CD30.

91. 82. The method of any one of claims 59-81, wherein the cancer is multiple myeloma.

92. 92. The method of any one of claims 59-91, wherein the target antigen is BCMA, G protein-coupled receptor class C group 5 member D (GPRC5D), CD38 (cyclic ADP ribose hydrolase), CD138 (syndecan-1, syndecan, SYN-1), CS-1 (CS1, CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24), BAFF-R, TACI, or FcRH5.

93. The method of any one of claims 59 to 92, wherein the target antigen is BCMA.

94. 94. The method of any one of claims 20-93, wherein administration of the compound continues for a period extending from 3 months, or about 3 months, or more than 3 months after initiation of administration of T cell therapy.

95. 75. The method of claim 74, wherein the effective amount is less than or equal to about 4 mg per day.

96. 75. The method of claim 74, wherein the effective amount is at or about 1.0 mg to at or about 4 mg per day.

97. 75. The method of claim 74, wherein the effective amount is less than or equal to about 3 mg per day.

98. 98. The method of claims 74 and 97, wherein the effective amount is at or about 1.0 mg to at or about 3 mg.

99. 75. The method of claim 74, wherein the effective amount is less than or equal to about 2.5 mg per day.

100. 100. The method of any one of claims 74 and 95-99, wherein for each week of the cycling regimen, or for at least one week of the cycling regimen, administration of the compound comprises administration of the compound on each of no more than five consecutive days of the week, followed by a rest period during which the compound is not administered for the remainder of the week.

101. 101. The method of claim 100, wherein said five or fewer consecutive days is three consecutive days per week followed by a four day rest period during which the compound is not administered.

102. 101. The method of claim 100, wherein said five or fewer consecutive days is four consecutive days per week followed by a three day rest period during which the compound is not administered.

103. 101. The method of claim 100, wherein said five or fewer consecutive days is five consecutive days per week followed by a two day rest period during which the compound is not administered.

104. The method of any one of claims 20-103, wherein said administration continues for a period extending from 4 months, or about 4 months, or more than 4 months after initiation of administration of T cell therapy.

105. The method of any one of claims 20-104, wherein said administration continues for a period extending from 5 months, or about 5 months, or more than 5 months after initiation of administration of T cell therapy.

106. The method of any one of claims 20-105, wherein said administration continues for a period extending from 6 months, or about 6 months, or more than 6 months after initiation of administration of T cell therapy.

107. The method of any one of claims 74 and 95-106, wherein the administration of said compound per day is in an amount of 3 mg or about 3 mg.

108. The method of any one of claims 74 and 95-106, wherein the administration of said compound per day is in an amount of 2.5 mg or about 2.5 mg.

109. The method of any one of claims 74 and 95-106, wherein the administration of said compound per day is in an amount of 2 mg or about 2 mg.

110. The method of any one of claims 74 and 95-106, wherein the administration of said compound per day is in an amount of 1.5 mg or about 1.5 mg.

111. The method of any one of claims 74 and 95-106, wherein said administration of said compound per day is in an amount of 1 mg or about 1 mg per day.

112. The method of any one of claims 20-111, wherein administration of said compound is discontinued at the end of said period if, at the end of said period, the subject exhibits a complete response (CR) after treatment.

113. The method of any one of claims 20-112, wherein administration of the compound is discontinued at the end of the period if, at the end of the period, the cancer has progressed after treatment or has recurred following remission.

114. 114. The method of any one of claims 20-113, wherein administration of the compound continues for a period ranging from or about 3 months to or about 6 months.

115. The method of any one of claims 20-114, wherein administration of the compound continues for a period extending to 3 months or about 3 months after initiation of administration of T cell therapy.

116. The method of any one of claims 20-114, wherein if the subject achieves a complete response (CR) following treatment prior to at or about 3 months, or the cancer progresses following treatment or recurs following remission, administration of the compound continues for a period extending to at or about 3 months following initiation of administration of T cell therapy.

117. The method of claim 116, wherein if the subject achieves a complete response (CR) at 3 months, administration of the compound continues for a period extending to 3 months or about 3 months after initiation of administration of T cell therapy.

118. The method of any one of claims 20-114, wherein administration of the compound continues for a period extending to 6 months or about 6 months after initiation of administration of T cell therapy.

119. The method of any one of claims 20-118, wherein administration of the compound continues for a period extending to 6 months or about 6 months after initiation of administration of T cell therapy if the subject achieves a complete response (CR) following treatment prior to 6 months or about 6 months, or if the cancer progresses following treatment or recurs following remission.

120. 120. The method of claim 119, wherein said time period extends to 6 months or about 6 months after initiation of administration of T cell therapy, if the subject achieves a complete response (CR) at 6 months.

121. The method of any one of claims 20-120, wherein said administration is continued for the duration even if the subject achieves a complete response (CR) prior to the end of the period.

122. The method of any one of claims 20-121, wherein the subject achieves a complete response (CR) during the administration period and prior to the end of the administration period.

123. The method of any one of claims 20-111, 114, 115, 119, 121, and 122, further comprising continuing the administration after the end of the time period if, at the end of the time period, the subject exhibits a partial response (PR) or stable disease (SD).

124. The method of any one of claims 20-123, wherein if at or about 6 months the subject exhibits a partial response (PR) or stable disease (SD) after treatment, said administration is continued for more than 6 months.

125. The method of claim 123 or claim 124, wherein said administration is continued until the subject achieves a complete response (CR) after treatment, or until the cancer progresses after treatment or recurs following remission.

126. The method of any one of claims 20-125, wherein administration of the compound begins at or after peak or maximum levels of T cell therapy cells are detectable in the subject's blood.

127. The method of any one of claims 20-126, wherein administration of the compound is initiated about 14 to about 35 days after initiation of administration of T cell therapy.

128. The method of any one of claims 20-127, wherein administration of the compound is initiated about 21 to about 35 days after initiation of administration of T cell therapy.

129. The method of any one of claims 20-128, wherein administration of the compound is initiated about 21 to about 28 days after initiation of administration of T cell therapy.

130. 130. The method of any one of claims 20-129, wherein administration of the compound is initiated at or about 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, or 27 days, or 28 days after initiation of administration of T cell therapy.

131. The method of any one of claims 20-130, wherein administration of the compound is initiated 28 days or about 28 days after initiation of administration of T cell therapy.

132. The method of any one of claims 20-131, wherein upon initiation of administration of the compound, the subject does not exhibit severe toxicity following administration of T cell therapy.

133. said severe toxicity being severe cytokine release syndrome (CRS), optionally Grade 3 or greater, prolonged Grade 3 or greater, or Grade 4 or 5 CRS; and / or the severe toxicity is severe neurotoxicity, optionally grade 3 or greater, prolonged grade 3 or greater, or grade 4 or 5 neurotoxicity; The method of claim 132.

134. The method of any one of claims 20 to 133, wherein if the subject exhibits toxicity, optionally hematological toxicity, following administration of the compound, administration of said compound is stopped and / or modified.

135. 135. The method of claim 134, wherein said toxicity is selected from severe neutropenia, optionally febrile neutropenia, prolonged grade 3 or greater neutropenia.

136. 136. The method of claim 134 or 135, wherein administration of the compound is resumed after the subject no longer exhibits toxicity.

137. 137. The method of claim 136, wherein the administration is altered after administration of the compound is resumed.

138. The method of any one of claims 134-137, wherein said modified administration comprises administering a reduced amount of the compound and / or reducing the frequency of administration of the compound.

139. 139. The method of any one of claims 134-138, wherein said altered administration comprises administering a reduced amount of the compound.

140. 140. The method of claim 139, wherein the dose of the compound is reduced, the reduced amount being from at or about 1 mg to at or about 2 mg per day for no more than 5 days per week.

141. The method of any one of claims 1 to 67 and 75 to 139, wherein the compound is or comprises a pharma- ceutically acceptable salt of (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione.

142. The method of any one of claims 1 to 67 and 75 to 139, wherein the compound is or comprises a hydrate of (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione.

143. The method of any one of claims 1 to 67 and 75 to 139, wherein the compound is or comprises a solvate of (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione.

144. The method of any one of claims 1 to 67 and 75 to 139, wherein the compound is or comprises (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione.

145. The method of any one of claims 1-74 and 80-140, wherein the compound is or comprises a solvate of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

146. The method of any one of claims 1-74 and 80-140, wherein the compound is or comprises a hydrate of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

147. The method of any one of claims 1-74 and 80-140, wherein the compound is or comprises a pharma- ceutically acceptable salt of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

148. The method of any one of claims 1 to 74 and 80 to 140, wherein the compound is or comprises 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

149. The method of any one of claims 20-148, wherein the compound is administered orally.

150. Administering the compound comprises: reversing the exhaustion phenotype in recombinant receptor-expressing T cells in a subject; Preventing, inhibiting, or delaying the onset of an exhaustion phenotype in recombinant receptor-expressing T cells in a subject; or reducing the level or degree of an exhaustion phenotype in recombinant receptor-expressing T cells in a subject; or reducing the percentage of the total number of recombinant receptor-expressing T cells in a subject that have an exhaustion phenotype; The method of any one of claims 20 to 149.

151. The method of any one of claims 3-149, wherein initiation of administration of the compound occurs subsequent to administration of T cell therapy, and following administration or initiation of the compound, the subject exhibits restoration or rescue of antigen-specific or tumor-specific activity or function of recombinant receptor-expressing T cells in the subject, and optionally, said restoration, rescue, and / or initiation of administration of the compound is at a time after recombinant receptor-expressing T cells in the subject or in the subject's blood exhibit an exhausted phenotype.

152. Administering the compound comprises: (a) resulting in increased antigen-specific or antigen receptor-driven activity of naive or non-exhausted T cells in a subject optionally comprising T cells expressing said recombinant receptor, following exposure of the T cells to an antigen or to an antigen receptor-specific agent, compared to the absence of said administration of the compound; or (b) preventing, suppressing, or delaying the onset of an exhaustion phenotype in T cells of naive or non-exhausted T cells in a subject optionally comprising T cells expressing said recombinant receptor following exposure of the T cells to an antigen or to an antigen receptor-specific agent, compared to the absence of said administration of said compound; or (c) reversing an exhausted phenotype in exhausted T cells, optionally including T cells that express the recombinant receptor, in a subject compared to the absence of said administration in said subject. The method of any one of claims 3 to 149, comprising administration in an amount, frequency, and / or duration effective to

153. Administering the compound comprises: (i) resulting in an increase in said activity; and (ii) preventing, inhibiting or delaying the onset of the wasting phenotype and / or reversing the wasting phenotype 153. The method of claim 152, comprising administration in an amount, frequency, and / or duration effective to

154. The method of claim 152 or 153, wherein T cells in the subject comprise T cells that express the recombinant receptor and / or the antigen is a target antigen.

155. An exhaustion phenotype for a T cell or population of T cells, an increase in the level or degree of surface expression on one or more T cells, or the percentage of the population of said T cells exhibiting surface expression, of one or more exhaustion markers, optionally two, three, four, five, or six exhaustion markers, compared to a reference T cell population under the same conditions; or A decrease in the level or degree of activity exhibited by the T cell or population of T cells upon exposure to an antigen or antigen receptor-specific agent, as compared to a reference T cell population under the same conditions. The method of any one of claims 150 to 154, comprising:

156. 156. The method of claim 155, wherein said increase in level, degree, or percentage is greater than or equal to 1.2-fold, 1.5-fold or about 1.5-fold, 2.0-fold or about 2.0-fold, 3-fold or about 3-fold, 4-fold or about 4-fold, 5-fold or about 5-fold, 6-fold or about 6-fold, 7-fold or about 7-fold, 8-fold or about 8-fold, 9-fold or about 9-fold, 10-fold or about 10-fold, or more.

157. 156. The method of claim 155, wherein said level, degree, or percentage decrease is greater than or equal to 1.2-fold, 1.5-fold or about 1.5-fold, 2.0-fold or about 2.0-fold, 3-fold or about 3-fold, 4-fold or about 4-fold, 5-fold or about 5-fold, 6-fold or about 6-fold, 7-fold or about 7-fold, 8-fold or about 8-fold, 9-fold or about 9-fold, 10-fold or about 10-fold, or more.

158. The method of any one of claims 155-157, wherein said reference population of T cells is optionally a population of T cells known to have a non-exhausted phenotype from the same subject from which the one or more T cells with an exhausted phenotype are derived, or of the same species as the subject, a population of naive T cells, a population of central memory T cells, or a population of stem central memory T cells.

159. (a) the reference T cell population is a subject-matched population comprising bulk T cells isolated from the blood of the subject from which one or more T cells having an exhausted phenotype are derived, optionally wherein the bulk T cells do not express a recombinant receptor; and / or (b) the reference T cell population is obtained from a subject from which one or more T cells having an exhausted phenotype were derived prior to receiving a dose of T cells expressing a recombinant receptor; The method of any one of claims 155 to 158.

160. The method of any one of claims 155-158, wherein said reference T cell population is a composition comprising a sample of a T cell therapy prior to its administration to a subject, or a pharmaceutical composition comprising T cells expressing a recombinant receptor, optionally wherein said composition is a cryopreserved sample.

161. The method of any one of claims 155-160, wherein said one or more exhaustion markers is an inhibitory receptor.

162. The method of any one of claims 155-161, wherein said one or more exhaustion markers are selected from among PD-1, CTLA-4, TIM-3, LAG-3, BTLA, 2B4, CD160, CD39, VISTA, and TIGIT.

163. The method of any one of claims 155-162, wherein said activity is one or more of proliferation, cytotoxicity, or production of one or a combination of inflammatory cytokines, optionally wherein the one or a combination of cytokines is selected from the group consisting of IL-2, IFN-gamma, and TNF-alpha.

164. 164. The method of any one of claims 155 to 163, wherein said exposure to an antigen or antigen receptor-specific agent comprises incubation with an antigen or antigen receptor-specific agent, optionally an agent that binds to a recombinant receptor, said antigen optionally being a target antigen.

165. The method of claim 164, wherein said antigen or antigen receptor specific agent comprises an antigen-expressing target cell, optionally a cell of said disease, disorder, or condition.

166. The method of any one of claims 2 and 11 to 165, wherein the target antigen is a human antigen.

167. The method of any one of claims 1 to 166, wherein the subject is a human.

168. The method of any one of claims 1 to 167, wherein the recombinant antigen receptor is a chimeric antigen receptor that specifically binds to a target antigen.

169. The method of claim 16 or claim 168, wherein the chimeric antigen receptor (CAR) comprises an extracellular antigen recognition domain that specifically binds to a target antigen and an intracellular signaling domain that comprises an ITAM.

170. The method of claim 169, wherein the intracellular signaling domain comprises the signaling domain of the CD3-zeta (CD3ζ) chain, optionally a human CD3-zeta chain.

171. The method of claim 169 or claim 170, wherein said chimeric antigen receptor (CAR) further comprises a costimulatory signaling region.

172. The method of claim 171, wherein said costimulatory signaling region comprises the signaling domain of CD28 or 4-1BB, optionally human CD28 or human 4-1BB.

173. The method of claim 171 or claim 172, wherein the costimulatory domain is or comprises the signal transduction domain of human 4-1BB.

174. the CAR comprises an scFv specific for a target antigen; a transmembrane domain; optionally a cytoplasmic signaling domain derived from a costimulatory molecule, which is or comprises 4-1BB, optionally human 4-1BB; and optionally a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule, which is or comprises a CD3 zeta signaling domain, optionally human CD3 zeta signaling domain; and optionally the CAR further comprises a spacer between the transmembrane domain and the scFv; the CAR, in order, comprises: an scFv specific for a target antigen; a transmembrane domain; optionally a cytoplasmic signaling domain derived from a costimulatory molecule, which is or comprises a 4-1BB signaling domain, optionally a human 4-1BB signaling domain; and optionally a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule, which is a CD3 zeta signaling domain, optionally a human CD3 zeta signaling domain; or The CAR, in order, comprises: an scFv specific for a target antigen; a spacer; a transmembrane domain, optionally a cytoplasmic signaling domain derived from a costimulatory molecule, which is a 4-1BB signaling domain, and optionally a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule, which is or includes a CD3 zeta signaling domain. The method of any one of claims 16 and 168-173.

175. The dose of engineered T cells was 1 × 10 5 ~5×10 8 or about 1 x 10 5 ~5×10 8 Total CAR-expressing T cells, 1 x 10 6 ~2.5×10 8 or about 1 x 10 6 ~2.5×10 8 Total CAR-expressing T cells, 5 x 10 6 ~1×10 8 or about 5 x 10 6 ~1×10 8 Total CAR-expressing T cells, 1 x 10 7 ~2.5×10 8 or about 1 x 10 7 ~2.5×10 8 Total CAR-expressing T cells, 5 x 10 7 ~1×10 8 or about 5 x 10 7 ~1×10 8 The method of any one of claims 21-174, comprising a total of CAR-expressing T cells, each of which is inclusive.

176. The dose of engineered T cells is at least 1 × 10 5 Or at least about 1 × 10 5 CAR-expressing cells, at least 2.5 x 10 5 Or at least about 2.5 × 10 5 CAR-expressing cells, at least 5 x 10 5 Or at least about 5×10 5 CAR-expressing cells, at least 1 x 10 6 Or at least about 1 × 10 6 CAR-expressing cells, at least 2.5 x 10 6 Or at least about 2.5 × 10 6 CAR-expressing cells, at least 5 x 10 6 Or at least about 5×10 6 CAR-expressing cells, at least 1 x 10 7 Or at least about 1 × 10 7 CAR-expressing cells, at least 2.5 x 10 7 Or at least about 2.5 × 10 7 CAR-expressing cells, at least 5 x 10 7 Or at least about 5×10 7 CAR-expressing cells, at least 1 x 10 8 Or at least about 1 × 10 8 CAR-expressing cells, at least 2.5 x 10 8 Or at least about 2.5 × 10 8 of CAR-expressing cells, or at least 5 x 10 8 Or at least about 5×10 8 The method of any one of claims 21-175, comprising a CAR-expressing cell of.

177. The dose of engineered T cells was 5 × 10 7 or about 5 x 10 7 The method of any one of claims 21-176, comprising a total of CAR-expressing T cells.

178. The dose of engineered T cells was 1 × 10 8 or about 1 x 10 8 The method of any one of claims 21-177, comprising a CAR-expressing cell of.

179. The method of any one of claims 21-178, wherein the dose of cells is administered parenterally, optionally intravenously.

180. The method of any one of claims 21-179, wherein the T cells are primary T cells obtained from the subject.

181. The method of any one of claims 21-180, wherein the T cells are autologous to the subject.

182. The method of any one of claims 21-180, wherein the T cells are allogeneic to the subject.

183. The method of any one of claims 21-182, wherein the dose of engineered T cells comprises CD4+ T cells expressing a CAR and CD8+ T cells expressing a CAR, and wherein administering the dose comprises administering a plurality of separate compositions, the plurality of separate compositions comprising a first composition comprising one of the CD4+ T cells and CD8+ T cells, and a second composition comprising the other of the CD4+ T cells or CD8+ T cells.

184. The method of any one of claims 21-183, wherein prior to said administering, the subject is preconditioned with a lymphodepleting therapy comprising administration of fludarabine and / or cyclophosphamide.

185. The method of any one of claims 21-184, further comprising administering to the subject a lymphodepleting therapy comprising administration of fludarabine and / or cyclophosphamide immediately prior to said administering.

186. The lymphodepleting therapy is administered at a dose of about 200 to 400 mg / m 2 , optionally 300 mg / m 2 or about 300 mg / m 2 (inclusive) cyclophosphamide, and / or about 20-40 mg / m 2 , optionally 30 mg / m 2 of fludarabine daily for 2-4 days, optionally 3 days, or said lymphodepleting therapy comprises about 500 mg / m 2 186. The method of claim 184 or claim 185, comprising administration of cyclophosphamide.

187. The lymphodepleting therapy is administered at a dose of 300 mg / m 2 or about 300 mg / m 2 of cyclophosphamide and approximately 30 mg / m 2 of fludarabine administered daily for three days; and / or The lymphodepleting therapy is administered at a dose of 500 mg / m 2 or about 500 mg / m 2 of cyclophosphamide and approximately 30 mg / m 2 of fludarabine daily for three days, The method of any one of claims 184 to 186.

188. At least 35%, at least 40%, or at least 50% of subjects treated according to the method achieve a complete response (CR) that is durable for 6 or more months or 9 or more months, or that is durable in at least 60, 70, 80, 90, or 95% of subjects who achieve a CR; and / or At least 60, 70, 80, 90, or 95% of subjects who achieve a CR by 6 months remain in response, remain in CR, and / or are alive or alive without disease for at least 3 months and / or longer than 6 months and / or longer than 9 months; and / or at least 50%, at least 60%, or at least 70% of subjects treated according to the method achieve an objective response (OR), optionally with the OR being durable for 6 or more months or 9 or more months, or with the OR being durable in at least 60, 70, 80, 90, or 95% of subjects who achieve an OR; and / or At least 60, 70, 80, 90, or 95% of subjects who achieve an OR by 6 months remain in response or are alive for 3 months or longer and / or 6 months or longer. The method of any one of claims 20 to 187.

189. (a) a T cell therapy comprising a dose of T cells expressing a recombinant antigen receptor that binds to a target antigen; and (b) an immunomodulatory compound selected from the group consisting of: a thalidomide analog; a thalidomide derivative; a compound that interacts with and / or binds to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; an inhibitor of Ikaros (IKZF1); an inhibitor of Aiolos (IKZF3); and a compound that enhances or promotes the ubiquitination and / or depletion and / or degradation of Ikaros (IKZF1) and / or Aiolos (IKZF3); and (c) instructions for administering the compound and / or the T cell therapy according to the method of any one of claims 1-187. Including the kit.

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