COMBINATIONS FOR USE IN THE TREATMENT AND MODULATION OF T CELLS

Abstract

This description relates in some respects to methods, compositions, and uses involving immunotherapies, such as adoptive cell therapy, for example, T-cell therapy, and an immunomodulatory compound, such as a structural or functional analogue or derivative of thalidomide and / or an E3-ubiquitin ligase inhibitor. The methods, compositions, and uses provided include those for combination therapies involving the administration or use of one or more immunomodulatory compounds in conjunction with a T-cell therapy, such as genetically modified T-cell therapy involving cells modified with a recombinant receptor, such as chimeric antigen receptor (CAR)-expressing T cells. Compositions, methods of administration to subjects, articles of manufacture, and kits for use in the methods are also provided.In some respects, the characteristics of the methods and cells provide increased or improved activity, efficacy, persistence, expansion and / or proliferation of T cells for adoptive cell therapy or endogenous T cells recruited by immunotherapeutic agents.

Description

METHODS AND COMBINATIONS FOR TREATMENT AND T CELLMODULATIONCross-Reference to Related Applications

[0001] This application claims priority to U.S. Provisional Application No. 62 / 757,755, filed November 8, 2018, and U.S. Provisional Application No. 62 / 826,928, filed March 29, 2019, the contents of which are hereby incorporated by reference in their entirety for all purposes.Incorporation by Reference of Sequence Listing

[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 7350420l9440SeqList.txt, created November 7, 2019 which is 320 kilobytes in size. The information in the electronic format of the Sequence Listing is incorporated by reference in its entirety.Field

[0003] The present disclosure relates in some aspects to methods, compositions and uses involving immunotherapies, such as adoptive cell therapy, e.g., T cell therapy, and an immunomodulatory compound, such as a structural or functional analog or derivative of thalidomide and / or an inhibitor of E3-ubiquitin ligase. The provided methods, compositions and uses include those for combination therapies involving the administration or use of one or more immunomodulatory compounds in conjunction with a T cell therapy, such as a genetically engineered T cell therapy involving cells engineered with a recombinant receptor, such as chimeric antigen receptor (CAR)-expressing T cells. Also provided are compositions, methods of administration to subjects, articles of manufacture and kits for use in the methods. In some aspects, features of the methods and cells provide for increased or improved activity, efficacy, persistence, expansion and / or proliferation of T cells for adoptive cell therapy or endogenous T cells recruited by immunotherapeutic agents.Background

[0004] Various strategies are available for immunotherapy, for example administering engineered T cells for adoptive therapy. For example, strategies are available for engineering T cells expressing genetically engineered antigen receptors, such as CARs, and administeringcompositions containing such cells to subjects. Improved strategies are needed to improve efficacy of the cells, for example, improving the persistence, activity and / or proliferation of the cells upon administration to subjects. Provided are methods, compositions, kits, and systems that meet such needs.Summary

[0005] Provided herein are methods for rescuing T cell activity, involving exposing a plurality of T cells having an exhausted phenotype to an effective amount of animmunomodulatory 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 embodiments 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] Provided herein are methods for preventing or inhibiting or reducing or delaying the onset of T cell exhaustion, the 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 ubiquitination, depletion and / or degradation of Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein at least a portion of the exposing is carried out under conditions that induce, or are capable of inducing, an exhausted phenotype in T cells of the plurality in the absence of the compound.

[0007] Provided herein are methods for reducing or delaying the onset of T cell exhaustion, the method involving exposing a plurality of T cells to an effective amount of animmunomodulatory 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), wherein at least a portion of theexposing is carried out during conditions that induce, or are capable of inducing, an exhausted phenotype in T cells of the plurality in the absence of the compound.

[0008] Provided herein are methods for increasing T cell activity or potency and preventing or inhibiting, reducing or delaying the onset of T cell exhaustion, involving 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 ubiquitination, depletion and / or degradation of Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein at least a portion of the exposing is carried out under conditions that induce, or are capable of inducing, an exhausted phenotype in T cells of the plurality in the absence of the compound.

[0009] In some embodiments of any of the methods provided herein, the conditions include T cell stimulatory conditions, optionally including exposure to at least one T cell stimulatory agent that is capable of stimulating a signal in T cells of the plurality, said signal optionally including a primary and / or costimulatory signal. In some embodiments, the conditions include persistent, repeat, prolonged or long term exposure to the 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 T cells of the plurality or an agent that is bound by an antigen receptor expressed by T cells of the plurality. 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 a TCR complex, optionally wherein the agent specifically binds to a CD3, optionally a CD3zeta.

[0011] In some embodiments of any of the methods provided herein, the at least one T cell stimulatory agent includes an anti-CD3 antibody. In some embodiments, the at least one T cell stimulatory agent specifically binds to a T cell costimulatory molecule, optionally wherein the T cell costimulatory molecule is CD28, CD137 (4-l-BB), 0X40, CD40F or ICOS or wherein the at least one T cell stimulatory agent further includes an agent that specifically binds to a T cell costimulatory molecule, optionally wherein the T cell costimulatory molecule is CD28, CD137(4-l-BB), 0X40, CD40F or ICOS. In some embodiments, the at least one T cell stimulatory agent includes an anti-CD28 antibody. In some embodiments, the at least one T cell stimulatory agent includes or further includes an MHC-peptide complex recognized by an antigen receptorexpressed by one or more T cells of the plurality, or an antigen recognized by an antigen receptor expressed by one or more T cells of the plurality. In some embodiments, the one or more of the plurality of T cells express a recombinant antigen receptor that binds a target antigen. In some embodiments, the at least one T cell stimulatory agent binds to the recombinant antigen receptor. In some embodiments, the at least one T cell stimulatory agent is or comprises an anti-idioptypic antibody specific to the recombinant antigen receptor. In some embodiments, the at least one T cell stimulatory agent is or includes the target antigen or a portion thereof recognized by or bound by the recombinant antigen receptor and / or wherein the conditions include 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 embodiments of any of the methods provided herein, the one or more T cells are primary human T cells, optionally from a subject. In some embodiments, the exposing of the T cells to an effective amount of an immunomodulatory compound is carried out ex vivo. In other embodiments, the exposing is carried out in vivo , and the exposing includes administration of the compound to a subject, optionally wherein, where the T cells are from the subject, wherein the administration of the compound is to said subject; and / or the exposing includes administration of said plurality of T cells to a subject, optionally wherein, where the T cells are from the subject, wherein the administration of the compound is to said subject. In some embodiments of any of the methods provided herein, the exposing of the T cells to an effective amount of an immunomodulatory compound includes said administration of said compound and, wherein, prior to the exposing, said subject has been administered a composition comprising the plurality of T cells to the subject for treating a disease or condition, optionally wherein the target antigen is associated with the disease or condition.

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

[0014] Provided herein are methods of treatment that involve administering, to a subject, an immunomodulatory compound, wherein said 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), wherein, (a) said subject, prior to the administration of the compound, has been administered a T cell therapy that includes a dose of T cells expressing a recombinant antigen receptor that binds a target antigen, or (b) prior to or at the time of administration of said compound, said subject or a blood sample from the subject contains, or has been confirmed to contain, one or more T cells expressing a recombinant antigen receptor, wherein at the time of the administration of the compound: (i) one or more of the recombinant receptor-expressing T cells in the subject has an exhausted phenotype; (ii) one or more of the recombinant receptor-expressing T cells in the subject have been determined to have an exhausted phenotype; (iii) an exhausted 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 from the subject; (iv) at least at or about 10%, at least at or about 20%, at least at or about 30%, at least at or about 40%, or at least at or about 50% of the total recombinant receptor-expressing T cells in a biological sample from the subject has an exhausted phenotype; and / or (v) greater than at or about 10%, greater than at or about 20%, greater than at or about 30%, greater than at or about 40%, or greater than at or about 50% of the recombinant receptor-expressing T cells in a biological sample from the subject has an exhausted phenotype compared to the percentage of the recombinant receptor-expressing cells having the exhausted phenotype in a comparable biological sample at a prior time point.

[0015] Provided herein are methods of treatment that involve (a) selecting a subject as a candidate for administration of an immunomodulator compound, said selected subject having exhausted recombinant receptor-expressing T cells; and (b) administering to the subject the immunomodulatory compound, 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).

[0016] In some embodiments of any of the methods provided herein, a tissue, tumor, biological fluid or biological sample of or from said selected subject: (i) includes one or more T cells that express a recombinant antigen receptor that binds to a target antigen and that have an exhausted phenotype; (ii) includes a plurality of T cells that express a recombinant antigen receptor that binds to a target antigen, wherein at least at or about 10%, at least at or about 20%, at least at or about 30%, at least at or about 40%, at least at or about 50%, at least at or about 60 %, at least at or about 70 % or at least at or about 80 %, of the T cells in said tissue, fluid, tumor or sample expressing the recombinant receptor have an exhausted phenotype; and / or (iii) includes a plurality of T cells that express a recombinant antigen receptor that binds to a target antigen, wherein greater than at or about 10% more, greater than at or about 20% more, greater than at or about 30% more, greater than at or about 40% more, or greater than at or about 50% more, or greater than 2-fold more, or greater than 3 -fold more, or greater than 5-fold more, or greater than lO-fold more, of the T cells in the tissue, tumor, fluid or sample of or from the selected subject that express the recombinant antigen receptor have an exhausted phenotype, as compared to the percentage or number of T cells expressing the recombinant receptor in the, or in a comparable, fluid, tissue, tumor or sample from said subject at earlier time point had said exhausted phenotype. In some embodiments of any of the methods provided herein, prior to said administration of the compound, said subject has been administered a plurality of T cells expressing the recombinant receptor, and the earlier time point is a time just prior to the administration of the plurality of T cells that express a recombinant antigen receptor to the subject.

[0017] In some embodiments of any of the methods provided herein, said selection of said subject includes determining that, or is based on determination that, a tissue, tumor, biological fluid or biological sample of or from said selected subject: (i) one or more T cells that express a recombinant antigen receptor that binds to a target antigen and that have an exhausted phenotype; (ii) includes a plurality of T cells that express a recombinant antigen receptor that binds to a target antigen, wherein at least at or about 10%, at least at or about 20%, at least at or about 30%, at least at or about 40%, at least at or about 50%, at least at or about 60 %, at least at or about 70 % or at least at or about 80 %, of the T cells in said tissue, fluid, tumor or sample expressing the recombinant receptor have an exhausted phenotype; and / or (iii) includes a plurality of T cells that express a recombinant antigen receptor that binds to a target antigen,wherein greater than at or about 10% more, greater than at or about 20% more, greater than at or about 30% more, greater than at or about 40% more, or greater than at or about 50% more, or greater than 2-fold more, or greater than 3 -fold more, or greater than 5-fold more, or greater than lO-fold more, of the T cells in the tissue, tumor, fluid or sample of or from the selected subject that express the recombinant antigen receptor have an exhausted phenotype, as compared to the percentage or number of T cells expressing the recombinant receptor in the, or in a comparable, fluid, tissue, tumor or sample from said subject at earlier time point had said exhausted phenotype.

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

[0019] In some embodiments of any of the methods provided herein, the prior time point is a time: subsequent to the administration of T cells expressing said recombinant receptor to said selected subject and is at or before a peak or maximum level of T cells expressing recombinant receptor are detectable in the blood of the subject; 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 prior to said determination or selection.

[0020] In some embodiments of any of the methods provided herein, at the time of the administration of the T cell therapy the subject had a disease or condition; at the time of the administration of the T cell therapy and at the time of the administration of the compound the subject has a disease or condition; at the time of the administration of the T cell therapy the subject had a disease or condition and at the time of the administration of the compound the disease or condition has relapsed or progressed or been deemed non-responsive to said compound in the subject following the administration of the T cell therapy.

[0021] In some embodiments of any of the methods provided herein, the exhaustion phenotype, with reference to a T cell or population of T cells, includes an increase in the level or degree of surface expression on the T cell or T cells, or in the percentage of T said population of T cells exhibiting surface expression, of one or more exhaustion marker, optionally 2, 3, 4, 5 or 6 exhaustion markers, compared to a reference T cell population under the same conditions. In other embodiments, the exhaustion phenotype, with reference to a T cell or population of T cells, includes a decrease in the level or degree of an activity exhibited by said T cells orpopulation 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, the increase in the level, degree or percentage is by greater than at or about 1.2-fold, at or about 1.5-fold, at or about 2.0-fold, at or about 3-fold, at or about 4-fold, at or about 5-fold, at or about 6-fold, at or about 7-fold, at or about 8-fold, at or about 9-fold, at or about lO-fold or more. In some embodiments, the decrease in the level, degree or percentage is by greater than at or about 1.2- fold, at or about 1.5-fold, at or about 2.0-fold, at or about 3-fold, at or about 4-fold, at or about 5-fold, at or about 6-fold, at or about 7-fold, at or about 8-fold, at or about 9-fold, at or about 10- fold or more.

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

[0024] In some embodiments of any of the methods provided herein, one or more of the one or more exhaustion marker is an inhibitory receptor. In some embodiments, one or more of the one or more exhaustion marker is selected from among PD-l, CTLA-4, TIM-3, LAG-3, BTLA, 2B4, CD160, CD39, VISTA, and TIGIT. In some embodiments, the activity or 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 IL-2, IFN-gamma and TNF-alpha. In some embodiments, the exposure to said antigen or antigen receptor- specific agent includes incubation with the antigen or antigen receptor- specific agent, optionally an agent that binds the recombinant receptor, wherein said antigen is optionally the target antigen.

[0025] In some embodiments of any of the methods provided herein, the antigen or antigen receptor- specific agent includes antigen-expressing target cells, optionally cells of said disease, disorder or condition. In some embodiments, the target antigen is associated with, specific to, and / or expressed on a cell or tissue of a disease, disorder or condition. In certain embodiments, the target antigen is a tumor antigen. In some embodiments, the target antigen is selected from among anbό integrin (avb6 integrin), B cell maturation antigen (BCMA), BAFF-R, B7-H3, B7-H6, carbonic anhydrase 9 (CA9, also known as CAIX or G250), a cancer-testis antigen, cancer / testis antigen 1B (CTAG, also known as NY-ESO-l and LAGE-2), carcinoembryonic antigen (CEA), a cyclin, cyclin A2, C-C Motif Chemokine Ligand 1 (CCL-l), CD19, CD20,CD22, CD23, CD24, CD30, CD33, CD38, CD44, CD44v6, CD44v7 / 8, CD123, CD133, CD138,CD 171, CS-l, chondroitin sulfate proteoglycan 4 (CSPG4), epidermal growth factor protein(EGFR), truncated epidermal growth factor protein (tEGFR), type III epidermal growth factor receptor mutation (EGFR vIII), epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40(EPG-40), ephrinB2, ephrine receptor A2 (EPHa2), estrogen receptor, Fc receptor like 5(FCRL5; also known as Fc receptor homolog 5 or FCRH5), fetal acetylcholine receptor (fetalAchR), a folate binding protein (FBP), folate receptor alpha, ganglioside GD2, O-acetylatedGD2 (OGD2), ganglioside GD3, glycoprotein 100 (gplOO), glypican-3 (GPC3), G ProteinCoupled Receptor 5D (GPCR5D), Her2 / neu (receptor tyrosine kinase erb-B2), Her3 (erb-B3),Her4 (erb-B4), erbB dimers, Human high molecular weight-melanoma-associated antigen(HMW-MAA), hepatitis B surface antigen, Human leukocyte antigen Al (HLA-A1), Human leukocyte antigen A2 (HLA-A2), IL-22 receptor alpha(IL-22Ra), IL-13 receptor alpha 2 (IL- l3Ra2), kinase insert domain receptor (kdr), kappa light chain, Ll cell adhesion molecule (Ll-CAM), CE7 epitope of Ll-CAM, Leucine Rich Repeat Containing 8 Family Member A(LRRC8A), Lewis Y, Melanoma-associated antigen (MAGE)-Al, MAGE-A3, MAGE-A6,MAGE-A10, mesothelin (MSLN), c-Met, murine cytomegalovirus (CMV), mucin 1 (MUC1),MUC16, natural killer group 2 member D (NKG2D) ligands, melan A (MART-l), neural cell adhesion molecule (NCAM), oncofetal antigen, Preferentially expressed antigen of melanoma(PRAME), progesterone receptor, a prostate specific antigen, prostate stem cell antigen(PSCA), prostate specific membrane antigen (PSMA), Receptor Tyrosine Kinase Like OrphanReceptor 1 (ROR1), survivin, TACI, Trophoblast glycoprotein (TPBG also known as 5T4), tumor-associated glycoprotein 72 (TAG72), Tyrosinase related protein 1 (TRP1, also known asTYRP1 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-l), a pathogen- specific or pathogen-expressed antigen, or an antigen associated with a universal tag, and / or biotinylated molecules, and / or molecules 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, Igkappa, Iglambda, 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 a 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-l, syndecan, SYN-l), CS-l (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] Provided herein are methods of treatment involving (a) administering a T cell therapy to a subject having a cancer, said T cell therapy including a dose of T cells expressing a recombinant antigen receptor that binds to a target antigen; and (b) administering to the subject an immune modulatory 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), whereby, following said administration of said therapy and said compound, a factor indicative of expansion or activity of T cells expressing the recombinant receptor and a factor indicative of durability of response are increased as compared to a reference method, wherein: the reference method involving the administering in (a), alone, or the administration in (a) without the administration of the immune modulatory compound; the factor indicative of expansion or activity involving (i) a measure of the maximum number of T cells observed in the blood or cancer of the subject following said administration, (ii) the number of days elapsed between said administration and reaching of said maximum number of 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.

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

[0030] Provided herein are methods of treatment involving (a) administering a T cell therapy to a subject having a cancer, said T cell therapy including a dose of T cells expressing a recombinant antigen receptor that binds to a target antigen; and (b) administering to the subject an immune modulatory 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), at an amount, duration and / or frequency effective to: (1) effect an increase in antigen- specific or antigen receptor-driven activity of naive or non-exhausted T cells in the subject, which optionally include T cells expressing said recombinant receptor, following exposure of the T cells to antigen or to an antigen receptor- specific agent as compared to the absence of said administration of said compound; or (2) prevent, inhibit or delay the onset of an exhaustion phenotype, in naive or non-exhausted T cells T cells in the subject, which optionally include T cells expressing said recombinant receptor, following exposure of the T cells to antigen or to an antigen receptor- specific agent, as compared to the absence of said administration of said compound; or (3) reverse an exhaustion phenotype in exhausted T cells, optionally including T cells expressing said recombinant receptor, in the subject, as compared to the absence of said administration of said subject.

[0031] In some embodiments of any of the methods provided herein, the amount, duration and / or frequency is effective (i) to effect said increase in antigen-specific or antigen receptor- driven activity and (ii) to prevent, inhibit or delay said onset of exhaustion phenotype and / or to reverse said exhaustion phenotype. In some embodiments, the amount, duration and / or frequency is effective (i) to effect said increase in antigen-specific or antigen receptor-driven activity and (ii) to prevent, inhibit or delay said onset of exhaustion phenotype. In other embodiments, the amount, duration and / or frequency is effective (i) to effect said increase in antigen-specific or antigen receptor-driven activity and (ii) to prevent, inhibit or delay said onset of exhaustion phenotype and to reverse said exhaustion phenotype.

[0032] Provided herein are methods of treatment involving (a) administering a T cell therapy to a subject having a cancer, said T cell therapy including a dose of T cells expressing a recombinant antigen receptor that binds to a target antigen; and (b) administering to the subjectan immune modulatory 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), at an amount, duration and / or frequency effective to: (1) effect an increase in antigen- specific or antigen receptor-driven activity of naive or non-exhausted T cells in the subject, which optionally include T cells expressing said recombinant receptor, following exposure of the T cells to antigen or to an antigen receptor- specific agent as compared to the absence of said administration of said compound; or (2) prevent, inhibit or delay the onset of an exhaustion phenotype, in naive or non-exhausted T cells T cells in the subject, which optionally include T cells expressing said recombinant receptor, following exposure of the T cells to antigen or to an antigen receptor- specific agent, as compared to the absence of said administration of said compound; or (3) reverse an exhaustion phenotype in exhausted T cells, optionally including T cells expressing said recombinant receptor, in the subject, as compared to the absence of said administration of said subject.

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

[0034] In some embodiments of any of the methods provided herein, the immunomodulatory compound is administered in an effective amount of from or from about 1 mg to 50 mg per day it is administered, from or from about 1 mg to 25 mg per day it is administered, from or from about 1 mg to 10 mg per day it is administered, from or from about 1 mg to 5 mg per day it is administered, from or from about 5 mg to 50 mg per day it is administered, from or from about 5 mg to 25 mg per day it is administered, from or from about 5 mg to 10 mg per day it is administered. In some embodiments, the administration of the compound is carried out in a cycling regimen involving administration of an effective amount of the compound (i) daily for a period of more than one week, (ii) per day for no more than 6 days per week for a period ofmore than one week, (ii) per day for no more than 5 days per week for a period of more than one week; or per day for no more than 4 days per week for a period of more than one week. In certain embodiments, the administration of the compound is carried out in a cycling regimen involving administration of an effective amount of the compound per day for no more than 5 days per week for a period of more than one 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 is a compound of the following structure:whereinone of X and Y is -C(O)- and the other of X and Y is -C(O)- or -CH2-;(1) each of R1, R2, R3, and R4are independently halo, alkyl of 1 to 4 carbon atoms, or alkoxy or 1 to 4 carbon atoms, or(2) one of R1, R3, R4, and R5is -NHRaand the remaining of R1, R2, R3, and R4is are hydrogen, wherein Rais hydrogen or alkyl of 1 to 8 carbon atoms;R5is hydrogen or alkyl of 1 to 8 carbon atoms, benzyl, or halo;provided that R5is other than hydrogen if X and Y are -C(O)- and (i) each of R1, R2, R3, and R4is fluoro; or (ii) one of R1, R2, R3, and R4is amino;or a pharmaceutically acceptable salt thereof.

[0037] In some embodiments of any of the methods provided herein, the compound is a compound of the following structure:wherein one of X and Y is -C(O)- and the other of X and Y is -C(O)- or -CH2-, and R5is hydrogen or lower alkyl, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound that is or includes 3-(4-amino-l-oxo-l,3-dihydro-2H-isoindol-2-yl)piperidine-enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. In some embodiments, the compound is 3-(4-amino-l-oxo-l,3- dihydro-2H-isoindol-2-yl)piperidine-2,6-dione.

[0038] In some embodiments, the compound is a compound that is or includes 3-(5-amino- 2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione having the following structure:, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, 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 from or from about 1 mg to 50 mg per day, from or from about 1 mg to 25 mg per day, from or from about 1 mg to 10 mg per day, from or from about 1 mg to 5 mg per day, from or from about 5 mg to 50 mg per day, from or from about 5 mg to 25 mg per day, from or from about 5 mg to 10 mg per day, optionally wherein the administration is daily for a duration in a cycling regimen.

[0040] In some embodiments of any of the methods provided herein, the compound is a compound of the following structure:or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein:Z is C=0 or CH2;R11is -Z^R13;R12is H or (Ci-C6)alkyl;Z1is 6 to 10 membered aryl, heteroaryl, or heterocycle, each of which may be optionally substituted with one or more halogen; or a bond;R13is -(CFh)n-aryl, -0-(CH2)n-aryl, or -(CFh)n-O-aryl, wherein the aryl is optionally substituted with one or more: (Ci-C6)alkyl; itself optionally substituted with one or more halogen; (Ci-C6)alkoxy, itself substituted with one or more halogen; oxo; amino; carboxyl; cyano; hydroxyl; halogen; deuterium; 6 to 10 membered aryl or heteroaryl, optionally substituted with one or more (Ci-C6)alkyl, (Ci-C6)alkoxy, or halogen; -CONFh; or -COO-(Ci- C6)alkyl, wherein the alkyl may be optionally substituted with one or more halogen; -(CFh)n- heterocycle, -0-(CH2)n-heterocycle or -(CH2)n-0-heterocycle, wherein the heterocycle is optionally substituted with one or more: (Ci-C6)alkyl, itself optionally substituted with one or more halogen; (Ci-C6)alkoxy, itself substituted with one or more halogen; oxo; amino; carboxyl; cyano; hydroxyl; halogen; deuterium; 6 to 10 membered aryl or heteroaryl, optionally substituted with one or more (Ci-C6)alkyl, (Ci-C6)alkoxy or halogen; -CONFh; or -COO-(Ci- C6)alkyl, wherein the alkyl may be optionally substituted with one or more halogen; or -(CFh)n- heteroaryl, -0-(CH2)n-heteroaryl or -(CH2)n-0-heteroaryl, wherein the heteroaryl is optionally substituted with one or more: (Ci-C6)alkyl, itself optionally substituted with one or more halogen; (Ci-C6)alkoxy, itself substituted with one or more halogen; oxo; amino; carboxyl; cyano; hydroxyl; halogen; deuterium; 6 to 10 membered aryl or heteroaryl, optionally substituted with one or more (Ci-C6)alkyl, (Ci-C6)alkoxy or halogen; -CONFh; or -COO-(Ci- C6)alkyl, wherein the alkyl may be optionally substituted with one or more halogen; and n is 0, 1, 2 or 3.

[0041] In some embodiments, the compoundpharmaceutically acceptable salt, solvate, or stereoisomer thereof. In certain embodiments, the compound is the Form A crystal form of the hydrochloride salt ofsome embodiments, the XRPD pattern of the Form Acrystal form of the hydrochloride saltcharacterized byXRPD peaks located at 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 or approximately 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 2Q.

[0042] In some embodiments of any of the methods provided herein, the immunomodulatory compound is administered from or from about 0.1 mg to 1 mg per day, from or from about 0.1 mg to 0.6 mg per day, from or from about 0.1 mg to 0.3 mg, optionally wherein theadministration is daily for a period of time in a cycling regimen.

[0043] Provided herein are methods of treatment involving (a) administering a T cell therapy to a subject having a cancer, said T cell therapy including a dose of T cells expressing a recombinant antigen receptor that binds to a target antigen; and (b) administering to the subject a compound that is or includes 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione having the following structure:, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co crystal, clathrate, or polymorph thereof (Compound 1), wherein the administration of the compound is carried out in a cycling regimen involving administration of an effective amount of the compound per day for no more than 5 days per week for a period of more than one week.

[0044] In some embodiments of any of the methods provided herein, the administration of the compound is initiated subsequently to initiation of administration of the T cell therapy. In some embodiments, the administration of the compound is initiated concurrently with the T cell therapy and / or is initiated within one day of, prior to or subsequently to, initiating the administration of the T cell therapy.

[0045] In some embodiments, the administration of the compound is initiated at or about or within at or about one day prior to or subsequently to initiating the administration of the T cell therapy.

[0046] Provided herein are methods of treatment involving administering to a subject having a cancer a compound that is or includes 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3- yl)-piperidine-2,6-dione having the following structure:enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof (Compound 1), said subject having been administered, prior to the administration of the compound, a T cell therapy including a dose of genetically engineered T cells expressing a recombinant antigen receptor, wherein the administration of the compound is carried out in a cycling regimen involving administration of an effective amount of the compound per day for no more than 5 days per week for a period of more than one week. In some embodiments, the cancer is a B cell malignancy, B cell-derived malignancy, non- hematological cancer or a solid tumor.

[0048] In some embodiments of any of the methods provided herein, the target antigen is a tumor antigen, optionally wherein the target antigen is associated with, specific to, and / or expressed on a cell or tissue of the cancer. In some embodiments, the target antigen is selected from B cell maturation antigen (BCMA), anb6 integrin (avb6 integrin), BAFF-R, B7-H3, B7- H6, carbonic anhydrase 9 (CA9, also known as CAIX or G250), a cancer-testis antigen, cancer / testis antigen 1B (CTAG, also known as NY-ESO-l and LAGE-2), carcinoembryonic antigen (CEA), a cyclin, cyclin A2, C-C Motif Chemokine Ligand 1 (CCL-l), CD5, CD19, CD20, CD21, CD22, CD23, CD24, CD30, CD38, CD44, CD44v6, CD44v7 / 8, CD45, CD79a, CD79b, CD123, CD133, CD138, CD171, CS-l, chondroitin sulfate proteoglycan 4 (CSPG4), epidermal growth factor protein (EGFR), truncated epidermal growth factor protein (tEGFR), type III epidermal growth factor receptor mutation (EGFR vIII), epithelial glycoprotein 2 (EPG- 2), epithelial glycoprotein 40 (EPG-40), ephrinB2, ephrine receptor A2 (EPHa2), estrogen receptor, Fc receptor like 5 (FCRL5; also known as Fc receptor homolog 5 or FCRH5), fetalacetylcholine receptor (fetal AchR), a folate binding protein (FBP), folate receptor alpha, ganglioside GD2, O-acetylated GD2 (OGD2), ganglioside GD3, glycoprotein 100 (gplOO), glypican-3 (GPC3), G Protein Coupled Receptor 5D (GPCR5D), Her2 / neu (receptor tyrosine kinase erb-B2), Her3 (erb-B3), Her4 (erb-B4), erbB dimers, Human high molecular weight- melanoma-associated antigen (HMW-MAA), hepatitis B surface antigen, Human leukocyte antigen Al (HLA-A1), Human leukocyte antigen A2 (HLA-A2), Igkappa, Iglambda, IL-22 receptor alpha(IL-22Ra), IL-13 receptor alpha 2 (IL-l3Ra2), kinase insert domain receptor (kdr), Ll cell adhesion molecule (Ll-CAM), CE7 epitope of Ll-CAM, Leucine Rich Repeat Containing 8 Family Member A (LRRC8A), Lewis Y, Melanoma-associated antigen (MAGE)- Al, MAGE-A3, MAGE-A6, MAGE-A10, mesothelin (MSLN), c-Met, murine cytomegalovirus (CMV), mucin 1 (MUC1), MUC16, natural killer group 2 member D (NKG2D) ligands, melan A (MART-l), neural cell adhesion molecule (NCAM), oncofetal antigen, Preferentially expressed antigen of melanoma (PRAME), progesterone receptor, a 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-l), a pathogen- specific or 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 includes aggressive NHL, diffuse large B cell lymphoma (DLBCL), DLBCL-NOS, optionally transformed indolent; 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).

[0049] In some embodiments of any of the methods provided herein, the subject is or has been identified as having an Eastern Cooperative Oncology Group Performance Status (ECOG) status of less than or equal to 1.

[0050] In some embodiments of any of the methods provided herein, the target antigen isCD20, CD19, CD22, ROR1, CD45, CD21, CD5, CD33, Igkappa, Iglambda, CD79a, CD79b orCD30. In certain embodiments, the target antigen is CD19. In some embodiments, the target antigen is not CD20, CD19, CD22, ROR1, CD45, CD21, CD5, CD33, Igkappa, Iglambda,CD79a, CD79b or CD30. In some embodiments, the cancer is a 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-l, syndecan, SYN-l), CS-l (CS1, CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24), BAFF-R, TACI or FcRH5.

[0051] In some embodiments of any of the methods provided herein, the method further includes continuing the cycling regimen after the end of the period, if, at the end of the period, the subject exhibits a partial response (PR) or stable disease (SD). In some embodiments, the cycling regimen is continued for greater than six months if, at or about six months, the subject exhibits a partial response (PR) or stable disease (SD) after the treatment. In other embodiments, the cycling regimen is continued until the subject has achieved a complete response (CR) following the treatment or until the cancer has progressed or relapsed following remission after the treatment.

[0052] In some embodiments of any of the methods provided herein, the administration of the compound is initiated at or after peak or maximum level of the cells of the T cell therapy are detectable in the blood of the subject. In some embodiments, the administration of the compound is initiated about 14 to about 35 days after initiation of administration of the T cell therapy. In certain embodiments, the administration of the compound is initiated about 21 to about 35 days after initiation of administration of the T cell therapy. In other embodiments, the administration of the compound is initiated about 21 to about 28 days after initiation of administration of the T cell therapy. In some embodiments, the administration of the compound is initiated at or about 21 days, at or about 22 days, at or about 23 days, at or about 24 days, at or about 25 days, at or about 26 days, at or about 27 days, or at or about 28 days after initiation of administration of the T cell therapy. In certain embodiments, the administration of the compound is initiated at or about 28 days after the initiation of the administration of the T cell therapy. In some embodiments of any of the methods provided herein, at the time of the initiation of the administration of the compound, the subject does not exhibit a severe toxicity following the administration of the T cell therapy.

[0053] In some embodiments of any of the methods provided herein, the severe toxicity is severe cytokine release syndrome (CRS), optionally grade 3 or higher, prolonged grade 3 or higher or grade 4 or 5 CRS; and / or the severe toxicity is severe neurotoxicity, optionally grade 3 or higher, prolonged grade 3 or higher or grade 4 or 5 neurotoxicity.

[0054] In some embodiments of any of the methods provided herein, the administration of the compound is suspended and / or the cycling regimen is modified if the subject exhibits atoxicity following the administration of the compound, optionally a hematologic toxicity. In some embodiments, the toxicity is selected from severe neutropenia, optionally febrile neutropenia, prolonged grade 3 or higher neutropenia. In some embodiments, the administration of the compound is restarted after the subject no longer exhibits the toxicity. In some embodiments, the cycling regimen is modified after the administration of the compound is restarted. In some embodiments, the modified cycling regimen involves administering a reduced amount of the compound and / or decreasing frequency of the administration of the compound. In certain embodiments, the modified cycling regimen involves administering a reduced amount of the compound. In some embodiments, the dose of the compound is reduced and the reduced amount is between at or about 1 mg and at or about 2 mg per day for no more than 5 days per week. In some embodiments, the reduced amount is at or about 1 mg or at or about 2 mg per day for no more than 5 days per week. In some embodiments, the cycling regimen is not modified after the administration of the compound is restarted. In some embodiments, the cycling regimen involves administration of no more than about 2 mg of the compound per day for no more than 5 days per week. In certain embodiments, the cycling regimen involves administration of at or about 1 mg of the compound per day for no more than 5 days a week.

[0055] In some embodiments of any of the methods provided herein, the compound is or comprises a solvate of (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-l-oxo-l, 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.

[0056] In some embodiments of any of the methods provided herein, the compound is or includes a solvate of 3-(5-amino-2- methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2, 6-dione. In some embodiments, the compound is or includes a hydrate of 3-(5-amino-2- methyl-4-oxo-4H- quinazolin-3-yl)-piperidine-2, 6-dione. In some embodiments, the compound is or includes a pharmaceutically acceptable salt of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine- 2, 6-dione. In certain embodiments, the compound is or includes 3-(5-amino-2-methyl-4- oxo- 4H-quinazolin-3-yl)-piperidine-2, 6-dione.

[0057] In some embodiments of any of the methods provided herein, the compound is administered orally. In some embodiments, the period extends for at or about 6 months after initiation of administration of the T cell therapy if the subject has at 6 months achieved a complete response (CR). In other embodiments, the cycling regimen is continued for the duration of the period even if the subject has achieved a complete response (CR) at a time pointprior to the end of the period. In some embodiments, the subject achieves a complete response (CR) during the period and prior to the end of the period.

[0058] In some embodiments of any of the methods provided herein, the method further involves continuing the cycling regimen after the end of the period, if, at the end of the period, the subject exhibits a partial response (PR) or stable disease (SD). In some embodiments any of the methods provided herein, the cycling regimen is continued for greater than six months if, at or about six months, the subject exhibits a partial response (PR) or stable disease (SD) after the treatment. In some embodiments, the cycling regimen is continued until the subject has achieved a complete response (CR) following the treatment or until the cancer has progressed or relapsed following remission after the treatment.

[0059] In some embodiments of any of the methods provided herein, the administration of the compound is initiated at or after peak or maximum level of the cells of the T cell therapy are detectable in the blood of the subject. In some embodiments of any of the methods provided herein, the administration of the compound is initiated about 14 to about 35 days after initiation of administration of the T cell therapy. In some embodiments of any of the methods provided herein, the administration of the compound is initiated about 21 to about 35 days after initiation of administration of the T cell therapy. In some embodiments of any of the methods provided herein, the administration of the compound is initiated about 21 to about 28 days after initiation of administration of the T cell therapy. In some embodiments of any of the methods provided herein, the administration of the compound is initiated at or about 21 days, at or about 22 days, at or about 23 days, at or about 24 days, at or about 25 days, at or about 26 days, at or about 27 days, or at or about 28 days after initiation of administration of the T cell therapy.

[0060] In some embodiments of any of the methods provided herein, the administration of the compound is initiated at or about 28 days after the initiation of the administration of the T cell therapy. In some embodiments of any of the methods provided herein, at the time of the initiation of the administration of the compound, the subject does not exhibit a severe toxicity following the administration of the T cell therapy. In some embodiments, the severe toxicity is severe cytokine release syndrome (CRS), optionally grade 3 or higher, prolonged grade 3 or higher or grade 4 or 5 CRS; and / or the severe toxicity is severe neurotoxicity, optionally grade 3 or higher, prolonged grade 3 or higher or grade 4 or 5 neurotoxicity.

[0061] In some embodiments of any of the methods provided herein, the administration of the compound is suspended and / or the cycling regimen is modified if the subject exhibits a toxicity following the administration of the compound, optionally a hematologic toxicity. Insome embodiments, the toxicity is selected from severe neutropenia, optionally febrile neutropenia, prolonged grade 3 or higher neutropenia. In some embodiments, the administration of the compound is restarted after the subject no longer exhibits the toxicity. In some embodiments, the cycling regimen is modified after the administration of the compound is restarted. In some embodiments, the modified cycling regimen involves administering a reduced amount of the compound and / or decreasing frequency of the administration of the compound. In certain embodiments, the modified cycling regimen involves administering a reduced amount of the compound. In some embodiments, the dose of the compound is reduced and the reduced amount is between at or about 1 mg and at or about 2 mg per day for no more than 5 days per week. In certain embodiments, the reduced amount is at or about 1 mg or at or about 2 mg per day for no more than 5 days per week. In some embodiments, the cycling regimen is not modified after the administration of the compound is restarted. In some embodiments, the cycling regimen involves administration of no more than about 2 mg of the compound per day for no more than 5 days per week. In some embodiments, the cycling regimen involves administration of at or about 1 mg of the compound per day for no more than 5 days a week.

[0062] In some embodiments of any of the methods provided herein, the compound is or includes a solvate of 3-(5-amino-2- methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. In some embodiments of any of the methods provided herein, the compound is or includes a hydrate of 3-(5-amino-2- methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. In some embodiments of any of the methods provided herein, the compound is or includes apharmaceutically acceptable salt of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine- 2,6-dione. In some embodiments of any of the methods provided herein, the compound is or includes 3-(5-amino-2-methyl-4- oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. In some embodiments of any of the methods provided herein, the compound is administered orally.

[0063] In some embodiments of any of the methods provided herein, the administration of the compound: reverses an exhaustion phenotype in recombinant receptor-expressing T cells in the subject; prevents, inhibits or delays the onset of an exhaustion phenotype in recombinant receptor-expressing T cells in the subject; or reduces the level or degree of an exhaustion phenotype in recombinant receptor-expressing T cells in the subject; or reduces the percentage, of the total number of recombinant receptor-expressing T cells in the subject, that have an exhaustion phenotype.

[0064] In some embodiments of any of the methods provided herein, the initiation of the administration of the compound is carried out subsequently to the administration of the T cell therapy and, following administration of the compound or initiation thereof, the subject exhibits a restoration or rescue of an antigen- or tumor- specific activity or function of recombinant receptor-expressing T cells in said subject, optionally wherein said restoration, rescue, and / or initiation of administration of said compound, is at a point in time after recombinant receptor expressing T cells in the subject or the in the blood of the subject have exhibited an exhausted phenotype.

[0065] In some embodiments of any of the methods provided herein, the administration of the compound includes administration at an amount, frequency and / or duration effective to: (a) effect an increase in antigen- specific or antigen receptor-driven activity of naive or non- exhausted T cells in the subject, which optionally include T cells expressing said recombinant receptor, following exposure of the T cells to antigen or to an antigen receptor- specific agent as compared to the absence of said administration of said compound; or (b) prevent, inhibit or delay the onset of an exhaustion phenotype, in naive or non-exhausted T cells T cells in the subject, which optionally include T cells expressing said recombinant receptor, following exposure of the T cells to antigen or to an antigen receptor- specific agent, as compared to the absence of said administration of said compound; or (c) reverse an exhaustion phenotype in exhausted T cells, optionally including T cells expressing said recombinant receptor, in the subject, as compared to the absence of said administration of said subject. In someembodiments, the administration of the compound includes administration at an amount, frequency and / or duration effective (i) to effect said increase in activity and (ii) to prevent, inhibit or delay said onset of said exhaustion phenotype and / or reverse said exhaustion phenotype. In some embodiments, the T cells in the subject include T cells expressing said recombinant receptor and / or said antigen is the target antigen.

[0066] In some embodiments of any of the methods provided herein, the exhaustion phenotype, with reference to a T cell or population of T cells, includes: an increase in the level or degree of surface expression on the T cell or T cells, or in the percentage of T said population of T cells exhibiting surface expression, of one or more exhaustion marker, optionally 2, 3, 4, 5 or 6 exhaustion markers, compared to a reference T cell population under the same conditions; or a decrease in the level or degree of an activity exhibited by said T cells 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 embodiments, the increase in the level,degree or percentage is by greater than at or about 1.2-fold, at or about 1.5-fold, at or about 2.0- fold, at or about 3 -fold, at or about 4-fold, at or about 5-fold, at or about 6-fold, at or about 7- fold, at or about 8-fold, at or about 9-fold, at or about lO-fold or more. In other embodiments, the decrease in the level, degree or percentage is by greater than at or about 1.2-fold, at or about 1.5-fold, at or about 2.0-fold, at or about 3-fold, at or about 4-fold, at or about 5-fold, at or about 6-fold, at or about 7-fold, at or about 8-fold, at or about 9-fold, at or about lO-fold or more.

[0067] In some embodiments of any of the methods provided herein, the reference T cell population is a population of T cells known to have a non-exhausted phenotype, is a population of naive T cells, is a population of central memory T cells, or is a population of stem central memory T cells, optionally from the same subject, or of the same species as the subject, from which the T cell or T cells having the exhausted phenotype are derived.

[0068] In some embodiments of any of the methods provided herein, the reference T cell population (a) is a subject-matched population including bulk T cells isolated from the blood of the subject from which the T cell or T cells having the exhausted phenotype is derived, optionally wherein the bulk T cells do not express the recombinant receptor and / or (b) is obtained from the subject from which the T cell or T cells having the exhausted phenotype is derived, prior to receiving administration of a dose of T cells expressing the recombinant receptor. In some embodiments, the reference T cell population is a composition including a sample of the T cell therapy, or pharmaceutical composition including T cells expressing the recombinant receptor, prior to its administration to the subject, optionally wherein the composition is a cryopreserved sample.

[0069] In some embodiments of any of the methods provided herein, the one or more exhaustion marker is an inhibitory receptor. In some embodiments, the one or more exhaustion marker is selected from among PD-l, CTLA-4, TIM-3, LAG-3, BTLA, 2B4, CD160, CD39, VISTA, and TIGIT.

[0070] In some embodiments of any of the methods provided herein, the activity or 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 IL-2, IFN- gamma and TNF-alpha. In some embodiments, the exposure to said antigen or antigen receptor- specific agent includes incubation with the antigen or antigen receptor- specific agent, optionally an agent that binds the recombinant receptor, wherein said antigen is optionally the target antigen. In some embodiments, the antigen or antigen receptor- specific agent includes antigen-expressing target cells, optionally cells of said disease, disorder or condition. In certain embodiments, the target antigen is a human antigen.

[0071] In some embodiments of any of the methods provided herein, the subject is a human. In some embodiments of any of the methods provided herein, the recombinant antigen receptor is a chimeric antigen receptor that specifically binds the target antigen. In some embodiments, the chimeric antigen receptor (CAR) includes an extracellular antigen-recognition domain that specifically binds to a target antigen and an intracellular signaling domain including an IT AM.In some embodiments, the intracellular signaling domain includes a signaling domain of a CD3- zeta ^ϋ3z) chain, optionally a human CD3-zeta chain. In some embodiments, the chimeric antigen receptor (CAR) further includes a costimulatory signaling region. In other embodiments, the costimulatory signaling region includes a signaling domain of CD28 or 4-1BB, optionally human CD28 or human 4-1BB. In some embodiments, the costimulatory domain is or includes a signaling domain of human 4-1BB.

[0072] In some embodiments of any of the methods provided herein, the CAR includes an scFv specific for the target antigen; a transmembrane domain,; a cytoplasmic signaling domain derived from a costimulatory molecule, which optionally is or includes a 4-1BB, optionally human 4-1BB; and a cytoplasmic signaling domain derived from a primary signaling ITAM- containing molecule, which optionally is or includes a CD3zeta signaling domain, optionally a human CD3zeta signaling domain; and optionally wherein the CAR further includes a spacer between the transmembrane domain and the scFv; the CAR includes, in order, an scFv specific for the target antigen; a transmembrane domain; a cytoplasmic signaling domain derived from a costimulatory molecule, which optionally is or includes a 4-1BB signaling domain, optionally a human 4-1BB signaling domain; and a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule, which optionally is a CD3zeta signaling domain, optionally human CD3zeta signaling domain; or the CAR includes, in order, an scFv specific for the target antigen; a spacer; a transmembrane domain, a cytoplasmic signaling domain derived from a costimulatory molecule, which optionally is a 4-1BB signaling domain, and a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule, which optionally is or includes a CD3zeta signaling domain.

[0073] In some embodiments of any of the methods provided herein, the dose of genetically engineered T cells includes from or from about 1 x 105to 5 x 108total CAR-expressing T cells,1 x 106to 2.5 x 108total CAR-expressing T cells, 5 x 106to 1 x 108total CAR-expressing T cells, 1 x 107to 2.5 x 108total CAR-expressing T cells, 5 x 107to 1 x 108total CAR-expressingT cells, each inclusive. In some embodiments of any of the methods provided herein, the dose of genetically engineered T cells includes at least or at least about 1 x 105CAR-expressing cells, at least or at least about 2.5 x 105CAR-expressing cells, at least or at least about 5 x 105CAR- expressing cells, at least or at least about 1 x 106CAR-expressing cells, at least or at least about 2.5 x 106CAR-expressing cells, at least or at least about 5 x 106CAR-expressing cells, at least or at least about 1 x 107CAR-expressing cells, at least or at least about 2.5 x 107CAR- expressing cells, at least or at least about 5 x 107CAR-expressing cells, at least or at least about 1 x 108CAR-expressing cells, at least or at least about 2.5 x 108CAR-expressing cells, or at least or at least about 5 x 108CAR-expressing cells. In certain embodiments, the dose of genetically engineered T cells includes at or about 5 x 107total CAR-expressing T cells. In other embodiments, the dose of genetically engineered T cells includes at or about 1 x 108CAR- expressing cells.

[0074] In some embodiments of any of the methods provided herein, the dose of cells is administered parenterally, optionally intravenously.

[0075] 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.

[0076] In some embodiments of any of the methods provided herein, the dose of genetically engineered T cells includes CD4+ T cells expressing the CAR and CD8+ T cells expressing the CAR and the administration of the dose includes administering a plurality of separate compositions, said plurality of separate compositions including a first composition including one of the CD4+ T cells and the CD8+ T cells and the second composition including the other of the CD4+ T cells or the CD8+ T cells.

[0077] In some embodiments of any of the methods provided herein, prior to theadministration, the subject has been preconditioned with a lymphodepleting therapy including the administration of fludarabine and / or cyclophosphamide. In some embodiments of any of the methods provided herein, the method further involves, immediately prior to the administration, administering a lymphodepleting therapy to the subject including the administration of fludarabine and / or cyclophosphamide. In some embodiments, the lymphodepleting therapy includes administration of cyclophosphamide at about 200-400 mg / m2, optionally at or about300 mg / m2, inclusive, and / or fludarabine at about 20-40 mg / m2, optionally 30 mg / m2, daily for2-4 days, optionally for 3 days, or wherein the lymphodepleting therapy includes administration of cyclophosphamide at about 500 mg / m2. In some embodiments, the lymphodepleting therapyincludes administration of cyclophosphamide at or about 300 mg / m2and fludarabine at about 30 mg / m2daily for 3 days; and / or the lymphodepleting therapy includes administration of cyclophosphamide at or about 500 mg / m2and fludarabine at about 30 mg / m2daily for 3 days.

[0078] In some embodiments of any of the methods provided herein, 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, or is durable in at least 60, 70, 80, 90, or 95 % of subjects achieving the CR, for at or greater than 6 months or at or greater than 9 months; and / or wherein at least 60, 70, 80, 90, or 95 % of subjects achieving a CR by six months remain in response, remain in CR, and / or survive or survive without progression, for greater at or greater than 3 months and / or at or greater than 6 months and / or at greater than nine months; and / or at least 50%, at least 60% or at least 70% of the subjects treated according to the method achieve objective response (OR) optionally wherein the OR is durable, or is durable in at least 60, 70, 80, 90, or 95 % of subjects achieving the OR, for at or greater than 6 months or at or greater than 9 months; and / or wherein at least 60, 70, 80, 90, or 95 % of subjects achieving an OR by six months remain in response or surviving for greater at or greater than 3 months and / or at or greater than 6 months.

[0079] Also provided herein are kits that include (a) a T cell therapy including a dose of T cells expressing a recombinant antigen receptor that binds to a target antigen; and (b) an immune modulatory 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); and (c) instructions for administering the compound and / or the T cell therapy according any of the methods provided herein.Brief Description of the Drawings

[0080] FIG.1A shows the surface BCMA expression of multiple myeloma cells lines (RPMI-8226, MM1.S, and OPM-2). The dotted line indicates background and BCMA-negative cell lines were stained with anti-BCMA antibody. MFI, median fluorescence intensity.

[0081] FIG. IB shows the percent of reduction of BCMA-expressing target cells (RPMI- 8226) by anti-BCMA CAR+ T cells in the presence and absence of lenalidomide (10 mM) after 6 days of co-culture. FIG. 1C shows the effect of lenalidomide on the cytolytic activity of anti- BCMA CAR+ T cells against RPMI-8226 target cells.

[0082] FIGs. 2A-2C show the amount of IL-2 (FIG. 2A), IFNy (FIG. 2B), and TNF-a (FIG. 2C) observed in supernatants after incubation of RPMI-8226 target cells with anti-BCMA CAR T cells in the presence and absence of lenalidomide.

[0083] FIG. 3A shows the effect of increasing concentrations of lenalidomide on the cytolytic activity of anti-BCMA CAR+ T cells against OPM2 target cells.

[0084] FIGs. 3B-D show the amount of IFNy (FIG. 3B), IL-2 (FIG. 3C), and TNF-a (FIG. 3D) observed in supernatants after incubation of OPM2 target cells with anti-BCMA CAR T cells in the presence of increasing concentrations of lenalidomide, or in the absence of lenalidomide.

[0085] FIG. 3E shows the antigen- specific anti-BCMA CAR-T cytolytic activity and cytokine production of anti-BCMA CAR+ T cells derived from representative healthy donors and multiple myeloma patients against OPM-2 target cells in the presence of varyingconcentrations of lenalidomide (0.01 mM, 0.1 pM, 1.0 pM or 10 pM lenalidomide) or in the absence of lenalidomide.

[0086] FIG. 3F shows the antigen- specific anti-BCMA CAR-T cytolytic activity of anti- BCMA CAR+ T cells derived from three healthy donors and one multiple myeloma patient against OPM-2 and RPMI-8226 target cells in the presence of varying concentrations of lenalidomide (0.01 pM, 0.1 pM, 1.0 pM or 10 pM lenalidomide) or in the absence of lenalidomide. FIG. 3G shows cytokine production of anti-BCMA CAR+ T cells derived from three healthy donors and one multiple myeloma patient against OPM-2 target cells in the presence of varying concentrations of lenalidomide (0.01 pM, 0.1 pM, 1.0 pM or 10 pM lenalidomide) or in the absence of lenalidomide.. FIG. 3H shows cytokine production of anti- BCMA CAR+ T cells derived from three healthy donors and one multiple myeloma patient against RPMI-8226 target cells in the presence of varying concentrations of lenalidomide (0.01 pM, 0.1 pM, 1.0 pM or 10 pM lenalidomide) or in the absence of lenalidomide.

[0087] FIG. 4A depicts the expansion of anti-BCMA CAR T cells after restimulation in the presence of varying concentrations of lenalidomide.

[0088] FIG. 4B depicts the expansion of anti-BCMA CAR T cells after restimulation both in the presence and absence of lenalidomide.

[0089] FIG. 5A shows the cell counts (projected population doublings) of the anti-BCMA CAR+ T cells from three donors for each time point in the restimulation assay, in the presence of a vehicle or 0.1 pM lenalidomide. The“x” indicates insufficient cells for re-plating in the assay. FIG. 5B shows CD25 median fluorescent intensity (MFI) (gated on live CD3+CAR+).FIG. 5C shows cytokine production normalized for cell number plated (top and left bottom panels) and CD25 median fluorescent intensity (MFI) (gated on live CD3+CAR+) (right bottom panel).

[0090] FIG. 6A shows the total number of CD3+ cells in culture on days 2 and 7 after incubating anti-BCMA CAR T-Cells or T cells that did not express a CAR (mock) in the presence or absence of lenalidomide. FIGs. 6B and 6C show the CD25+ expression in CD4+ (FIG. 6B) and CD8+ (FIG. 6C) T cells in culture on days 2 and 7 after incubating anti-BCMA CAR T-Cells or T cells that did not express a CAR (mock) in the presence or absence of lenalidomide.

[0091] FIG. 7A shows the tumor volume of mice over time after administration of a low dose of anti-BCMA CAR+ T cells in the presence and absence of lenalidomide.

[0092] FIG. 7B shows the percent survival of mice that were administered a low dose of anti-BCMA CAR+ T cells in the presence and absence of lenalidomide. For the control groups,T cells that did not express a CAR (mock) were administered in the presence and absence of lenalidomide, and lenalidomide without T cells was also administered.

[0093] FIG. 8A shows the levels of CD4+ CAR+ T cells in the blood from mice treated with anti-BCMA CAR+ T cells and lenalidomide compared to the other treatment groups at days 7, and 14. FIG. 8B shows the levels of CD4+ CAR+ T cells in the blood from mice treated with anti-BCMA CAR+ T cells and lenalidomide compared to the other treatment groups at days 21 and 36. FIG. 8C shows the levels of CD8+ CAR+ T cells in the blood from mice treated with anti-BCMA CAR+ T cells and lenalidomide compared to the other treatment groups at days 7 and 14. FIG. 8D shows the levels of CD8+ CAR+ T cells in the blood from mice treated with anti-BCMA CAR+ T cells and lenalidomide compared to the other treatment groups at days 21 and 36.

[0094] FIG. 8E shows the levels of CD4+ CAR+ T cells in the blood from mice treated with non-CAR+ T cells and lenalidomide compared to the other treatment groups at days 7, and 14. FIG. 8F shows the levels of CD4+ CAR+ T cells in the blood from mice treated with non- CAR+ T cells and lenalidomide compared to the other treatment groups at days 21 and 36. FIG. 8G shows the levels of CD8+ CAR+ T cells in the blood from mice treated with non-CAR+ T cells and lenalidomide compared to the other treatment groups at days 7 and 14. FIG. 8H shows the levels of CD8+ CAR+ T cells in the blood from mice treated with non-CAR+ T cells and lenalidomide compared to the other treatment groups at days 21 and 36.

[0095] FIGs. 9A and 9B depict tumor burden results of mice treated under Regimen A (LenA), in which mice were administered lenalidomide one day prior to receiving CAR+ T cells.

[0096] FIG. 9C shows the tumor burden of individual mice through up to day 53.

[0097] FIG. 9D shows tumor imaging results at day 46 post CAR+ cell administration for individual mice having received the higher CAR+ dose (l x 106), with lenalidomide at day -1 (Len A). FIG. 9E shows tumor imaging results at day 46 post CAR+ cell administration for individual mice having received the higher CAR+ dose (l x 106) without lenalidomide at day -1 (Len A).

[0098] FIGs. 9F and 9G depict tumor burden results of mice treated under Regimen B (LenB), in which administration of lenalidomide was initiated at day 14 post CAR+Tadministration.

[0099] FIG. 9H shows the tumor burden of individual mice through up to day 53.

[0100] FIG. 91 shows tumor imaging results (day 46 post-CAR+ cell administration) for individual mice having received the higher CAR+ dose (l x 106), with lenalidomide at day -1 (Len A). FIG. 9J shows tumor imaging results (day 46 post-CAR+ cell administration) for individual mice having received the higher CAR+ dose (l x 106), without lenalidomide at day - 1 (Len A).

[0101] FIGs. 10A-10D show the survival of mice in the presence or absence oflenalidomide. Lenalidomide was administered via Regimen A (Len A; administration of lenalidomide initiated at day -1) or Regimen B (Len B; administration of lenalidomide initiated at day 14) in combination with low (5 x 105or 5e5) or high (l x 106or le6) doses of CAR+ T cells. For the control groups, T cells that did not express a CAR (mock) were administered in the presence and absence of lenalidomide via both Regimen A and Regimen B, and lenalidomide without T cells was also administered via both Regimen A and Regimen B.

[0102] FIG. 10E shows the results of tumor burden assessment for mice having received the higher CAR+ dose (l x 106) and given a daily intraperitoneal administration of 10 mg / kg lenalidomide or vehicle control initiated at either day - 1 (one day prior to C AR-Tadministration) (concurrent lenalidomide (lenalidomide (C) or vehicle (vehicle (C)) or at day 14 post-CAR-T (or mock) cell administration (delayed lenalidomide (D)). Results are shown through day 60, as analyzed by the bioluminescence measured by flow cytometry. FIG. 10F shows the percent survival of mice in the presence or absence of lenalidomide. FIGs. 10G and10H show the flow cytometric analysis of mock control cells and CAR-T cells in the blood of the mice at days 8, 14, 22, and 28 following injection of the CAR-T cells from two donors.

[0103] FIG. 11 shows the number of CD4+ and CD8+ T cells in cultures of anti-CDl9 CAR T cells stimulated with a suboptimal concentration of anti-CD3 in the presence and absence of lenalidomide.

[0104] FIG. 12A shows the number of CD3+ / CAR+T cells in peripheral blood measured at certain time points post-infusion for subjects grouped by best overall response.

[0105] FIG. 12B shows CD3+ / CAR+T cells in peripheral blood measured at certain time points post-infusion for subjects who achieved a response, grouped by continued response at 3 months.

[0106] FIGs. 12C-2D show CD4+ / CAR+T and CD8+ / CAR+T cell levels in peripheral blood measured at certain time points post-infusion for subjects who achieved a response, grouped by continued response at 3 months.

[0107] FIG. 13A shows the number of CD3+ / CAR+, CD4+ / CAR+ , CD8+ / CAR+ T cells in peripheral blood of a subject with chemorefractory transformed DLBCL measured at certain time points. FIG. 13B depicts a pretreatment axial PET-CT image showing an intracranial abnormality in the right middle cranial foss and extensive abnormality in subcutaneous tissues in the right posterior auricular region. FIG. 13C is a post-treatment PET-CT image depicting resolution of the abnormality in FIG. 13B after treatment with anti-CDl9 CAR+ T cells. FIG. 13D is a pretreatment brain MRI (high-resolution Ti-weighted image with the use of contrast material; axial view) showing a homogeneously enhancing mass in the right middle cranial fossa. FIG. 13E is a post-treatment MRI image showing near-complete resolution of the enhancing mass. FIG. 13F is an axial PET-CT image at relapse showing right posteriour auricular tumor recurrence associated with intense uptake of18F-flurodeoxyglycose (arrow).FIG. 13G is a PET-CT imaging showing resolution of the posterior auricular tumor after incisional biopsy and re-expansion of CAR+ T cells.

[0108] FIG. 14 shows the level of viable target cells over a period of approximately 120 hours when anti-CD 19 CAR+ T cells are incubated with K562-CD19 effector cells at an effector to target cell (E:T) ratio of 5:1 in the presence or absence of 1 nM, 5 nM, 60 nM, 550 nM or 5000 nM lenalidomide or in the absence of lenalidomide (control).

[0109] FIG. 15A shows the levels of CD25+ expression in both CD4+ and CD8+T cells when anti-CD 19 CAR+ T cells are incubated with K562-CD19 effector cells in the presence of lenalidomide or an alternative compound targeting a kinase.

[0110] FIG. 15B shows the levels of CD25+ expression in both CD4+ and CD8+T cells when anti-CD 19 CAR+ T cells are incubated with PD-l effector cells in the presence of lenalidomide or an alternative compound targeting a kinase.

[0111] FIG. 16 shows the amount of IL-10 in culture supernatants after incubating anti- CD19 CAR+ T cells with K562-CD19 effector cells at an effector to target cell (E:T) ratio of 3:1 or 9:1, in the presence or absence of various concentrations of lenalidomide.

[0112] FIG. 17A shows the fold-change of cell number after stimulation of anti-CD 19 CAR+ T cells from two donors (pt 1 and pt 2) with K562-CD19 effector cells in the presence or absence of 1 mM lenalidomide or 50 nM or 500 nM of an alternative compound targeting a kinase. FIG. 17B shows the number of cell doublings compared to the initial number after the 2ndand 4thstimulations.

[0113] FIG. 18A shows the cytolytic activity of the anti-CD 19 CAR+ T cells from two donor cells (pt 1 and pt 2) restimulated with K562-CD19 cells (labeled with NucLight Red (NLR)) and in the presence of 1 pM lenalidomide or 50 nM or 500 nM of the alternative compound targeting a kinase.

[0114] FIG. 18B shows the percent target cell killing of the anti-CD 19 CAR+ T cells from two donor cells (1 or 2) restimulated with K562-CD19 cells compared to the vehicle-only control (set at 100%).

[0115] FIG. 19A shows a histogram plot of CTV staining of total cells in an anti-BCMA CAR+ T cell composition after incubation with beads (200 pg / mL BCMA-conjugated bead composition) at a ratio of 1:1 T cells to beads and in the presence or absence of 5pMlenalidomide.

[0116] FIG. 19B and FIG. 19C show flow cytometry histograms for CD25 in CD4+ T cells (left panel) or CD8+ T cells (right panel) present in an anti-BCMA CAR+ T cell composition after incubation with beads (200 pg / mL BCMA-conjugated bead composition) at a ratio of 1:1 T cells to beads or immobilized anti-CD3, respectively, in the presence or absence oflenalidomide.

[0117] FIGS. 20A-20I show graphs displaying the levels of transcription factors and activation markers in or on CD4+ T cells (left panels) or CD8+ T cells (right panels) present in an anti-BCMA CAR+ T cell composition after incubation without stimulation or with different amounts of BCMA-conjugated bead or anti-CD3 and anti-CD28 conjugated beads and in the presence of 0 pM, 0.5 pM, or 50 pM lenalidomide. Levels of Blimp 1 (FIG. 20A), CD25 (FIG.20B), CD31 (FIG. 20C), PD-l (FIG. 20D), Tbet (FIG. 20E), EOMES (FIG. 20F), GATA3(FIG. 20G), Helios (FIG. 20H), and Ikaros (FIG. 201) are shown. 200 BCMA, 50 BCMA, and 5 BCMA indicate BCMA-conjugated beads generated by incubating BCMA with the beads in an amount of 200, 50, and 5 mg of BCMA per approximately 4xl08beads, respectively.

[0118] FIG. 21A-C shows graphs displaying the levels of extracellular IFN-gamma (FIG. 21A), IL-2 (FIG. 21B), and TNF alpha (FIG. 21C) from cultures following incubation of an anti-BCMA CAR+ T cell composition with two different amounts of BCMA-conjugated beads in the presence or absence of 5mM lenalidomide. 50mg BCMA and 5mg BCMA indicate BCMA-conjugated beads generated by incubating BCMA with the beads in an amount of 50 and 5 mg of BCMA per approximately 4xl08beads, respectively.

[0119] FIG. 21D shows a graph displaying the levels of extracellular IL-2 from cultures following incubation of an anti-BCMA CAR+ T cell composition from two different donors with different amounts of BCMA-conjugated beads in the presence of 0 mM, 1 mM, or 5 mM lenalidomide. 200 BCMA and 5 BCMA indicate BCMA-conjugated beads generated by incubating BCMA with the beads in an amount of 200 pg and 5 pg of BCMA per approximately 4xl08beads, respectively.

[0120] FIG. 21E and FIG. 21F shows total cell count following culture of an anti-BCMA CAR+ T cell composition after incubation for 4 days (FIG. 21E) or 7 days (FIG. 21F) with different amounts of BCMA-conjugated beads in the presence of 5 pM lenalidomide. 50 BCMA and 5 BCMA indicate BCMA-conjugated beads generated by incubating BCMA antigen with the beads in an amount of 50 pg and 5 pg of BCMA per approximately 4xl08beads, respectively.

[0121] FIG. 21G shows histogram plots of CTV staining of CD4+ T cells or CD8+ T cells in an anti-BCMA CAR+ T cell composition after incubation for 4 or 7 days with BCMA- conjugated beads in the presence of 5mM lenalidomide or absence of lenalidomide (vehicle).

[0122] FIG. 21H and 211 show graphs displaying the percentage of cells positive for the surrogate marker EGFRt as determined with an anti-EGFR antibody following incubation of an anti-BCMA CAR+ T cell composition for 4 days (FIG. 21H) or 7 days (FIG. 211) with different amounts of BCMA-conjugated beads in the presence of 5mM lenalidomide or absence of lenalidomide (vehicle). “50” and“5” indicate beads generated by incubating BCMA with the beads in an amount of 50 pg and 5 pg of BCMA per approximately 4xl08beads, respectively.

[0123] FIG. 21J shows the percent cell killing of RPMI-8226 target cells by anti-BCMA CAR+ T cells effector cells that had been incubated with different amounts of BCMA- conjugated beads in the presence of 5mM lenalidomide or absence of lenalidomide (vehicle).Cytolytic activity of compositions containing a ratio of effector cells to target cells of 3:1 or 1:1 and in the further presence or absence of lenalidomide are shown. “50” and“5” indicate BCMA conjugated beads generated by incubating BCMA with the beads in an amount of 50 and 5 pg of BCMA per approximately 4xl08beads, respectively.

[0124] FIG. 22A shows the flow cytometric analysis of phosphorylated STAT5 after 2 hours of CAR stimulation (stim) with 50 pg BCMA beads. No stimulation control shown with dotted line. FIG. 22B shows the flow cytometric analysis of intracellular cytokine levels on a representative normal CAR T donor after 24 hours of BCMA bead stimulation (gated on transduced, live CD3+).

[0125] FIG. 23A-23B depicts results of a serial restimulation assay of anti-BCMA CAR T cell compositions that had been incubated for seven days with BCMA-conjugated beads (50 pg / mL). Results from three different donor compositions are shown. FIG. 23A and FIG. 23B show the cytolytic activity of the anti-BCMA CAR+ T cells at each of the time points for two different donors.

[0126] FIG. 24A shows results for CAR antigen- specific cytolytic activity and FIG. 24B shows results for cytokine production for anti-BCMA CAR-T cells that had been prestimulated with BCMA beads (compared to freshly-thawed (non-prestimulated) anti-BCMA CAR-T cells) in the co-cultures, comparing cells cultured in the presence versus absence of lenalidomide.FIG. 24C shows the overall viability and cell count assessed for three anti-BCMA CAR T donors. FIG. 24D shows results of flow cytometric analysis of surface CD25 and PD-1 expression (mean fluorescent intensity (MFI), for CD4+ or CD8+ anti-BCMA CAR T-cells after stimulation (pretreatment) with BCMA beads for 7 days, in the presence or absence of 1 pM lenalidomide. FIG. 24E shows the flow cytometric analysis across CAR T donors for median fluorescence intensity (MFI; CD25 and Tim3) or percentage positive PD-l and Lag3 on the surface of T-cell markers in CD4+ CAR+ and CD8+ CAR+ subsets (gated on live CD3+ cells). Values shown are percentage baseline (Veh) MFI, viability, or count.

[0127] FIG. 25A shows the analysis of effector cytokine production following CAR-specific stimulation on 50 pg BCMA beads for 24 hours in the presence of 1 pM lenalidomide compared with baseline (vehicle) response for each of three donors.

[0128] FIG. 25B shows the effects of anti-BCMA CAR T cells activated on different concentrations of BCMA beads (i.e., 5 pg, 50 pg, and 200 pg) in the presence or absence of lenalidomide (0.1 pM or 1 pM) on CAR T effector cytokine production.

[0129] FIG. 25C shows the cytokine production of anti-BCMA CAR T cells derived from representative healthy donors and multiple myeloma patients stimulated on BCMA beads with or without addition of PD-L1 on the beads, in the presence of 1 mM lenalidomide) or in the absence of lenalidomide.

[0130] FIGS. 26A and 26B show results of principal component analysis (PCA) for gene expression (based on RNA-seq results; FIG. 26A) and chromatin accessibility (based on ATAC- seq results; FIG. 26B), in anti-BCMA CAR-expressing T cells generated from 4 different donors (Donors 1-4), stimulated with BCMA-conjugated beads, for 24 hours (24 hr + stim) or 7 days (d7 + stim), or cultured without stimulation for 24 hours (24 hr), in the presence or absence of lenalidomide.

[0131] FIGS. 27 A and 27B show volcano plots depicting statistical significance of expression (loglO of adjusted p-value) with the log2 fold-change in gene expression, including genes or peaks that show increased (right side) or decreased (left side) expression, in CAR+ T cells stimulated with BCMA-conjugated beads, for 24 hours (24 hr + stim, FIG. 27A) or 7 days (d7 + stim, FIG. 27B), in the presence or absence of lenalidomide. The tables indicate the number of genes or peaks that showed statistically significant increase (up) or decrease (down) in expression.

[0132] FIGS. 27C and 27D show volcano plots depicting statistical significance of expression (loglO of adjusted p-value) with the log2 fold-change in g chromatin accessibility, including genes or peaks that show increased (right side) or decreased (left side) accessibility, in CAR+ T cells stimulated with BCMA-conjugated beads, for 24 hours (24 hr + stim, FIG. 27C) or 7 days (d7 + stim, FIG. 27D). The tables indicate the number of genes or peaks that showed statistically significant increase (up) or decrease (down) in accessibility.

[0133] FIGS. 28A and 28B depict directionality and significance of expression for the genes in biological signaling pathways that were enriched in the sets of genes whose expression was statistically significantly increased or decreased, in CAR+ T cells stimulated with BCMA- conjugated beads, for 24 hours (24 hr + stim, FIG. 28A) or 7 days (d7 + stim, FIG. 28B).

[0134] FIG. 29 shows a plot comparing individual chromatin accessibility peaks (diamond) and the mean chromatin accessibility changes for each gene (circle), with the gene expression changes, for selected genes involved in T cell activation and signaling.

[0135] FIG. 30 shows motif enrichment analysis, enrichment log p-value, prevalence and transcription factors predicted to bind the motifs for peaks with increased accessibility in the presence of lenalidomide in day 7 cultures.

[0136] FIGS. 31A-31C show flow cytometry analysis of intracellular Ikaros or Aiolos expression on both CD4+ anti-CDl9 CAR-expressing T cells and CD8+ anti-CDl9 CAR- expressing T cells. CAR-expressing T cells were stimulated with CAR-T anti-idiotypic antibody at 5 pg / mL (FIG. 31A-B) or 1 pg / mL (FIG. 31C) treated across a concentration range of lenalidomide or Compound 1. Median fluorescence intensity (MFI) values for Ikaros and Aiolos were normalized and calculated as a percentage relative to as a percentage relative to vehicle control.

[0137] FIGS. 32A and 32B show analysis of cytokine production of anti-CD 19 CAR- expressing T cells in the presence of Compound 1 (FIG. 32A) or lenalidomide (FIG. 32B) following incubation with target cells. Multiplex cytokine assay of supernatants taken at 24 hours from triplicate wells of anti-CDl9 CAR-expressing T cells co-cultured with K562.CD19 target cells in the presence of several concentrations of Compound 1 or lenalidomide. IFN-g, IL- 2, and TNF-a concentrations were determined for CAR-expressing T cell from three different donors over two E:T ratios. Data represents the mean + / - S.D. across 3 experiments.

[0138] FIGS. 33A-33D show analysis of cytolytic function or cytokine production of anti- CD^ CAR-expressing T cells in the presence of Compound 1 or lenalidomide following incubation with target cells. Anti-CD 19 CAR-expressing T cells from three different donors were co-cultured with K562.CD19 (FIG. 33A), or Granta-5l9 or Raji cells (FIGS. 33B-33D) target cells in triplicate at two E:T ratios in the presence of Compound 1 or lenalidomide over 5 days. Results were calculated as a normalized killing index. Data represents the mean + / - S.D. across 3 experiments.

[0139] FIGS. 34A-34D show analysis of cytokine production of anti-CD 19 CAR-expressing T cells or STAT5 phosphorylation in the presence of Compound 1 (FIG. 34A and FIG. 34C) or lenalidomide (FIG. 34B) following anti-idiotypic antibody stimulation. Multiplex cytokine assay of supernatants taken at 24 hours from triplicate wells of anti-CDl9 CAR-expressing T cells co-cultured with agonist anti-idiotypic antibody in the presence of 100 or 1000 nMCompound 1 (FIG. 34A and FIG. 34C-34D), or 500 or 5000 nM lenalidomide (FIG. 34B). IFN-g, IL-2, and TNF-a concentrations (FIGS. 34A-34C) and median fluorescence intensity of phosphorylated STAT5 (pSTAT5) (FIG. 34D) were determined for CAR-expressing T cells from three different donors. Data represents the mean + / - S.D. across 3 experiments.

[0140] FIGS. 35A and 35B show analysis of surface marker expressions on CD4+ anti-CD19 CAR-expressing T cells (FIG. 35A) and CD8+ anti-CDl9 CAR-expressing T cells (FIG.35B) in the presence of Compound 1 following anti-idiotypic antibody stimulation. Anti-CD 19CAR-expressing T cells from three different donors were stimulated with anti-idiotypic antibody at 0, 0.3, 3, or 30 mg / mL in the presence of 100 or 1000 nM of Compound 1. Cells were analyzed by flow cytometry at day 4. The absolute change in median fluorescence intensity relative to vehicle control for each concentration of anti-idiotypic antibody was calculated. Data are representative of 3 experiments.

[0141] FIGS. 36A and 36B show analysis of surface marker expressions on CD4+ anti- CD19 CAR-expressing T cells (FIG. 36A) and CD8+ anti-CDl9 CAR-expressing T cells (FIG. 36B) in the presence of lenalidomide following anti-idiotypic antibody stimulation. Anti-CD 19 CAR-expressing T cells from three different donors were stimulated with anti-idiotypic antibody at 0, 0.3, 3, or 30 mg / mL in the presence of 500 or 5000 nM of lenalidomide. Cells were analyzed by flow cytometry at day 4. The absolute change in median fluorescence intensity relative to vehicle control for each concentration of anti-idiotypic antibody was calculated. Data are representative of 3 experiments.

[0142] FIGS. 37A and 37B show analysis of CD28 surface expression on CD4+ and CD8+ anti-CD19 CAR-expressing T cells in the presence of Compound 1 (FIG. 37A) or lenalidomide (FIG. 37B) after serial stimulation. Anti-CD19 CAR-expressing T cells from three different donors were stimulated with K562.CD19 at an E:T ratio of 2.5:1 every 3-4 days in the presence of Compound 1 (FIG. 37A) or lenalidomide (FIG. 37B). The percentage of cells positive for CD28 was measured by flow cytometry at day 28.

[0143] FIG. 38 shows analysis of cytolytic function of anti-CD19 CAR-expressing T cells in the presence of Compound 1 or lenalidomide following serial stimulation. Anti-CD 19 CAR- expressing T cells from three different donors after 24 days of serial stimulation were co cultured with irradiated K562.CD19 target cells in triplicate at two E:T ratios in the presence of Compound lor lenalidomide. Results were calculated as a normalized killing index.

[0144] FIGS. 39A and 39B show analysis of population doublings of anti-CD 19 CAR- expressing T cells during a 28-day serial stimulation period in the presence of absence of Compound 1. Anti-CD 19 CAR-expressing T cells from three different donors were stimulated with with K562.CD19 target cells at an E:T ratio of 2.5:1 or 10:1 every 3-4 days in the presence of 500 nM Compound 1 for 28 days (represented by x-axis). Cells were counted after each stimulation and cell doublings were calculated. (FIG. 39A) Percentage change in cell doublings at day 24 of serial stimulation in the presence of 10 nM, 100 nM or 500 nM Compound 1 wasshown in FIG. 39B. Data represents mean+ / -S.E.M of triplicated treatments from 3 donors.Each arrow represents a re-stimulation time point.

[0145] FIGS. 40A and 40B show analysis of population doublings of anti-CD 19 CAR- expressing T cells during a 28-day serial stimulation period in the presence of absence of lenalidomide. Anti-CD 19 CAR-expressing T cells from three different donors were stimulated with with K562.CD19 target cells at an E:T ratio of 2.5: 1 or 10: 1 every 3-4 days in the presence of 1000 nM lenalidomide for 28 days (represented by x-axis). Cells were counted after each stimulation and cell doublings were calculated. (FIG. 40A) Percentage change in cell doublings at day 24 of serial stimulation in the presence of 100 nM or 1000 nM lenalidomide was shown in FIG. 40B. Data represents mean+ / -S.E.M of triplicated treatments from three donors. Each arrow represents a re- stimulation time point.

[0146] FIG. 41 shows analysis of anti-tumor efficacy of CAR-expressing T cells in combination with Compound 1, as shown by percent survival. NO D . Cg . Prkdcst 1 dI L2rg1"'; / / / S zJ (NSG) mice were injected intravenously (i.v.) with 0.5 x 106Raji lymphoma tumor cells and tumor engraftment was allowed to occur for 6 days. On day 7, mice either received no treatment, or a single i.v. injection of anti-CDl9 CAR-expressing cells. In one study group (designated“Concurrent”), mice were administered Compound 1 or vehicle control one day prior to administration of the CAR-expressing cells (day 6), which was continued once a day for the study duration. In a second group (designated“Delayed”), mice were administered either a vehicle control or Compound 1 starting from day 14, which was after the peak of CAR- expressing T cell expansion, and administration was continued once a day for the study duration. Survival of mice were assessed and compared until day 100 post-infusion of CAR-expressing T cells.

[0147] FIG. 42 shows analysis of CAR signaling in the presence of Compound 1. The expression level of dTomato in Jurkat Nur77-dTomato reporter cells expressing either an anti- CD19 CAR or an anti-RORl CAR, as detected by flow cytometry, was measured following incubation in the presence of Compound 1 or a vehicle control for up to 6 hours.

[0148] FIGS. 43A-43M show analysis of cytolytic function and gene expression analysis of anti-CD 19 CAR-expressing T cells in the presence of Compound 1 or a vehicle control, following long-term stimulation. Anti-CDl9 CAR-expressing T cells were subjected to chronic stimulation conditions by being incubated with plate-bound anti-idiotypic (anti-ID) antibody for a period of 5 or 6 days. After the 5 or 6-day culture period, the anti-CDl9 CAR-expressing T cells were removed from culture and incubated with CD 19+ tumor spheroids in the presence ofCompound 1, at concentrations ranging from 0.001 mM to 10 mM, or a vehicle control, for up to 10 days. Freshly thawed anti-CDl9 CAR-expressing T cells that had not been subjected to chronic stimulatory conditions were incubated with the tumor spheroids in parallel as controls. Cells were assessed at various times for cytolytic function (FIGS. 43A, 43E, and 43F), tumor volume reduction (FIGS. 43B, 43C right panel, 43D, 43F, 43G and 43 H), CAR T cell number (FIG. 431), and cytokine production (FIG. 43C left panel and 43 J). FIG 43K shows plots of log2 fold change (log2FC) of gene expression in anti-CD 19 CAR-T cells after both the long term stimulation and subsequent incubation with Compound 1 relative to chronic stimulation control (y-axis), versus gene expression in anti-CD 19 CAR+ T cells that that were chronically stimulated and compared to those had not been stimulated in the long-term stimulation assay (x- axis). FIG. 43L shows plot of log2fold change with Compound l(y-axis) versus without Compound 1 (x-axis). FIG. 43M shows KEGG pathway analysis of CAR-T RNA-seq data.

[0149] FIGS. 44A-44F show cytolytic function and analysis of gene expression in CAR- expressing T cells subjected to long-term stimulation in the presence of Compound 1 or lenalidomide, or a vehicle control, or IL-2 for comparison. Gene expression was analyzed by RNA-seq on the cDNA samples prepared from RNA isolated from the long-term stimulated CAR-expressing T cells, or on CAR-expressing T cells that had not undergone the long-term stimulation. Differential expression (DE) was calculated based on the treatment effects (long term stimulation vs. without long-term stimulation), for long-term stimulation in the presence of the compound (e.g. Compound 1 or lenalidomide) or IL-2, or a vehicle control. FIG. 44A shows plots of log2fold change (log2FC) of gene expression in anti-CDl9 CAR-expressing T cells after the long-term stimulation, in the presence of Compound 1 or IL-2 relative to chronic stimulation control (y-axis) versus gene expression in anti-CDl9 CAR-expressing T cells that were chronically stimulated and compared to those that had not been stimulated in the long-term stimulation assay (x-axis). FIG. 44B shows a plot of log2fold change with Compound 1 (y- axis) versus without Compound 1 (x-axis). In FIGS. 44A and 44B, genes with increased or decreased expression are identified. FIG. 44C shows gene set enrichment scores for genes showing increased or decreased expression in the presence of Compound 1.FIG. 44D shows KEGG pathway analysis of CAR-T RNA-seq data. Cells were assessed at various times for cytolytic function (FIG. 44E) and cytokine production (FIG. 44F).

[0150] FIGS. 45A-45D show cytolytic function and cytokine production for anti-CD 19CAR-expressing T cells from three donors stimulated under conditions to induce chronic stimulation either in the presence of (concurrent), or with subsequent treatment (rescue), with,0.1 mM and 1 mM Compound 1, or a vehicle control, or recombinant IL-2 (for comparison) co cultured by incubation with Granta-5l9 tumor spheroids. Tumor spheroid size was measured at day 9 for T cells under concurrent (FIG. 45A) or subsequent (FIG. 45B) treatment withCompound 1, and cytokine concentrations from supernatants harvested at day 5 were measured for T cells under concurrent (FIG. 45C) or subsequent (FIG. 45D) treatment with Compound 1.

[0151] FIG. 46 shows intracellular Ikaros and Aiolos expression in anti-CDl9 stimulated CAR-expressing T cells after incubation with varying concentrations of Compound 1 or Compound 2.

[0152] FIG. 47 A shows the proliferation of anti-CD 19 CAR T cell for three donors (mean ± SEM) in the presence of varying concentrations of Compound 1 or Compound 2. FIG. 47B shows the effect of varying concentrations of Compound 1 or Compound 2 on cell viability when the stimulation was carried out with 3 pg / mL anti-ID (left panel) or 30 pg / mL anti-ID (right panel). FIG. 47C shows the cell cycle analysis of the anti-CD 19 CAR T cells after treatment with 1000 nM Compound 1 or 100 nM Compound 2. FIG. 47D shows the percentage of anti-CD 19 CAR T cells in the Gl phase of the cell cycle when exposed to varyingconcentrations of Compound 1 or Compound 2. FIG. 47E shows the intracellular cytokine expression levels of IFNy, perforin, granzyme B and IL-2 in anti-CD 19 CAR T cells that have been stimulated for 24 hours or 72 hours with 30 pg / mL anti-ID and exposed to Compound 1 or Compound 2.

[0153] FIG. 48A shows the expression of Ikaros in anti-CDl9 CAR T cells that had been subjected to chronic stimulation in the presence of Compound 2 (10 nM or 100 nM). FIG. 48B shows the cytolytic activity, as measured by tumor cell number over time, for chronically stimulated cells that had been concurrently incubated in the presence of Compound 2 (0.001 pM or 0.01 pM) compared to absence of the compound (control) prior to rechallenge with CD 19- expressing target cells. FIG. 48C shows the size of Granta-5l9 tumor spheroids at various times following co-culture with 1 pM Compound 1 (left panel) or 0.001 pM or 0.01 pM of Compound 2 (right panel). FIG. 48D shows the average tumor volume of the Granta-5l9 tumor spheroids after 9 days in the presence of Compound 2. FIG. 48E shows the cytokine levels of IFNy, IL-2 and TNFalpha measured from the supernatant of the chronically stimulated anti-CD 19 CAR T cells that had been co-cultured for 5 days with CD 19 tumor spheroids and treated withCompound 1 or Compound 2.

[0154] FIG. 49A shows the effect of Compound 2 (0.001 pM or 0.01 pM) on the cytolytic activity of K562 cells transduced with CD19 (K562.CD19), Raji cells or Granta-5l9 cells. FIG.49B shows the averaged measurement of the size of Granta-5l9 tumor spheroids at Day 9 following co-culture with CAR-T cells. FIG. 49C shows the cytokine levels of IFNy, IL-2 and TNFalpha measured from the supernatant of the chronically stimulated anti-CD 19 CAR T cells that had been co-cultured for 5 days with CD 19 tumor spheroids and treated with Compound 1 or Compound 2.

[0155] FIG. 50B shows the averaged measurement of the size of A549.CD19 tumor spheroids at Day 9 following co-culture with CAR-T cells in the presence of Compound 2 (0.001 mM, 0.01 pM, or 0.1 pM). FIG. 50B shows the cytokine levels of IRNg, IL-2 and TNFalpha measured from the supernatant of the chronically stimulated anti-CD 19 CAR T cells that had been co-cultured for 5 days with CD 19 tumor spheroids and treated with Compound 1 or Compound 2. FIG. 50C shows the number of CAR T cells in co-cultures with A549.CD19 tumor spheroids, measured at day 5, with treatment with Compound 2 (0.01 pM or 0.1 pM).

[0156] FIG. 51A shows the cytolytic activity, as measured by tumor cell number, of RL CD 19+ tumor cells cocultured with anti-CD 19 CAR T cells in the presence of Compound 2 (0.001 pM, 0.01 pM or 0.1 pM). FIG. 51B shows FIG. 51C shows tumor size of RL tumor spheroids cocultured with anti-CD 19 CAR T cells in the presence of Compound 1 (1 pM) or Compound 2 (0.001 pM, 0.01 pM or 0.1 pM).

[0157] FIG. 52 shows the viability and count of anti-BCMA CAR T cells from three donors in the presence of lenalidomide (1000 nM) or Compound 2 (0.1 nM, 1 nM, or 10 nM) after 7 days.

[0158] FIG. 53A shows cytolytic activity of anti-BCMA CAR T cells from three donors during long term stimulation in the presence of lenalidomide (1000 nM) or Compound 2 (1 nM or 10 nM). FIGS. 53B-D shows the production of IFN-gamma (FIG. 53B), IL-2 (FIG. 53C), and TNF-alpha (FIG. 53D) in anti-BCMA CAR T cells from three donors during long term stimulation in the presence of lenalidomide (1000 nM) or Compound 2 (1 nM or 10 nM).

[0159] FIG. 54 shows cytolytic activity of anti-BCMA CAR T cells from three donors during chronic stimulation for 7 days with BCMA-conjugated beads and re-challenged with BCMA-expressing RPMI-8226 MM cells in the presence of Compound 2 (1 nM or 10 nM). FIGS. 54B-D shows the production of IFN-gamma (FIG. 54B), IL-2 (FIG. 54C), and TNF alpha (FIG. 54D) in anti-BCMA CAR T cells from three donors during chronic stimulation in the presence of Compound 2 (1 nM or 10 nM).

[0160] FIG. 55 shows cytolytic activity of anti-BCMA CAR T cells from three donors during chronic stimulation for 7 days with BCMA-conjugated beads in the presence ofIMiD / CELMoD resistant cell line DF-15R and Compound 2 (1 nM or 10 nM). FIGS. 55B-D shows the production of IFN-gamma (FIG. 55B), IF-2 (FIG. 55C), and TNF-alpha (FIG. 55D) in anti-BCMA CAR T cells from three donors during chronic stimulation in the presence of IMiD / CEFMoD resistant cell line DF-15R and Compound 2 (1 nM or 10 nM).Detailed Description

[0161] Provided herein are combination therapies involving administration of animmunotherapy involving T cell function or activity, such as a T cell therapy, and animmunomodulatory compound, such as a structural or functional analog or derivative of thalidomide and / or an inhibitor of E3-ubiquitin ligase. In some aspects, the provided methods enhance or modulate proliferation and / or activity of T cell activity associated withadministration of an immunotherapy or immunotherapeutic agent, such as a composition including cells for adoptive cell therapy, e.g., such as a T cell therapy (e.g. CAR-expressing T cells). In some embodiments, the combination therapy involves administration of animmunomodulatory compound, such as a structural or functional analog of thalidomide and / or an inhibitor of E3-ubiquitin ligase, and administration of the T cell therapy, such as a composition including cells for adoptive cell therapy, e.g., such as a T cell therapy (e.g. CAR- expressing T cells).

[0162] T cell-based therapies, such as adoptive T cell therapies (including those involving the administration of cells expressing chimeric receptors specific for a disease or disorder of interest, such as chimeric antigen receptors (CARs) and / or other recombinant antigen receptors, as well as other adoptive immune cell and adoptive T cell therapies) can be effective in the treatment of cancer and other diseases and disorders. The engineered expression of recombinant receptors, such as chimeric antigen receptors (CARs), on the surface of T cells enables the redirection of T-cell specificity. In clinical studies, CAR-T cells, for example anti-CDl9 CAR- T cells, have produced durable, complete responses in both leukemia and lymphoma patients (Porter et al. (2015) Sci Transl Med., 7:303ral39; Kochenderfer (2015) J. Clin. Oncol., 33: 540- 9; Fee et al. (2015) Fancet, 385:517-28; Maude et al. (2014) N Engl J Med, 371:1507-17).

[0163] In certain contexts, available approaches to adoptive cell therapy may not always be entirely satisfactory. For example, in certain cases, although CAR T cell persistence can be detected in many subjects with lymphoma, fewer complete responses (CRs) have been observed in subjects with NHF compared to subjects with AFF. More specifically, while higher overall response rates of up to 80 % (CR rate 47% to 60%) have been reported after CAR T cellinfusion, 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(l l): 1805-10).

[0164] In some aspects, an explanation for this is the immunological exhaustion of circulating CAR-expressing T cells and / or changes in T lymphocyte populations. In some contexts, optimal efficacy can depend on the ability of the administered cells to recognize and bind to a target, e.g., target antigen, to traffic, localize to and successfully enter appropriate sites within the subject, tumors, and environments thereof. In some contexts, optimal efficacy can depend on the ability of the administered cells to become activated, expand, to exert various effector functions, including cytotoxic killing and secretion of various factors such as cytokines, to persist, including long-term, to differentiate, transition or engage in reprogramming into certain phenotypic states (such as long-lived memory, less-differentiated, and effector states), to avoid or reduce immunosuppressive conditions in the local microenvironment of a disease, to provide effective and robust recall responses following clearance and re-exposure to target ligand or antigen, and avoid or reduce exhaustion, anergy, peripheral tolerance, terminal differentiation, and / or differentiation into a suppressive state.

[0165] In some embodiments, the exposure and persistence of engineered cells is reduced or declines after administration to the subject. Yet, observations indicate that, in some cases, increased exposure of the subject to administered cells expressing the recombinant receptors (e.g., increased number of cells or duration over time) may improve efficacy and therapeutic outcomes in adoptive cell therapy. Preliminary analysis conducted following the administration of different CD 19-targeting CAR-expressing T cells to subjects with various CD 19-expressing cancers in multiple clinical trials revealed a correlation between greater and / or longer degree of exposure to the CAR-expressing cells and treatment outcomes. Such outcomes included patient survival and remission, even in individuals with severe or significant tumor burden.

[0166] In some embodiments, following long-term stimulation or exposure to antigen and / or exposure under conditions in the tumor microenviroment, T cells can over time become hypofunctional and / or exhibit features associated with exhausted state. In some aspects, this reduces the persistence and efficacy of the T cells against antigen and limits their ability to be effective. There is a need for methods to improve the efficacy and function of CAR T cells, particularly to minimize, reduce, prevent or reverse hypofunctional or exhaustive states.

[0167] The provided methods involve administering T cell therapy, such as a composition including cells for adoptive cell therapy, e.g., such as a T cell therapy (e.g. CAR-expressing T cells) , and an immunomodulatory compound, such as a structural or functional analog or derivative of thalidomide and / or an inhibitor of E3 ubiquitin ligase, e.g. lenalidomide, Compound 1 or Compound 2. In some embodiments, the immunomodulatory compound for use in the provided methods and uses is an E3 ligase modulatory compound that is an inhibitor of E3 ubiquitin ligase. In some embodiments, the immunomodulatory compound for use in the provided methods and uses is lenalidomide. In some embodiments, the immunomodulatory compound for use in the provided methods and uses 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 provided methods and uses is Compound 2 ((S)-3-[4-(4-morpholin-4- ylmethyl-benzyloxy)- l-oxo- l,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione).

[0168] Lenalidomide, which has the structural formula 3-(4-amino-l-oxo-l,3-dihydro-2H- isoindol-2-yl)piperidine-2,6-dione, or is an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is an immunomodulatory drug currently approved for the treatment of multiple myeloma (MM) and mantle cell lymphoma (MCL), and clinically tested in the therapy of diffuse large B-cell lymphoma of activated B cell immunophenotype. In some cases, lenalidomide increases antitumor immune responses at least partially by modulating the activity of E3 ubiquitin ligase Cereblon (CRBN), which leads to increased ubiquitinylation of Ikaros and Aiolos transcription factors, which in turn results in changed expression of various receptors on the surface of tumor cells ( see e.g., Otahal et al. (2016) Oncoimmunology. , April; 5(4): el 115940).

[0169] Compound 1, which has the structural formula 3-(5-amino-2-methyl-4-oxo-4H- quinazolin-3-yl)-piperidine-2,6-dione), or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof, is an immunomodulatory drug that is a pleiotropic small molecule that can directly impair primary tumor growth, modulate the immunosuppressive tumor microenvironment and facilitate a more robust anti-tumor inflammatory response. Compound 1 exerts anti-proliferative activity against B-cells, and is being evaluated as a single agent treatment for targeting tumors in B-cell lymphoidmalignancies.

[0170] Compound 2, which as the structural formula (S)-3-[4-(4-morpholin-4-ylmethyl- benzyloxy)- l-oxo- 1, 3 -dihydro-isoindol-2-yl] -piperidine-2, 6-dione or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof, also is acereblon (CRBN) E3 ligase modulatory compound that modulates CRBN, which induces ubiquitination of the transcription factors Aiolos and Ikaros. In some aspects, the ubiquitination increases their proteasome-dependent degradation. Compound 2 binds more potently to CRBN, and is more efficient at degrading Aiolos and Ikaros than lenalidomide and pomalidomide. As shown herein, Compound 2 also is 10-20 times more potent at degrading Ikaros and Aiolos relative to Compound 1. Compound 2 has direct anti-proliferative effects on lymphoma cells.As shown herein, Compound 2 also augments T cell function.

[0171] Immunomodulatory drugs, such as Compound 1, Compound 2, and lenalidomide, have been shown to directly affect malignant lymphocyte survival through the degradation of Ikaros family transcription factors. The molecular target for such compounds has been identified as the protein Cereblon (CRBN), a substrate receptor of the Cullin 4 RING E3 ubiquitin ligase complex. Binding to a 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;2l(9):803-9; Gandhi, Br J Haematol. 2014 Mar; l64(6):811-21; Fu, Science. 2014 Jan 17;343(6168):305-9; and Kronke, Oncoimmunology, 2014; 3(7): e94l742.) Ikaros is expressed in immature stages of myeloid differentiation and regulates early neutrophil differentiation (Dumortier et al. (2003) Blood 101:2219). Thus, in some cases, depletion of Ikaros, such as by administration of an immunomodulatory compound, e.g. Compound 1, to subjects can, in some instances, result in neutropenia. To mitigate neutropenia while maintaining anti-tumor activity against B cell lymphomas, it has been found that a dose of 4 mg of Compound 1 given for five days followed by a two day rest period (5 / 7 days) is the maximum tolerated dose (MTD) for treatment of subjects with DFBCF (Carpio et al. (2015) Blood, 126:1594). See also, International Published Appl. No. W02017096024.

[0172] In addition to its cell autonomous activity against malignant B cells, E3 ligase modulatory compounds, such as Compound 1, also exerts co-stimulatory effects on immune cells such T and NK-cells. This activity also has been shown to be through CRBN mediated degradation of Aiolos and Ikaros, which are negative regulators of activation molecules and cytokines such as interleukin-2 (IF-2) expression. (Gandhi, Br J Haematol. 2014Mar;l64(6):8l l-2l, Kronke, Oncoimmunology, 2014; 3(7): e94l742.).

[0173] The provided methods are based on observations that the immunomodulatory compound, such as a structural or functional analog or derivative of thalidomide and / or an inhibitor of E3 ubiquitin ligase, e.g. lenalidomide, Compound 1 or Compound 2 as described,improves T cell function, including functions related to the ability to produce one or more cytokines, cytotoxicity, expansion, proliferation, and persistence of T cells. In some aspects, the provided methods enhance or modulate proliferation and / or activity of T cell activity associated with administration of the T cell therapy ( e.g . CAR-expressing T cells). It is found that such methods and uses provide for or achieve improved or greater T cell functionality, and thereby improved anti-tumor efficacy.

[0174] It also is found herein that, in addition to potentiating T cell function, such immunomodulatory compounds, e.g. lenalidomide, Compound 1 or Compound 2, exhibit effects to reverse, delay, or prevent T cell exhaustion, including by increasing T cell signaling and / or altering one or more genes that are differentially regulated following chronic (long-term) stimulation. Thus, while in some cases agents that increase or potentiate T cell activity may drive the cells to an exhausted state, it is found herein that activity of such immunomodulatory compounds, e.g. lenalidomide, Compound 1 or Compound 2, to exert a potentiating effect on T cell activity is decoupled from T cell exhaustion. In some embodiments, the provided methods involving compound administration of such immunomodulatory compounds, e.g. lenalidomide, Compound 1 or Compound 2, is capable of potentiating activity of naive T cells and delaying, limiting, reducing, inhibiting or preventing exhaustion.

[0175] Moreover, observations herein show that the immunomodulatory compounds, e.g. lenalidomide or Compound 1, exhibit activity to rescue T cells from T cell exhaustion, such as by restoring or partially restoring one or more T cell activities after a cell has shown features of exhaustion. Remarkably, results herein show that exposure of T cells, that have been chronically stimulated and exhibit features of exhausted T cells, to an immunomodulatory compound described herein, such as Compound 1, are able to recover activity or have their activity restored or partially restored. These results are not observed with interleukin 2 (IL-2), which, in some cases, is a downstream modulator induced by such immunomodulatory compounds. The observations herein support that the provided methods may also achieve improved or more durable responses as compared to certain alternative methods, such as in particular groups of subjects treated.

[0176] These observations were made using a chronic stimulation assay to render CAR T cells hypofunctional (e.g. reduced cytolysis and IL-2 secretion). Using this model, CAR T cells were examined to assess impact of immunoodulatory compounds that inhibit E3 ligase, e.g. lenalidomide, Compound 1 or Compound 2, on CAR T cell function when present during(concurrent) or following (rescue) exposure to conditions leading to a hypofunctional,exhaustive state. Upon rechallenge with antigen, the findings provided herein demonstrate that concurrent treatment of CAR T cells during such conditions reversed activity and phenotypes, including gene signatures, associated with CAR T cell hypofunctionality and preserved more effector function. Likewise, the results show that immunoodulatory compounds that inhibit E3 ligase, e.g. lenalidomide, Compound 1 or Compound 2, could rescue or restore T cell function, including cytokine production and cytolytic activity, of exhausted T cells. Further, the results were seen with different target antigens and different CARs.

[0177] In some embodiments, the effect on T cell exhaustion as observed by theimmunomodulatory compounds, such as lenalidomide or Compound 1, is not observed by or induced by IL-2. In some embodiments, such effect, such as the ability to reduce, prevent or delay T cell exhaustion or to rescue or restore T cell activity in exhausted T cells, is not induced by a physiologically relevant amount or a therapeutically effective amount of IL-2. In some embodiments, the effect induced by the immunomodulatory compound, e.g. 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, is induced by greater than or greater than or about 1.2-fold, 2.0-fold, 3-fold, 4.0-fold, 5.0-fold, 6.0-fold, 7.0-fold, lO.O-fold, or more seen or induced by IL-2, such as a physiologically relevant amount or a therapeutically effective amount of IL-2.

[0178] Observations provided herein also demonstrate that immunoodulatory compounds that inhibit E3 ligase exhbit activity to increase effector cytokine production by CAR T cells, while at the same time slowing their proliferative rate. This results is not due to an effect of the compounds on viability of T cells. This effect on proliferation was observed at varied concentration, and was found to be due to accumulation of the T cells in Gl phase. This decoupling of effector cytokine production from proliferation rate could be clinically beneficial, such as by limiting differentiation of T cells in vivo which could limit efficacy.

[0179] The provided findings indicate that combination therapy of the immunomodulatory compound, such as a structural or functional analog or derivative of thalidomide and / or an inhibitor of E3 ubiquitin ligase, e.g. lenalidomide, Compound 1, or Compound 2, in methods involving T cells, such as involving administration of adoptive T cell therapy, achieves improved function of the T cell therapy, such as by potentiating T cell activity and reducing , preventing or delaying T cell exhaustion or rescuing cells from T cell exhaustion. In some embodiments, combination of the cell therapy (e.g., administration of engineered T cells) with the immunomodulatory compound, e.g., lenalidomide or Compound 1, improves or enhancesone or more functions and / or effects of the T cell therapy, such as persistence, expansion, cytotoxicity, and / or therapeutic outcomes, e.g., ability to kill or reduce the burden of tumor or other disease or target cell.

[0180] In particular aspects, it is found herein that an immunomodulatory compound, such as a structural or functional analog or derivative of thalidomide and / or an inhibitor of E3 ubiquitin ligase, e.g. lenalidomide, Compound 1 or Compound 2, promotes continued function and / or survival of cells of a T cell therapy (e.g. CAR-T cells) after activation, including after encounter with antigen. In some aspects, lenalidomide, Compound 1 or Compound 2 increases the ability of such T cells to persist or function long-term, such as by preventing exhaustion or cell death. In particular embodiments, combination therapy with an immunomodulatory compound that is an inhibitor of an E3 ligase, e.g. lenalidomide, Compound 2 or Compund 2, may 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 persistent anti-tumor function fo CAR T cells. In some cases, the compound may also have direct anti-tumor effects on lymphoma cells. In some embodiments, such improvements can result in a combination therapy exhibiting improved overall responses, e.g. reduction in tumor burden, and / or increased survival compared to in subjects treated with a monotherapy involving administration of the T cell therapy (e.g. CAR-T cell) or immunomodulatory compound (e.g. lenalidomide, Compound 1 or Compound 2) alone. In some aspects, the provided methods increase overall response and / or survival by or more than 1.5-fold, 2.0-fold, 3.0-fold, 4.0-fold, 5.0-fold, 10-fold or more compared to an alternative treatment, such as compared to a monotherapy involving administration of the T cell therapy (e.g. CAR-T cell) orimmunomodulatory compound (e.g. lenalidomide or Compound 1) alone.

[0181] The provided methods include administering Compound 1 in an effective amount to exhibit a T cell modulatory effect. It is found herein that particular dosages of exemplary immunomodulatory compounds as described, e.g. lenalidomide or Compound 1, increase or enhance T cell function of a T cell therapy, e.g. CAR-T cell therapy. In some cases, doses that are too high may negatively impact T cell function. As shown herein, prolonged treatment of Compound 1 at physiologically-relevant concentrations (10 or 100 nM) can increase long-term proliferative potential of CAR-expressing T cells while higher concentrations, e.g. such as at or about 500 mM, may be detrimental to long term product performance. In some embodiments, the dose of Compound 1 that is administered from or from about 1 mg to about 10 mg, such asfrom or from about 1 mg to about 5 mg. The dose can be administered daily in a course of treatment or cycling regimen.

[0182] Similar results were seen with the immunomodulatory drug lenalidomide, although its T cell potency activity was lower than Compound 1. In CAR-expressing T cells, Ikaros expression was decreased in a concentration dependent manner in the presence of lenalidomide or Compound 1 at similar half maximal effective concentration (EC50) values, however, the magnitude of Ikaros loss was greater following Compound 1 treatment. In certain embodiments, doses of 40-150 nM Compound 1 (correlating to ~l mg dose level) results in 50% Ikaros degradation in the T cells ( e.g ., CAR-expressing T cells). Further, in vitro studies assessing the effect of Compound 1 on antigen-dependent cytokine production by CD 19 directed CAR- expressing T cells demonstrated increased levels of IFNy and IF-2 compared to vehicle control or equimolar concentrations of lenalidomide. Thus, administering Compound 1 according to the provided methods could increase the activity of CAR-expressing cells for treating a cancer by potentiating and / or restoring T cell function and activity of the engineered T cells, and, in some aspects, may also exhibit its cell autonomous antineoplastic effects.

[0183] In particular embodiments, Compound 2 can be used in any of the provided methods. As described, findings indicate that Compound 2 is 10-20 times more potent than Compound 1 and thus also is more potent than Compound 2. In some embodiments, the provided methods include administering Compound 2 in an effective amount to exhibit a T cell modulatory effect. In some embodiments, the effective amount is 10-20 less than the amount of Compound 1 for the same or similar effect. In some embodiments, the dose of Compound 2 that is administered is from or from about 0.1 mg to about 1 mg, such as from or from about 0.3 mg to about 0.6 mg. The dose can be administered daily in a course of treatment or cycling regimen.

[0184] In some embodiments, the combination with the immunomodulatory compound, while improving one or more outcomes or functional attributes, does not affect one or more side effects or unwanted changes in the T cells, such as does not reduce the ability of the cells to become activated, secrete one or more desired cytokines, expand and / or persist, e.g., as measured in an in vitro assay as compared to such cells cultured under conditions otherwise the same but in the absence of the immunomodulatory compound. Thus in some embodiments, provided are methods and combinations that result in improvements in T cell function or phenotype, e.g., in intrinsic T cell functionality and / or intrinsic T cell phenotype, generally without compromising one or more other desired properties of functionality, e.g., of CAR-T cell functionality.

[0185] In some embodiments, the provided methods can potentiate T cell therapy, e.g. CAR- T cell therapy, which, in some aspects, can improve outcomes for treatment. In some embodiments, the methods are particularly advantageous in subjects in which the cells of the T cell therapy exhibit weak expansion, have become exhausted, exhibit a reduced or decreased persistence in the subject and / or in subjects that have a cancer that is resistant or refractory to other therapies, is an aggressive or high-risk cancer, and / or that is or is likely to exhibit a relatively lower response rate to a CAR-T cell therapy administered without theimmunomodulatory compound compared to another type of cancer or compared toadministration with a different CAR-T cell therapy.

[0186] In some embodiments, the provided methods are used at a time at which a T cell therapy (e.g. CAR T cells) may exhibit or are likely to exhibit features of exhaustion. In some embodiments, an exhaustive phenotype is evident after T cells, having reached peak expansion, begin to decline in number in the blood of the subject. In some embodiments, the methods of exposing or contacting T cells of a T cell therapy (CAR T cells) with an immunomodulatory compound that inhibits E3 ligase, e.g. lenalidomide, Compound 1 or Compound 2, are carried out at a time at which the T cells exhibit an increase in a hypofunctional or exhaustive state compared to at the time just prior to exposure of the T cells to an antigen (baseline) or to a time point at which the cells have been exposed to the antigen but are continuing to proliferate and have not yet reached peak expansion. In some embodiments, an increase in hypofunctional or exhaustive state can be determined by increased expression of an exhaustion marker compared to tge previous earlier timepoint. In some embodiments, the increase in the hypofunctional or exhaustive state, such as increase in expression of an exhaustion marker, is at a time following administration of the 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. The T cells, such as T cells in peripheral blood after administration to a subject, can be monitored for markers of T cell activiation or exhaustion such as PD-l. TIM-3 and LAG-3.

[0187] In some aspects, the provided methods can enhance, increase or potentiate T cell therapy, such as to overcome lack of persistence and / or exhaustion of T cells, e.g. in subjects in which, at or about day 12-15 days after initiation of administration of the T cell therapy, less than 10 pL, such as less than 5 pL or less than 1 pL of such cells, or a CD8+ or CD3+ subset thereof, are detectable in the blood. In some embodiments, a subject having receivedadministration of a T cell therapy, e.g. CAR-T cell, is monitored for the presence, absence or level of T cells of the therapy in the subject, such as in a biological sample of the subject, e.g. inthe blood of the subject. In some embodiments, an immunomodulatory compound, such as a structural or functional analog or derivative of thalidomide and / or an inhibitor of E3 ubiquitin ligase, e.g. lenalidomide, Compund 1 or Compound 2, is administered to a subject having received the T cell therapy (e.g. CAR-T cells) but in which such cells have weakly expanded and / or are at or below a threshold level in a sample of the subject, e.g. blood sample, at a time when strong or robust expansion of the CAR-T cells in the subject is typically observed in a plurality of subjects administered a T cell therapy (e.g. CAR-T), in some cases, this same T cell therapy (e.g. same CAR-T cells). In some aspects, an immunomodulatory compound, such as a structural or functional analog or derivative of thalidomide and / or an inhibitor of E3 ubiquitin ligase, e.g., lenalidomide, Compound 1 or Compound 2, is administered if, at or about day 12- 15 after initiation of administration of the T cell therapy, less than 10 pL, such as less than 5 pL or less than 1 pL of such cells, or a CD8+ or CD3+ subset thereof, are detectable in the blood.

[0188] In certain aspects, the provided methods can enhance, increase or potentiate T cell therapy in subjects in which a peak response to the T cell therapy has been observed but in which the response, e.g. presence of T cells and / or reduction in tumor burden, has become reduced or is no longer detectable. In some aspects, an immunomodulatory compound, such as a structural or functional analog or derivative of thalidomide and / or an inhibitor of E3 ubiquitin ligase, e.g. lenalidomide, Compound 1 or Compound 2, is administered to a subject within a week, such as within 1, 2 or 3 days after: (i) peak or maximum level of the cells of the T cell therapy are detectable in the blood of the subject; (ii) the number of cells of the T cell therapy detectable in the blood, after having been detectable in the blood, is not detectable or is reduced, optionally reduced compared to a preceding time point after administration of the T cell therapy;(iii) the number of cells of the T cell therapy detectable in the blood is decreased by or more than 1.5-fold, 2.0-fold, 3.0-fold, 4.0-fold, 5.0-fold, lO-fold or more the peak or maximum number cells of the T cell therapy detectable in the blood of the subject after initiation of administration of the T cell therapy; (iv) at a time after a peak or maximum level of the cells of the T cell therapy are detectable in the blood of the subject, the number of cells of or derived from the T cells detectable in the blood from the subject is less than less than 10%, less than 5%, less than 1% or less than 0.1% of total peripheral blood mononuclear cells (PBMCs) in the blood of the subject; (v) the subject exhibits disease progression and / or has relapsed following remission after treatment with the T cell therapy; and / or (iv) the subject exhibits increased tumor burden as compared to tumor burden at a time prior to or after administration of the T cells and prior to initiation of administration of the immunomodulatory compound.

[0189] In some embodiments, the methods can be used for treating a disease or condition, e.g. a B cell malignancy or hematological malignancy, and in particular such diseases, conditions or malignancies in which responses, e.g. complete response, to treatment with the T cell therapy alone, such as a composition including cells for adoptive cell therapy, e.g., such as a T cell therapy (e.g. CAR-expressing T cells), is relatively low compared to treatment with other T cell therapies or treatment of other diseases or malignancies (e.g. a CR in a less than or less than about 60%, less than about 50% or less than about 45% of the subjects so treated) and / or in which the subject is not responsive to treatment with the immunomodulatory compound, such as a structural or functional analog or derivative of thalidomide and / or an inhibitor of E3 ubiquitin ligase, e.g. lenalidomide, Compound 1 or Compound 2, alone.

[0190] In some embodiments, the combination therapy provided herein is for use in a subject having a cancer in which after initiation of administration of the T cell therapy, such as a composition including cells for adoptive cell therapy, e.g., CAR-expressing T cells, the subject has relapsed following remission after treatment with the T cell therapy. In some embodiments, subjects that have relapsed following such remission are administered an immunomodulatory compound, such as a structural or functional analog or derivative of thalidomide and / or an inhibitor of E3 ubiquitin ligase, e.g. lenalidomide, Compound 1 or Compound 2. In some embodiments, the combination therapy provided herein is for use in a subject having a disease or condition, e.g. cancer, in which the amount of the immunomodulatory compound administered is insufficient, as a single agent and / or in the absence of administration of the T cell therapy, to ameliorate, reduce or prevent the disease or condition or a symptom or outcome thereof, such as is insufficient to ameliorate, reduce or prevent the disease or condition in the subject or a symptom or outcome thereof. In some embodiments, the method thereby reduces or ameliorates a symptom or outcome or burden of the disease or condition to a degree that is greater than the combination of (i) the degree of reduction or amelioration effected by the administration of the immunomodulatory agent alone, optionally on average in a population of subjects having the disease or condition, and (ii) the degree of reduction or amelioration by the administration of the T cell therapy alone, optionally on average in a population of subjects having the disease or condition. In some embodiment, the method reduces or ameliorates such symptoms, outcomes or burdens of the disease, e.g. compared to on average in a population of subjects having the disease or condition, by greater than or greater than about 1.5-fold, 2.0-fold, 3.0-fold, 4.0-fold, 5.0-fold, 6.0-fold, 7.0-fold, 8.0-fold, 9.0-fold, 10.0 fold, 20.0-fold, 30.0-fold, 40.0-fold, 50.0- fold or more.

[0191] In some embodiments, the provided combination therapy is used in connection with treating certain diseases or conditions, e.g., cancer, in which optimal stimulation of arecombinant antigen receptor, e.g. CAR-T cell, is difficult to achieve and / or is not consistently observed. In some embodiments, less than optimal stimulation may be a result of low or inaccessible levels of disease antigen in vivo, e.g. at or on the tumor. In some embodiments, certain cancers, such as NHL, e.g. high-risk or aggressive NHL, such as DLBCL, and / or chronic lymphocytic leukemia (CLL) can be associated with defects in or reduction in intrinsic T cell functionality, which, in some cases, is influenced by the disease itself. For example, the pathogenesis of many cancers, such as CLL and NHL, e.g. DLBCL, can be associated with immunodeficiency, leading to promotion of tumor growth and immune evasion, such as due to immunosuppression of T cells, e.g. driven by one or more factors in the tumormicroenvironment. In some cases, alleviating intrinsic T cell defects obtained from cancers of such patients for use in connection with adoptive cell therapy could provide for more potent responses to adoptive T cell therapy, e.g. CAR-T cell therapy. In some cases, less than optimal stimulation can be due to differences in expression level of the CAR on engineered T cells administered to the subject. In any of such embodiments, administration of theimmunomodulatory compound, such as a structural or functional analog or derivative of thalidomide and / or an inhibitor of E3 ubiquitin ligase, e.g., lenalidomide, Compound 1 or Compound 2, can enhance the stimulation or activity of such T cells in vivo in the subject.

[0192] In some embodiments of the provided methods, one or more properties of administered genetically engineered cells can be improved or increased or greater compared to administered cells of a reference composition, such as increased or longer expansion and / or persistence of such administered cells in the subject or an increased or greater recall response upon restimulation with antigen. In some embodiments, the increase can be at least a 1.2-fold, at least l.5-fold, at least 2-fold, at last 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 lO-fold increase in such property or feature compared to the same property or feature upon administration of a reference cell composition.In some embodiments, the increase in one or more of such properties or features can be observed or is present within 7 days, 14 days, 21 days, within one months, two months, three months, four months, five months, six months, or 12 months after administration of the genetically engineered cells and the initiation of administration of the immunomodulatory compound, such as a structural or functional analog or derivative of thalidomide and / or an inhibitor of E3 ubiquitin ligase, e.g., lenalidomide or Compound 1.

[0193] In some embodiments, a reference cell composition can be a composition of T cells from the blood of a subject not having or not suspected of having the cancer or is a population of T cells obtained, isolated, generated, produced, incubated and / or administered under the same or substantially the conditions, except not having been incubated or administered in the presence of the immunomodulatory compound. In some embodiments, the reference cell composition contains genetically engineered cells that are substantially the same, including expression of the same recombinant receptor, e.g., CAR. In some aspects, such T cells are treated identically or substantially identically, such as manufactured similarly, formulated similarly, administered in the same or about the same dosage amount and other similar factors.

[0194] In some embodiments, the provided methods result in genetically engineered cell with increased persistence and / or better potency in a subject to which it is administered. In some embodiments, the persistence of genetically engineered cells, such as CAR-expressing T cells, in the subject is greater as compared to that which would be achieved by alternative methods, such as those involving administration of a reference cell composition, e.g.administration of the T cell therapy but in the absence of administration of theimmunomodulatory compound. In some embodiments, the persistence is increased at least or about at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, lO-fold, 20- fold, 30-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, lOO-fold or more.

[0195] In some embodiments, the degree or extent of persistence of administered cells can be detected or quantified after administration to a subject. For example, in some aspects, quantitative PCR (qPCR) is used to assess the quantity of cells expressing the recombinant receptor (e.g., CAR-expressing cells) in the blood or serum or organ or tissue (e.g., disease site) of the subject. In some aspects, persistence is quantified as copies of DNA or plasmid encoding the receptor, e.g., CAR, per microgram of DNA, or as the number of receptor-expressing, e.g., CAR-expressing, cells per microliter of the sample, e.g., of blood or serum, or per total number of peripheral blood mononuclear cells (PBMCs) or white blood cells or T cells per microliter of the sample. In some embodiments, flow cytometric assays detecting cells expressing the receptor generally using antibodies specific for the receptors also can be performed. Cell-based assays may also be used to detect the number or percentage of functional cells, such as cells capable of binding to and / or neutralizing and / or inducing responses, e.g., cytotoxic responses, against cells of the disease or condition or expressing the antigen recognized by the receptor. In any of such embodiments, the extent or level of expression of another marker associated withthe recombinant receptor (e.g. CAR-expressing cells) can be used to distinguish the administered cells from endogenous cells in a subject.

[0196] Also provided are methods for engineering, preparing, and producing the cells, compositions containing the cells and / or immunomodulatory compound, and kits and devices containing and for using, producing and administering the cells and / or immunomodulatory compound, such as in accord with the provided combination therapy methods.

[0197] All publications, including patent documents, scientific articles and databases, referred to in this application are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication were individually incorporated by reference. If a definition set forth herein is contrary to or otherwise inconsistent with a definition set forth in the patents, applications, published applications and other publications that are hereinincorporated by reference, the definition set forth herein prevails over the definition that is incorporated herein by reference.

[0198] The section heading used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.I. COMBINATION THERAPY

[0199] Provided herein are methods for combination therapy for treating a disease or disorder, e.g. a cancer or proliferative disease, that includes administering to a subject a combination therapy of 1) an immunomodulatory compound, such as a structural or functional analog or derivative of thalidomide and / or an inhibitor of E3 ubiquitin ligase, e.g. lenalidomide or Compound 1, and Compound 2) a T cell therapy, e.g. CAR-expressing cell, e.g. T cells. In particular embodiments, the immunomodulatory compound is an inhibitor of E3 ubiquitin ligase. In some embodiments, the T cell therapy is an adoptive immune cell therapy comprising T cells that specifically recognize and / or target an antigen associated with a disease or disorder, e.g. a cancer or proliferative disease. Also provided are combinations and articles of manufacture, such as kits, that contain a composition comprising the T cell therapy and / or a composition comprising the immunomodulatory compound, and uses of such compositions and combinations to treat or prevent diseases, conditions, and disorders, including cancers.

[0200] In some embodiments, such methods can include administration of theimmunomodulatory compound, such as a structural or functional analog or derivative of thalidomide and / or an inhibitor of E3 ubiquitin ligase, e.g. lenalidomide, Compound 1 or Compound 2, prior to, simultaneously with, during, during the course of (including once and / orperiodically during the course of), and / or subsequently to, the administration (e.g., initiation of administration) of the T cell therapy (e.g. CAR-expressing T cells). In some embodiments, the administrations can involve sequential or intermittent administrations of the immunomodulatory compound and T cell therapy.

[0201] In some embodiments, the cell therapy is adoptive cell therapy. In someembodiments, the cell therapy is or comprises a tumor infiltrating lymphocytic (TIL) therapy, a transgenic TCR therapy or a recombinant-receptor expressing cell therapy (optionally T cell therapy), which optionally is a chimeric antigen receptor (CAR)-expressing cell therapy. In some embodiments, the therapy is a B cell targeted therapy. In some embodiments, the therapy targets B cell maturation antigen (BCMA). In some embodiments, the therapy targets CD19. In some embodiments, the cells and dosage regimens for administering the cells can include any as described in the following subsection A under“Administration of T Cell therapy.”

[0202] In some embodiments, the immunomodulatory compound potentiates T-cell functionality. In some embodiments, the immunomodulatory compound drives anti-myeloma activity. In some embodiments, the immunomodulatory compound alters the suppressive microenvironment.

[0203] 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 E3 ubiquitin ligase. In some embodiments, the immunomodulatory compound is lenalidomide or a compound with the same or similar properties of lenalidomide, including analogs or derivatives, a stereoisomer of lenalidomide or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. In some embodiments, the immunomodulatory compound is Compound 1 as described or a compound with the same or similar properties of Compound 1, including analogs or derivatives, a stereoisomer ofCompound 1 or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. In some embodiments, the immunomodulatory compound is Compound 1 as described or a compound with the same or similar properties of Compound 1, including analogs or derivatives, a stereoisomer of Compound 1 or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. In some embodiments, the dosage regimens for administering the immunomodulatory compound can include any as described in the following subsection B under“Administration of the Immunomodulatory Compound.”

[0204] In some embodiments, the T cell therapy (e.g. CAR-expressing T cells) and immunomodulatory compound are provided as pharmaceutical compositions for administrationto the subject. In some embodiments, the pharmaceutical compositions contain therapeutically effective amounts of one or both of the agents for combination therapy, e.g., T cells for adoptive cell therapy and an immunomodulatory compound as described. 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 dosage forms appropriate for each route of administration.

[0205] In some embodiments, the combination therapy, which includes administering the T cell therapy, including engineered cells, such as CAR-T cell therapy, and theimmunomodulatory compound is administered to a subject or patient having a disease or condition to be treated (e.g. cancer) or at risk for having the disease or condition (e.g. cancer).In some aspects, the methods treat, e.g., ameliorate one or more symptom of, the disease or condition, such as by lessening tumor burden in a cancer expressing an antigen recognized by the immunotherapy or immunotherapeutic agent, e.g. recognized by an engineered T cell.

[0206] In some embodiments, the disease or condition that is treated can be any in which expression of an antigen is associated with and / or involved in the etiology of a disease condition or disorder, e.g. causes, exacerbates or otherwise is involved in such disease, condition, or disorder. Exemplary diseases and conditions can include diseases or conditions associated with malignancy or transformation of cells (e.g. cancer), autoimmune or inflammatory disease, or an infectious disease, e.g. caused by bacterial, viral or other pathogens. Exemplary antigens, which include antigens associated with various diseases and conditions that can be treated, include any of antigens described herein. In particular embodiments, the recombinant receptor expressed on engineered cells of a combination therapy, including a chimeric antigen receptor or transgenic TCR, specifically binds to an antigen associated with the disease or condition.

[0207] In some embodiments, the disease or condition is a tumor, such as a solid tumor, lymphoma, leukemia, blood tumor, metastatic tumor, or other cancer or tumor type.

[0208] In some embodiments, the cancer or proliferative disease is a B cell malignancy or hematological malignancy. In some embodiments the cancer or proliferative disease is lymphoblastic leukemia (ALL), non-Hodgkin’s lymphoma (NHL), or chronic lymphocytic leukemia (CLL). In some embodiments, the cancer is CLL. In some embodiments, the methods can be used to treat a myeloma, a lymphoma or a leukemia. In some embodiments, the methods can be used to treat a non-Hodgkin lymphoma (NHL), an acute lymphoblastic leukemia (ALL), a chronic lymphocytic leukemia (CLL), a diffuse large B-cell lymphoma (DLBCL), acutemyeloid leukemia (AML), or a myeloma, e.g., a multiple myeloma (MM). In some embodiments, the methods can be used to treat a MM or a DBCBL.

[0209] In some embodiments, the antigen associated with the disease or disorder is selected from the group consisting of ROR1, B cell maturation antigen (BCMA), Her2, Ll-CAM, CD19, CD20, CD22, mesothelin, CEA, and hepatitis B surface antigen, anti-folate receptor, CD23, CD24, CD30, CD33, CD38, CD44, EGFR, EGP-2, EGP-4, EPHa2, ErbB2, 3, or 4, erbB dimers, EGFR vIII, FBP, FCRL5, FCRH5, fetal acethycholine e receptor, GD2, GD3, HMW-MAA, IL- 22R-alpha, IL-l3R-alpha2, kdr, kappa light chain, Lewis Y, Ll-cell adhesion molecule, (Ll- CAM), Melanoma-associated antigen (MAGE)-Al, MAGE- A3, MAGE-A6, Preferentially expressed antigen of melanoma (PRAME), survivin, EGP2, EGP40, TAG72, B7-H6, IL-13 receptor a2 (IL-l3Ra2), CA9, GD3, HMW-MAA, CD171, G250 / CAIX, HLA-AI MAGE Al, HLA-A2 NY-ESO-l, PSCA, folate receptor-a, CD44v6, CD44v7 / 8, avb6 integrin, 8H9, NCAM, VEGF receptors, 5T4, Foetal AchR, NKG2D ligands, CD44v6, dual antigen, and an antigen associated with a universal tag, a cancer-testes antigen, mesothelin, MUC1, MUC16, PSCA, NKG2D Ligands, NY-ESO-l, MART-l, gplOO, G Protein Coupled Receptor 5D (GPCR5D), oncofetal antigen, ROR1, TAG72, VEGF-R2, carcinoembryonic antigen (CEA), prostate specific antigen, PSMA, Her2 / neu, estrogen receptor, progesterone receptor, ephrinB2, CD123, c-Met, GD-2, O-acetylated GD2 (OGD2), CE7, Wilms Tumor 1 (WT-l), a cyclin, cyclin A2, CCL-l, CD138, and a pathogen- specific antigen. In some embodiments, the antigen is associated with or is a universal tag.

[0210] In some embodiments the cancer or proliferative disease expresses BCMA. In some embodiments, the provided methods employ a recombinant receptor-expressing T cell (e.g. CAR-T cell) that targets BCMA.

[0211] In some embodiments the cancer or proliferative disease expresses CD19. In some embodiments, the provided methods employ a recombinant receptor-expressing T cell (e.g. CAR-T cell) that targets CD 19.

[0212] In some embodiments, the methods can be used to treat a non-hematologic cancer, such as a solid tumor. In some embodiments, the methods can be used to treat a bladder, lung, brain, melanoma (e.g. small-cell lung, melanoma), breast, cervical, ovarian, colorectal, pancreatic, endometrial, esophageal, kidney, liver, prostate, skin, thyroid, or uterine cancers. In some embodiments, the cancer or proliferative disease is cancer is a pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal 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 cancers, CNS cancers, brain tumors, bone cancer, or soft tissue sarcoma.

[0213] In some embodiments, the disease or condition is an infectious disease or condition, such as, but not limited to, viral, retroviral, bacterial, and protozoal infections,immunodeficiency, Cytomegalovirus (CMV), Epstein-Barr virus (EBV), adenovirus, BK polyomavirus. In some embodiments, the disease or condition is an autoimmune orinflammatory disease or condition, such as 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 a disease or condition associated with transplant.

[0214] For the prevention or treatment of disease, the appropriate dosage ofimmunomodulatory compound (e.g., lenalidomide, Compound 1 or Compound 2) and / or immunotherapy, such as a T cell therapy (e.g. CAR-expressing T cells), may depend on the type of disease to be treated, the particular immunomodulatory compound, cells and / or recombinant receptors expressed on the cells, the severity and course of the disease, route of administration, whether the immunomodulatory compound and / or the T cell therapy are administered for preventive or therapeutic purposes, previous therapy, frequency of administration, the subject’s clinical history and response to the cells, and the discretion of the attending physician. The compositions and cells are in some embodiments suitably administered to the subject at one time or over a series of treatments. Exemplary dosage regimens and schedules for the provided combination therapy are described.

[0215] In some embodiments, the T cell therapy and the immunomodulatory compound are administered as part of a further combination treatment, which can be administeredsimultaneously with or sequentially to, in any order, another therapeutic intervention. In some contexts, the T cell therapy, e.g. engineered T cells, such as CAR-expressing T cells, are co administered with another therapy sufficiently close in time such that the T cell therapy enhances the effect of one or more additional therapeutic agents, or vice versa. In some embodiments, the cells are administered prior to the one or more additional therapeutic agents.In some embodiments, the T cell therapy, e.g. engineered T cells, such as CAR-expressing T cells, are administered after the one or more additional therapeutic agents. In someembodiments, the combination therapy methods further include a lymphodepleting therapy, such as administration of a chemotherapeutic agent. In some embodiments, the combination therapy further comprises administering another therapeutic agent, such as an anti-cancer agent, acheckpoint inhibitor, or another immune modulating agent. Uses include uses of thecombination therapies in such methods and treatments, and uses of such compositions in the preparation of a medicament in order to carry out such combination therapy methods. In some embodiments, the methods and uses thereby treat the disease or condition or disorder, such as a cancer or proliferative disease, in the subject.

[0216] Prior to, during or following administration of the immunotherapy (e.g. T cell therapy, such as CAR-T cell therapy) and / or an immunomodulatory compound, the biological activity of the T cell therapy, e.g. the biological activity of the engineered cell populations, in some embodiments is measured, e.g., by any of a number of known methods. Parameters to assess include the ability of the engineered cells to destroy target cells, persistence and other measures of T cell activity, such as measured using any suitable method known in the art, such as assays described further below in Section III. In some embodiments, the biological activity of the cells, e.g., T cells administered for the T cell based therapy, is measured by assaying cytotoxic cell killing, expression and / or secretion of one or more cytokines, proliferation or expansion, such as upon restimulation with antigen. In some aspects the biological activity is measured by assessing the disease burden and / or clinical outcome, such as reduction in tumor burden or load. In some embodiments, administration of one or both agents of the combination therapy and / or any repeated administration of the therapy, can be determined based on the results of the assays before, during, during the course of or after administration of one or both agents of the combination therapy.

[0217] In some embodiments, the combined effect of the immunomodulatory compound in combination with the cell therapy can be synergistic compared to treatments involving only the immunomodulatory compound or monotherapy with the cell therapy. For example, in some embodiments, the methods provided herein result in an increase or an improvement in a desired therapeutic effect, such as an increased or an improvement in the reduction or inhibition of one or more symptoms associated with cancer.

[0218] In some embodiments, the immunomodulatory compound increases the expansion or proliferation of the engineered T cells, such as CAR T-Cells. In some embodiments, the increase in expansion or proliferation is observed in vivo upon administration to a subject. In some embodiments, the increase in the number of engineered T cells, e.g. CAR-T cells, is increased by greater than or greater than about l.2-fold, 1.5-fold, 2.0-fold, 3.0-fold, 4.0-fold, 5.0-fold, 6.0- fold, 7.0-fold, 8.0-fold, 9.0-fold, 10.0 fold or more.A. ADMINISTRATION OF T CELL THERAPY

[0219] 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 a T cell therapy ( e.g . CAR-expressing T cells). Administration of such therapies can be initiated prior to, subsequent to, simultaneously with administration of one or more immunomodulatory compound as described.

[0220] In some embodiments, the cell-based therapy is or comprises administration of cells, such as immune cells, for example T cell or NK cells, that target a molecule expressed on the surface of a lesion, such as a tumor or a 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 a chimeric antigen receptor (CAR). In some embodiments, the cells are autologous to the subject. In some embodiments, the cells are allogeneic to the subject.

[0221] In some aspects, the T cell therapy is or comprises a tumor infiltrating lymphocytic (TIL) therapy, a transgenic TCR therapy or a T cell therapy comprising genetically engineered cells, such as a recombinant-receptor expressing cell therapy. In some embodiments, the recombinant receptor specifically binds to a ligand, such as one associated with a disease or condition, e.g. associated with or expressed on a cell of a tumor or cancer. In someembodiments, the T cell therapy includes administering T cells engineered to express a chimeric antigen receptor (CAR).

[0222] In some embodiments, the provided cells express and / or are engineered to express receptors, such as recombinant receptors, including those containing ligand-binding domains or binding fragments thereof, and T cell receptors (TCRs) and components thereof, and / or functional non-TCR antigen receptors, such as chimeric antigen receptors (CARs). In some embodiments, the recombinant receptor contains an extracellular ligand-binding domain that specifically binds to an antigen. In some embodiments, the recombinant receptor is a CAR that contains an extracellular antigen-recognition domain that specifically binds to an antigen. In some embodiments, the ligand, such as an antigen, is a protein expressed on the surface of cells. 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, like a TCR, is recognized on the cell surface in the context of a major histocompatibility complex (MHC) molecule.

[0223] Among the engineered cells, including engineered cells containing recombinant receptors, are described in Section II below. Exemplary recombinant receptors, including CARs and recombinant TCRs, as well as methods for engineering and introducing the receptors into cells, include those described, for example, in international patent application publication numbers W0200014257, WO2013126726, WO2012 / 129514, WO2014031687,WO2013 / 166321, W02013 / 071154, W02013 / 123061, WO2016 / 0046724, WO2016 / 014789, WO2016 / 090320, W02016 / 094304, WO2017 / 025038, WO2017 / 173256, U.S. patent application publication numbers US2002131960, US2013287748, US20130149337, U.S. PatentNos. 6,451,995, 7,446,190, 8,252,592, 8,339,645, 8,398,282, 7,446,179, 6,410,319, 7,070,995,7,265,209, 7,354,762, 7,446,191, 8,324,353, 8,479,118, and 9,765,342, and European patent application number EP2537416, and / or those described by Sadelain et al, Cancer Discov., 3(4): 388-398 (2013); Davila et al, PLoS ONE 8(4): e6l338 (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 a CAR as described in U.S. Patent No.:7,446,190, and those described in International Patent Application Publication No.:WO / 2014055668 Al.

[0224] In some embodiments, the antigen is or includes anb6 integrin (avb6 integrin), B cell maturation antigen (BCMA), B7-H3, B7-H6, carbonic anhydrase 9 (CA9, also known as CAIX or G250), a cancer-testis antigen, cancer / testis antigen 1B (CTAG, also known as NY-ESO-l and LAGE-2), carcinoembryonic antigen (CEA), a cyclin, cyclin A2, C-C Motif ChemokineLigand 1 (CCL-l), 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), type III epidermal growth factor receptor mutation (EGFR vIII), epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), ephrinB2, ephrine receptor A2 (EPHa2), estrogen receptor, Fc receptor like 5 (FCRL5; also known as Fc receptor homolog 5 or FCRH5), fetal acetylcholine receptor (fetal AchR), a folate binding protein (FBP), folate receptor alpha, ganglioside GD2, O-acetylated GD2 (OGD2), ganglioside GD3, glycoprotein 100 (gplOO), glypican-3 (GPC3), G Protein Coupled Receptor 5D (GPCR5D), Her2 / neu (receptor tyrosine kinase erb-B2), Her3 (erb-B3), Her4 (erb-B4), erbB dimers, Human high molecular weight- melanoma-associated antigen (HMW-MAA), hepatitis B surface antigen, Human leukocyte antigen Al (HLA-A1), Human leukocyte antigen A2 (HLA-A2), IL-22 receptor alpha(IL-22Ra), IL-13 receptor alpha 2 (IL-l3Ra2), kinase insert domain receptor (kdr), kappa lightchain, Ll cell adhesion molecule (Ll-CAM), CE7 epitope of Ll-CAM, Leucine Rich Repeat Containing 8 Family Member A (LRRC8A), Lewis Y, Melanoma-associated antigen (MAGE)- Al, MAGE-A3, MAGE-A6, MAGE-A10, mesothelin (MSLN), c-Met, murine cytomegalovirus (CMV), mucin 1 (MUC1), MUC16, natural killer group 2 member D (NKG2D) ligands, melan A (MART-l), neural cell adhesion molecule (NCAM), oncofetal antigen, Preferentially expressed antigen of melanoma (PRAME), progesterone receptor, a prostate specificantigen, prostate stem cell antigen (PSCA), prostate specific membrane antigen (PSMA), Receptor 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, 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-l), a pathogen-specific or pathogen-expressed antigen, or an antigen associated with a universal tag, and / or biotinylated molecules, and / or molecules expressed by HIV, HCV, HBV or other pathogens. Antigens targeted by the receptors in some embodiments include antigens associated with a B cell malignancy, such as any of a number of known B cell marker. In some embodiments, the antigen is or includes CD20, CD19, CD22, ROR1, CD45, CD21, CD5, CD33, Igkappa, Iglambda, CD79a, CD79b or CD30.

[0225] In some embodiments, the antigen is or includes a pathogen- specific or pathogen- expressed antigen. In some embodiments, the antigen is a viral antigen (such as a viral antigen from HIV, HCV, HBV, etc.), bacterial antigens, and / or parasitic antigens.

[0226] In some embodiments, the combination therapy includes administration to a subject cells, e.g. T cells, expressing a recombinant receptor that specifically recognize and / or target an antigen associated with the cancer and / or present on a universal tag . In some embodiments, the antigen recognized or targeted by the T cells is ROR1, B cell maturation antigen (BCMA), carbonic anhydrase 9 (CAIX), tEGFR, Her2 / neu (receptor tyrosine kinase erbB2), Ll-CAM,CD 19, 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 dimers, EGFR vIII, folate binding protein (FBP), FCRL5, FCRH5, fetal acetylcholine receptor, GD2, GD3, HMW-MAA,IL-22R-alpha, IL-l3R-alpha2, kinase insert domain receptor (kdr), kappa light chain, Lewis Y,Ll-cell adhesion molecule, (Ll-CAM), Melanoma-associated antigen (MAGE)-Al, MAGE-A3,MAGE-A6, Preferentially expressed antigen of melanoma (PRAME), survivin, TAG72, B7-H6,IL-13 receptor alpha 2 (IL-l3Ra2), 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 receptors, 5T4, Foetal AchR, NKG2D ligands, CD44v6, dual antigen, a cancer-testes antigen, mesothelin, murine CMV, mucin 1 (MUC1), MUC16, PSCA, NKG2D, NY-ESO-l, MART-l, gplOO, G Protein Coupled Receptor 5D (GPCR5D), oncofetal antigen, ROR1,TAG72, VEGF-R2, carcinoembryonic antigen (CEA), Her2 / neu, estrogen receptor, progesterone receptor, ephrinB2, CD123, c-Met, GD-2, O-acetylated GD2 (OGD2), CE7, Wilms Tumor 1 (WT-l), a cyclin, cyclin A2, CCL-l, CD138, optionally a human antigen of any of the foregoing; a pathogen- specific antigen.

[0227] Methods for administration of engineered cells for adoptive cell therapy are known and may be used in connection with the provided methods and compositions. For example, adoptive T cell therapy methods are described, e.g., in US Patent Application Publication No. 2003 / 0170238 to Gruenberg et al; US Patent No. 4,690,915 to Rosenberg; Rosenberg (2011) Nat Rev Clin Oncol. 8(l0):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): e6l338.

[0228] In some embodiments, the cell therapy, e.g., adoptive T cell therapy, is carried out by autologous transfer, in which the cells are isolated and / or otherwise prepared from the subject who is to receive the cell therapy, or from a sample derived from such a subject. Thus, in some aspects, the cells are derived from a subject, e.g., patient, in need of a treatment and the cells, following isolation and processing are administered to the same subject.

[0229] In some embodiments, the cell therapy, e.g., adoptive T cell therapy, is carried out by allogeneic transfer, in which the cells are isolated and / or otherwise prepared from a subject other than a subject who is to receive or who ultimately receives the cell therapy, e.g., a first subject.In such embodiments, the cells then are administered to a different subject, e.g., a second subject, of the same species. 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.

[0230] In certain embodiments, the cells, or individual populations of sub-types of cells, are administered to the subject at a range of about one million to about 100 billion cells and / or that amount of cells per kilogram of body weight, such as, e.g., 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 arange defined by any two of the foregoing 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 the foregoing values), and in some cases about 100 million cells 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 in between these ranges and / or per kilogram of body weight. Dosages may vary depending on attributes particular to the disease or disorder and / or patient and / or other treatments.

[0231] In some embodiments, for example, where the subject is a human, the dose includes fewer than about 1 x 108total recombinant receptor (e.g., CAR)-expressing cells, T cells, or peripheral blood mononuclear cells (PBMCs), e.g., in the range of about 1 x 106to 1 x 108such cells, such as 2 x 106, 5 x 106, 1 x 107, 5 x 107, or 1 x 108or total such cells, or the range between any two of the foregoing values.

[0232] 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. Dosing and administration may depend in part on the schedule of administration of the immunomodulatory compound, which can be administered prior to, subsequent to and / or simultaneously with initiation of administration of the T cell therapy. Various dosing schedules of the T cell therapy include but are not limited to single or multiple administrations over various time-points, bolus administration, and pulse infusion.I. Compositions and formulations

[0233] In some embodiments, the dose of cells of the T cell therapy, such a T cell therapy comprising cells engineered with a recombinant antigen receptor, e.g. CAR or TCR, is provided as a composition or formulation, such as a pharmaceutical composition or formulation. Such compositions can be used in accord with the provided methods, such as in the prevention or treatment of diseases, conditions, and disorders.

[0234] In some embodiments, the T cell therapy, 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 the particular cell or agent and / or by the method ofadministration. Accordingly, there are a variety of suitable formulations. For example, thepharmaceutical composition can contain preservatives. 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 mixtures thereof are typically present in an amount of about 0.0001% to about 2% by weight of the totalcomposition. Carriers are described, e.g., by Remington's Pharmaceutical Sciences l6th edition, Osol, A. Ed. (1980). Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as 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 dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and / or non-ionic surfactants such as polyethylene glycol (PEG).

[0235] Buffering agents in some aspects are included in the compositions. 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 mixtures thereof are typically present in an amount of about 0.001% to about 4% by weight of the total composition. Methods for preparing administrable pharmaceutical compositions are known. Exemplary methods are described in more detail in, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins; 21 st ed. (May 1, 2005).

[0236] The formulations can include aqueous solutions. The formulation or composition may also contain more than one active ingredient useful for the particular indication, disease, or condition being prevented or treated with the cells or agents, where the respective activities do not adversely affect one another. Such active ingredients are suitably present in combination in amounts that are effective for the purpose intended. Thus, in some embodiments, the pharmaceutical composition further includes other pharmaceutically active agents or drugs, such as chemotherapeutic agents, e.g., asparaginase, busulfan, carboplatin, cisplatin, daunorubicin,doxorubicin, fluorouracil, gemcitabine, hydroxyurea, methotrexate, paclitaxel, rituximab, vinblastine, vincristine, etc.

[0237] The pharmaceutical composition in some embodiments contains cells in amounts effective to treat or prevent the disease or condition, such as a therapeutically effective or prophylactically effective amount. Therapeutic or prophylactic efficacy in some embodiments is monitored by periodic assessment of treated subjects. For repeated administrations over several days or longer, depending on the condition, the treatment is repeated until a desired suppression of disease symptoms occurs. However, other dosage regimens may be useful and can 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.

[0238] The cells may be administered using standard administration techniques,formulations, and / or devices. Provided are formulations and devices, such as syringes and vials, for storage and administration of the compositions. With respect to cells, administration can be autologous or heterologous. For example, immunoresponsive cells or progenitors can be obtained from one subject, and administered to the same subject or a different, compatible subject. Peripheral blood derived immunoresponsive cells or their progeny (e.g., in vivo, ex vivo or in vitro derived) can be administered via localized injection, including catheteradministration, systemic injection, localized injection, intravenous injection, or parenteral administration. When administering a therapeutic composition (e.g., a pharmaceutical composition containing a genetically modified immunoresponsive cell), it will generally be formulated in a unit dosage injectable form (solution, suspension, emulsion).

[0239] Formulations include those for oral, intravenous, intraperitoneal, subcutaneous, pulmonary, transdermal, intramuscular, intranasal, buccal, sublingual, or suppositoryadministration. In some embodiments, the agent or cell populations are administeredparenterally. The term“parenteral,” as used herein, includes intravenous, intramuscular, subcutaneous, rectal, vaginal, and intraperitoneal administration. In some embodiments, the agent or cell populations are administered to a subject using peripheral systemic delivery by intravenous, intraperitoneal, or subcutaneous injection.

[0240] Compositions in some embodiments are provided as sterile liquid preparations, e.g., isotonic aqueous solutions, suspensions, emulsions, dispersions, or viscous compositions, which may in some aspects be buffered to a selected pH. Liquid preparations are normally easier to prepare than gels, other viscous compositions, and solid compositions. Additionally, liquidcompositions are somewhat more convenient to administer, especially by injection. Viscous compositions, on the other hand, can be formulated within the appropriate viscosity range to provide longer contact periods with specific tissues. Liquid or viscous compositions can comprise carriers, which can be a solvent or dispersing medium containing, for example, water, saline, phosphate buffered saline, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol) and suitable mixtures thereof.

[0241] Sterile injectable solutions can be prepared by incorporating the cells in a solvent, such as in admixture with a suitable carrier, diluent, or excipient such as sterile water, physiological saline, glucose, dextrose, or the like. The compositions can also be lyophilized. The compositions can contain auxiliary substances such as wetting, dispersing, or emulsifying agents (e.g., methylcellulose), pH buffering agents, gelling or viscosity enhancing additives, preservatives, flavoring agents, colors, and the like, depending upon the route of administration and the preparation desired. Standard texts may in some aspects be consulted to prepare suitable preparations.

[0242] Various additives which enhance the stability and sterility of the compositions, including antimicrobial preservatives, antioxidants, chelating agents, and buffers, can be added. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0243] The formulations to be used for in vivo administration are generally sterile. Sterility may be readily accomplished, e.g., by filtration through sterile filtration membranes.

[0244] For the prevention or treatment of disease, the appropriate dosage may depend on the type of disease to be treated, the type of agent or agents, the type of cells or recombinant receptors, the severity and course of the disease, whether the agent or cells are administered for preventive or therapeutic purposes, previous therapy, the subject's clinical history and response to the agent or the cells, and the discretion of the attending physician. The compositions are in some embodiments suitably administered to the subject at one time or over a series of treatments.

[0245] In some cases, the cell therapy is administered as a single pharmaceutical composition comprising the cells. In some embodiments, a given dose is administered by a single bolus administration of the cells or agent. In some embodiments, it is administered bymultiple bolus administrations of the cells or agent, for example, over a period of no more than 3 days, or by continuous infusion administration of the cells or agent.2. Dosage Schedule and Administration

[0246] In some embodiments, a dose of cells is administered to subjects in accord with the provided combination therapy methods. In some embodiments, the size or timing of the doses is determined as a function of the particular disease or condition in the subject. One may empirically determine the size or timing of the doses for a particular disease in view of the provided description.

[0247] In certain embodiments, the cells, or individual populations of sub-types of cells, are administered to the subject at a range of about 0.1 million to about 100 billion cells and / or that amount of cells per kilogram of body weight of the subject, such as, e.g., 0.1 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), 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), 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 the foregoing values), and in some cases about 100 million cells 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 in between these ranges and / or per kilogram of body weight of the subject. Dosages may vary depending on attributes particular to the disease or disorder and / or patient and / or other treatments. In some embodiments, such values refer to numbers of recombinant receptor-expressing cells; in other embodiments, they refer to number of T cells or PBMCs or total cells administered.

[0248] In some embodiments, the cell therapy comprises administration of a dose comprising a number of cell from or from about 1 x 105to 1 x 108total recombinant receptor expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), from or from about 5 x 105to 1 x 107total recombinant receptor-expressing cells, total T cells, or totalperipheral blood mononuclear cells (PBMCs) or from or from about 1 x 106to 1 x 107total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), each inclusive. In some embodiments, the cell therapy comprises administration of a dose of cells comprising a number of cells at least or about at least 1 x 105total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), such at least or at least 1 x 106, at least or about at least 1 x 107, at least or about at least 1 x 108of such cells.

[0249] In some embodiments, for example, where the subject is a human, the dose includes fewer than about 5 x 108total recombinant receptor (e.g., CAR)-expressing cells, T cells, or peripheral blood mononuclear cells (PBMCs), e.g., in the range of about 1 x 106to 5 x 108such cells, such as 2 x 106, 5 x 106, 1 x 107, 5 x 107, 1 x 108, or 5 x 108total such cells, or the range between any two of the foregoing values.

[0250] In some embodiments, the number is with reference to the total number of CD3+ or CD8+, in some cases also recombinant receptor-expressing (e.g. CAR+) cells. In some embodiments, the cell therapy comprises administration of a dose comprising a number of cell from or from about 1 x 105to 1 x 108CD3+ or CD8+ total T cells or CD3+ or CD8+recombinant receptor-expressing cells, from or from about 5 x 105to 1 x 107CD3+ or CD8+ total T cells or CD3+ or CD8+ recombinant receptor-expressing cells, or from or from about 1 x 106to 1 x 107CD3+ or CD8+ total T cells or CD3+ or CD8+recombinant receptor-expressing cells, each inclusive. In some embodiments, the cell therapy comprises administration of a dose comprising a number of cell from or from about 1 x 105to 1 x 108total CD3+ / CAR+ orCD8+ / CAR+ cells, from or from about 5 x 105to 1 x 107total CD3+ / CAR+ or CD8+ / CAR+ cells, or from or from about 1 x 106to 1 x 107total CD3+ / CAR+ or CD8+ / CAR+ cells, each inclusive.

[0251] In some embodiments, the dose of genetically engineered cells comprises from or from about 1 x 105to 5 x 108total CAR-expressing T cells, 1 x 105to 2.5 x 108total CAR- expressing T cells, 1 x 105to 1 x 108total CAR-expressing T cells, 1 x 105to 5 x 107total CAR- expressing T cells, 1 x 105to 2.5 x 107total CAR-expressing T cells, 1 x 105to 1 x 107totalCAR-expressing T cells, 1 x 105to 5 x 106total CAR-expressing T cells, 1 x 105to 2.5 x 106total CAR-expressing T cells, 1 x 105to 1 x 106total CAR-expressing T cells, 1 x 106to 5 x 108total CAR-expressing T cells, 1 x 106to 2.5 x 108total CAR-expressing T cells, 1 x 106to 1 x108total CAR-expressing T cells, 1 x 106to 5 x 107total CAR-expressing T cells, 1 x 106to 2.5 x 107total CAR-expressing T cells, 1 x 106to 1 x 107total CAR-expressing T cells, 1 x 106to 5x 106total CAR-expressing T cells, 1 x 106to 2.5 x 106total CAR-expressing T cells, 2.5 x106to 5 x 108total CAR-expressing T cells, 2.5 x 106to 2.5 x 108total CAR-expressing T cells, 2.5 x 106to 1 x 108total CAR-expressing T cells, 2.5 x 106to 5 x 107total CAR- expressing T cells, 2.5 x 106to 2.5 x 107total CAR-expressing T cells, 2.5 x 106to 1 x 107total CAR-expressing T cells, 2.5 x 106to 5 x 106total CAR-expressing T cells, 5 x 106to 5 x 108total CAR-expressing T cells, 5 x 106to 2.5 x 108total CAR-expressing T cells, 5 x 106to 1 x 108total CAR-expressing T cells, 5 x 106to 5 x 107total CAR-expressing T cells, 5 x 106to2.5 x 107total CAR-expressing T cells, 5 x 106to 1 x 107total CAR-expressing T cells, 1 x107to 5 x 108total CAR-expressing T cells, 1 x 107to 2.5 x 108total CAR-expressing T cells,1 x 107to 1 x 108total CAR-expressing T cells, 1 x 107to 5 x 107total CAR-expressing T cells, 1 x 107to 2.5 x 107total CAR-expressing T cells, 2.5 x 107to 5 x 108total CAR- expressing T cells, 2.5 x 107to 2.5 x 108total CAR-expressing T cells, 2.5 x 107to 1 x 108total CAR-expressing T cells, 2.5 x 107to 5 x 107total CAR-expressing T cells, 5 x 107to 5 x 108total CAR-expressing T cells, 5 x 107to 2.5 x 108total CAR-expressing T cells, 5 x 107to 1 x108total CAR-expressing T cells, 1 x 108to 5 x 108total CAR-expressing T cells, 1 x 108to2.5 x 108total CAR-expressing T cells, or 2.5 x 108to 5 x 108total CAR-expressing T cells.

[0252] In some embodiments, the dose of genetically engineered cells comprises at least or at least about 1 x 105CAR-expressing cells, at least or at least about 2.5 x 105CAR-expressing cells, at least or at least about 5 x 105CAR-expressing cells, at least or at least about 1 x 106CAR-expressing cells, at least or at least about 2.5 x 106CAR-expressing cells, at least or at least about 5 x 106CAR-expressing cells, at least or at least about 1 x 107CAR-expressing cells, at least or at least about 2.5 x 107CAR-expressing cells, at least or at least about 5 x 107CAR- expressing cells, at least or at least about 1 x 108CAR-expressing cells, at least or at least about2.5 x 108CAR-expressing cells, or at least or at least about 5 x 108CAR-expressing cells.

[0253] In some embodiments, the cell therapy comprises administration of a dose comprising a number of cell from or from about 1 x 105to 5 x 108total recombinant receptor expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), from or from about 5 x 105to 1 x 107total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs) or from or from about 1 x 106to 1 x 107total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), each inclusive. In some embodiments, the cell therapy comprises administration of a dose of cells comprising a number of cells at least or at least about 1 x 105total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs),such at least or at least 1 x 106, at least or at least about 1 x 107, at least or at least about 1 x 108of such cells. In some embodiments, the number is with reference to the total number of CD3+ or CD8+, in some cases also recombinant receptor-expressing (e.g. CAR+) cells. In some embodiments, the cell therapy comprises administration of a dose comprising a number of cell from or from about 1 x 105to 5 x 108CD3+ or CD8+ total T cells or CD3+ or CD8+recombinant receptor-expressing cells, from or from about 5 x 105to 1 x 107CD3+ or CD8+ total T cells or CD3+ or CD8+ recombinant receptor-expressing cells, or from or from about 1 x 106to 1 x 107CD3+ or CD8+ total T cells or CD3+ or CD8+recombinant receptor-expressing cells, each inclusive. In some embodiments, the cell therapy comprises administration of a dose comprising a number of cell from or from about 1 x 105to 5 x 108total CD3+ / CAR+ or CD8+ / CAR+ cells, from or from about 5 x 105to 1 x 107total CD3+ / CAR+ or CD8+ / CAR+ cells, or from or from about 1 x 106to 1 x 107total CD3+ / CAR+ or CD8+ / CAR+ cells, each inclusive.

[0254] In some embodiments, the T cells of the dose include CD4+ T cells, CD8+ T cells or CD4+ and CD8+ T cells.

[0255] In some embodiments, for example, where the subject is human, the CD8+ T cells of the dose, including in a dose including CD4+ and CD8+ T cells, includes between about 1 x 106and 5 x 108total recombinant receptor (e.g., CAR)-expressing CD8+cells, e.g., in the range of about 5 x 106to 1 x 108such cells, such cells 1 x 107, 2.5 x 107, 5 x 107, 7.5 x 107, 1 x 108, or 5 x 108total such cells, or the range between any two of the foregoing values. In someembodiments, the patient is administered multiple doses, and each of the doses or the total dose can be within any of the foregoing values. In some embodiments, the dose of cells comprises the administration of from or from about 1 x 107to 0.75 x 108total recombinant receptor-expressing CD8+ T cells, 1 x 107to 2.5 x 107total recombinant receptor-expressing CD8+ T cells, from or from about 1 x 107to 0.75 x 108total recombinant receptor-expressing CD8+ T cells, each inclusive. In some embodiments, the dose of cells comprises the administration of or about 1 x 107, 2.5 x 107, 5 x 1077.5 x 107, 1 x 108, or 5 x 108total recombinant receptor-expressing CD8+ T cells.

[0256] In some embodiments, the dose of cells, e.g., recombinant receptor-expressing T cells, is administered to the subject as a single dose or is administered only one time within a period of two weeks, one month, three months, six months, 1 year or more.

[0257] In some embodiments, the cell therapy comprises administration of a dose comprising a number of cells that is at least or at least about or is or is about 0.1 x 106cells / kgbody weight of the subject, 0.2 x 106cells / kg, 0.3 x 106cells / kg, 0.4 x 106cells / kg, 0.5 x 106cells / kg, 1 x 106cell / kg, 2.0 x 106cells / kg, 3 x 106cells / kg or 5 x 106cells / kg.

[0258] In some embodiments, the cell therapy comprises administration of a dose comprising a number of cells is between or between about 0.1 x 106cells / kg body weight of the subject and 1.0 x 107cells / kg, between or between about 0.5 x 106cells / kg and 5 x 106cells / kg, between or between about 0.5 x 106cells / kg and 3 x 106cells / kg, between or between about 0.5 x 106cells / kg and 2 x 106cells / kg, between or between about 0.5 x 106cells / kg and 1 x 106cell / kg, between or between about 1.0 x 106cells / kg body weight of the subject and 5 x 106cells / kg, between or between about 1.0 x 106cells / kg and 3 x 106cells / kg, between or between about 1.0 x 106cells / kg and 2 x 106cells / kg, between or between about 2.0 x 106cells / kg body weight of the subject and 5 x 106cells / kg, between or between about 2.0 x 106cells / kg and 3 x 106cells / kg, or between or between about 3.0 x 106cells / kg body weight of the subject and 5 x 106cells / kg, each inclusive.

[0259] In some embodiments, the dose of cells comprises between at or about 2 x 105of the cells / kg and at or about 2 x 106of the cells / kg, such as between at or about 4 x 105of the cells / kg and at or about 1 x 106of the cells / kg or between at or about 6 x 105of the cells / kg and at or about 8 x 105of the cells / kg. In some embodiments, the dose of cells comprises no more than 2 x 105of the cells (e.g. antigen-expressing, such as CAR-expressing cells) per kilogram body weight of the subject (cells / kg), such as no more than at or about 3 x 105cells / kg, no more than at or about 4 x 105cells / kg, no more than at or about 5 x 105cells / kg, no more than at or about 6 x 105cells / kg, no more than at or about 7 x 105cells / kg, no more than at or about 8 x 105cells / kg, nor more than at or about 9 x 105cells / kg, no more than at or about 1 x 106cells / kg, or no more than at or about 2 x 106cells / kg. In some embodiments, the dose of cells comprises at least or at least about or at or about 2 x 105of the cells (e.g. antigen-expressing, such as CAR- expressing cells) per kilogram body weight of the subject (cells / kg), such as at least or at least about or at or about 3 x 105cells / kg, at least or at least about or at or about 4 x 105cells / kg, at least or at least about or at or about 5 x 105cells / kg, at least or at least about or at or about 6 x 105cells / kg, at least or at least about or at or about 7 x 105cells / kg, at least or at least about or at or about 8 x 105cells / kg, at least or at least about or at or about 9 x 105cells / kg, at least or at least about or at or about 1 x 106cells / kg, or at least or at least about or at or about 2 x 106cells / kg.

[0260] In the context of adoptive cell therapy, administration of a given“dose” of cells encompasses administration of the given amount or number of cells as a single compositionand / or single uninterrupted administration, e.g., as a single injection or continuous infusion, and also encompasses administration of the given amount or number of cells as a split dose, provided in multiple individual compositions or infusions, over a specified period of time, which is no more than 3 days. Thus, in some contexts, the dose is a single or continuous administration of the specified number of cells, given or initiated at a single point in time. In some contexts, however, the dose is administered in multiple injections or infusions over a period of no more than three days, such as once a day for three days or for two days or by multiple infusions over a single day period.

[0261] Thus, in some aspects, the cells of the dose are administered in a singlepharmaceutical composition. In some embodiments, the cells of the dose are administered in a plurality of compositions, collectively containing the cells of the dose.

[0262] The term“split dose” refers to a dose that is split so that it is administered over more than one day. This type of dosing is encompassed by the present methods and is considered to be a single dose. In some embodiments, the cells of a split dose are administered in a plurality of compositions, collectively comprising the cells of the dose, over a period of no more than three days.

[0263] Thus, the dose of cells may be administered as a split dose. For example, in some embodiments, the dose may be administered to the subject over 2 days or over 3 days.Exemplary methods for split dosing include administering 25% of the dose on the first day and administering the remaining 75% of the dose on the second day. In other embodiments, 33% of the dose may be administered on the first day and the remaining 67% administered on the second day. In some aspects, 10% of the dose is administered on the first day, 30% of the dose is administered on the second day, and 60% of the dose is administered on the third day. In some embodiments, the split dose is not spread over more than 3 days.

[0264] In some embodiments, the dose of cells is generally large enough to be effective in reducing disease burden.

[0265] In some embodiments, the cells are administered at a desired dosage, which in some aspects includes a desired dose or number of cells or cell type(s) and / or a desired ratio of cell types. Thus, the dosage of cells in some embodiments is based on a total number of cells (or number per kg body weight) and a desired ratio of the individual populations or sub-types, such as the CD4+ to CD8+ ratio. In some embodiments, the dosage of cells is based on a desired total number (or number per kg of body weight) of cells in the individual populations or of individual cell types. In some embodiments, the dosage is based on a combination of suchfeatures, such as a desired number of total cells, desired ratio, and desired total number of cells in the individual populations.

[0266] In some embodiments, the populations or sub-types of cells, such as CD8+and CD4+T cells, are administered at or within a tolerated difference of a desired dose of total cells, such as a desired dose of T cells. In some aspects, the desired dose is a desired number of cells or a desired number of cells per unit of body weight of the subject to whom the cells areadministered, e.g., cells / kg. In some aspects, the desired dose is at or above a minimum number of cells or minimum number of cells per unit of body weight. In some aspects, among the total cells, administered at the desired dose, the individual populations or sub-types are present at or near a desired output ratio (such as CD4+to CD8+ratio), e.g., within a certain tolerated difference or error of such a ratio.

[0267] In some embodiments, the cells are administered at or within a tolerated difference of a desired dose of one or more of the individual populations or sub-types of cells, such as a desired dose of CD4+ cells and / or a desired dose of CD8+ cells. In some aspects, the desired dose is a desired number of cells of the sub-type or population, or a desired number of such cells per unit of body weight of the subject to whom the cells are administered, e.g., cells / kg. In some aspects, the desired dose is at or above a minimum number of cells of the population or sub- type, or minimum number of cells of the population or sub-type per unit of body weight.

[0268] Thus, in some embodiments, the dosage is based on a desired fixed dose of total cells and a desired ratio, and / or based on a desired fixed dose of one or more, e.g., each, of the individual sub-types or sub-populations. Thus, in some embodiments, the dosage is based on a desired fixed or minimum dose of T cells and a desired ratio of CD4+to CD8+cells, and / or is based on a desired fixed or minimum dose of CD4+and / or CD8+cells.

[0269] In some embodiments, the cells are administered at or within a tolerated range of a desired output ratio of multiple cell populations or sub-types, such as CD4+ and CD8+ cells or sub-types. In some aspects, the desired ratio can be a specific ratio or can be a range of ratios for example, in some embodiments, the desired ratio (e.g., ratio of CD4+to CD8+cells) is between at or about 5:1 and at or about 5:1 (or greater than about 1:5 and less than about 5:1), or between at or about 1:3 and at or about 3:1 (or greater than about 1:3 and less than about 3:1), such as between at or about 2:1 and at or about 1:5 (or greater than about 1:5 and less than about 2:1, such as at or about 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. In some aspects, the tolerated difference is within about 1%, about2%, 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 in between these ranges.

[0270] In particular embodiments, the numbers and / or concentrations of cells refer to the number of recombinant receptor ( e.g ., CAR)-expressing cells. In other embodiments, the numbers and / or concentrations of cells refer to the number or concentration of all cells, T cells, or peripheral blood mononuclear cells (PBMCs) administered.

[0271] In some aspects, the size of the dose is determined based on one or more criteria such as response of the subject to prior treatment, e.g. chemotherapy, disease burden in the subject, such as tumor load, bulk, size, or degree, extent, or type of metastasis, stage, and / or likelihood or incidence of the subject developing toxic outcomes, e.g., CRS, macrophage activation syndrome, tumor lysis syndrome, neurotoxicity, and / or a host immune response against the cells and / or recombinant receptors being administered.

[0272] In some embodiments, administration of the immunomodulatory compound in combination with the cells is able to significantly increase the expansion or proliferation of the cells, and thus a lower dose of cells can be administered to the subject. In some cases, the provided methods allow a lower dose of such cells to be administered, to achieve the same or better efficacy of treatment as the dose in a method in which the cell therapy is administered without administering the immunomodulatory compound, such as at least 1.5-fold, 2-fold, 3- fold, 4-fold, 5-fold or lO-fold less than the dose in a method in which the cell therapy is administered without administering the immunomodulatory compound, e.g.,lenalidomide or Compound 1.

[0273] In some embodiments, for example, the dose contains between or between about 5.0 x 106and 2.25 x 107, 5.0 x 106and 2.0 x 107, 5.0 x 106and 1.5 x 107, 5.0 x 106and 1.0 x 107, 5.0 x 106and 7.5 x 106, 7.5 x 106and 2.25 x 107, 7.5 x 106and 2.0 x 107, 7.5 x 106and 1.5 x 107, 7.5 x 106and 1.0 x 107, 1.0 x 107and 2.25 x 107, 1.0 x 107and 2.0 x 107, 1.0 x 107and 1.5 x 107, 1.5 x 107and 2.25 x 107, 1.5 x 107and 2.0 x 107, 2.0 x 107and 2.25 x 107. In some embodiments, the dose of cells contains a number of cells, that is between at least or at least about 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, 10 x l06and about 15 x 106recombinant- receptor expressing cells, such as recombinant-receptor expressing cells that are CD8+. In some embodiments, such dose, such as such target number of cells refers to the totalrecombinant-receptor expressing cells in the administered composition.

[0274] In some embodiments, for example, the lower dose contains less than about 5 x 106cells, recombinant receptor (e.g. CAR)-expressing cells, T cells, and / or PBMCs per kilogram body weight of the subject, such as less than about 4.5 x 106, 4 x 106, 3.5 x 106, 3 x 106, 2.5 x 106, 2 x 106, 1.5 x 106, 1 x 106, 5 x 105, 2.5 x 105, or 1 x 105such cells per kilogram body weight of the subject. In some embodiments, the lower dose contains less than about 1 x 105, 2 x 105, 5 x 105, or 1 x 106of such cells per kilogram body weight of the subject, or a value within the range between any two of the foregoing values. In some embodiments, such values refer to numbers of recombinant receptor-expressing cells; in other embodiments, they refer to number of T cells or PBMCs or total cells administered.

[0275] In some embodiments, the subject receives multiple doses, e.g., two or more doses or multiple consecutive doses, of the cells. In some embodiments, two doses are administered to a subject. In some embodiments, the subject receives the consecutive dose, e.g., 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, multiple consecutive doses are administered following the first dose, such that an additional dose or doses are administered following administration of the consecutive dose. In some aspects, the number of cells administered to the subject in the additional dose is the same as or similar to the first dose and / or consecutive dose. In some embodiments, the additional dose or doses are larger than prior doses. In some embodiments, one or more subsequent dose of cells can be administered to the subject. In some embodiments, the subsequent dose of cells is administered greater than or greater than about 7 days, 14 days, 21 days, 28 days or 35 days after initiation of administration of the first dose of cells. The subsequent dose of cells can be more than, approximately the same as, or less than the first dose. In some embodiments, administration of the T cell therapy, such asadministration of the first and / or second dose of cells, can be repeated.

[0276] In some embodiments, initiation of administration of the cell therapy, e.g. the dose of cells or a first dose of a split dose of cells, is administered before (prior to), concurrently with or after (subsequently or subsequent to) the administration of the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2.

[0277] In some embodiments, the dose of cells, or the subsequent dose of cells, is administered concurrently with initiating administration of the immunomodulatory compound in accord with the combination therapy methods. In some embodiments, the dose of cells, or the subsequent dose of cells, is administered on the same day as initiating administration of the immunomodulatory compound in accord with the combination therapy methods. In someembodiments, the dose of cells, or the subsequent dose of cells, is administered within 1 day, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, or within 7 days of initiating administration of the immunomodulatory compound in accord with the combination therapy methods.

[0278] In some embodiments, the dose of cells, or the subsequent dose of cells, is administered prior to starting or initiating administration of the immunomodulatory compound in accord with the provided combination therapy. In some embodiments, the dose of cells is administered at least or at least about 1 hour, at least or at least about 2 hours, at least or at least about 3 hours, at least or at least about 6 hours, at least or at least about 12 hours, at least or at least about 1 day, at least or at least about 2 days, at least or at least about 3 days, at least or about at least 4 days, at least or at least about 5 days, at least or about at least 6 days, at least or at least about 7 days, at least or about at least 12 days, at least or at least about 14 days, at least or about at least 15 days, at least or at least about 21 days, at least or at least about 28 days, at least or about at least 30 days, at least or at least about 35 days, at least or at least about 42 days, at least or about at least 60 days or at least or about at least 90 days prior to administering the immunomodulatory compound in accord with the provided combination therapy.

[0279] In some embodiments, the administration of the immunomodulatory compound (e.g., lenalidomide or Compound 1) immunomodulatory compound in accord with the provided combination therapy is at a time in which the prior administration of the immunotherapy (e.g., T cell therapy, such as CAR-T cell therapy) is associated with, or is likely to be associated with, a decreased functionality of the T cells compared to the functionality of the T cells at a time just prior to initiation of the immunotherapy (e.g., T cell therapy, such as CAR-T cell therapy) or at a preceding time point after initiation of the T cell therapy. In some embodiments, the method involves, subsequent to administering the dose of cells of the T cell therapy, e.g., adoptive T cell therapy, but prior to administering the immunomodulatory compound, assessing a sample from the subject for one or more function of T cells, such as expansion or persistence of the cells, e.g. as determined by level or amount in the blood, or other phenotypes or desired outcomes as described herein, e.g., such as those described in Section III. In some embodiments, the method involves, subsequent to administering the dose of cells of the T cell therapy, e.g., adoptive T cell therapy, but prior to administering the immunomodulatory compound, assessing a sample from the subject for expression of one or more exhaustion markers. Various parameters for determining or assessing the regimen of the combination therapy are described in Section III.B. ADMINISTRATION OF THE IMMUNOMODULATORY COMPOUND

[0280] The provided combination therapy methods, compositions, combinations, kits and uses involve administration of an immunomodulatory compound, such as a structural or functional analog or derivative of thalidomide and / or an inhibitor of E3 ubiquitin ligase, e.g. lenalidomide, Compound 1 or Compound 2, which can be administered prior to, subsequently to, during, simultaneously or near simultaneously, sequentially and / or intermittently with administration of the T cell therapy, e.g., administration of T cells expressing a chimeric antigen receptor (CAR).

[0281] In some embodiments, the immunomodulatory compound is one of a class of immunomodulatory compounds that is a structural or functional analog or derivative of thalidomide and / or an inhibitor of E3 ubiquitin ligase. In particular embodiments, the immunomodulatory compound is an inhibitor of E3 ubiquitin ligase.

[0282] In some embodiments, the immunomodulatory compound binds to cereblon (CRBN). In some embodiments, the immunomodulatory compound binds to the CRBN E3 ubiquitin- ligase complex. In some embodiments, the immunomodulatory compound binds to CRBN and the CRBN E3 ubiquitin-ligase complex. In some embodiments, the immunomodulatory compound up-regulates the protein or gene expression of CRBN. In some aspects, CRBN is the substrate adaptor for the CRL4CRBNE3 ubiquitin ligase, and modulates the specificity of the enzyme. In some embodiments, binding to CRB or the CRBN E3 ubiquitin ligase complex inhibits E3 ubiquitin ligase activity. In some embodiments, the immunomodulatory compound induces the ubiqutination of KZF1 (Ikaros) and IKZF3 (Aiolos) and / or induces degradation of IKZF1 (Ikaros) and IKZF3 (Aiolos). In some embodiments, the immunomodulatory compound induces the ubiquitination of casein kinase 1A1 (CKla) by the CRL4CRBNE3 ubiquitin ligase. In some embodiments, the ubiquitination of CKla results in CKla degradation.

[0283] In some embodiments, the immunomodulatory compound is an inhibitor of the Ikaros (IKZF1) transcription factor. In some embodiments, the immunomodulatory compound enhances ubiquitination of Ikaros. In some embodiments, the immunomodulatory compound enhances the degradation of Ikaros. In some embodiments, the immunomodulatory compound down-regulates the protein or gene expression of Ikaros. In some embodiments, administration of the immunomodulatory compound causes a decrease in Ikaros protein levels.

[0284] In some embodiments, the immunomodulatory compound is an inhibitor of the Aiolos (IKZF3) transcription factor. In some embodiments, the immunomodulatory compoundenhances ubiquitination of Aiolos. In some embodiments, the immunomodulatory compound enhances the degradation of Aiolos. In some embodiments, the immunomodulatory compound down-regulates the protein or gene expression of Aiolos. In some embodiments, administration of the immunomodulatory compound causes a decrease in Aiolos protein levels.

[0285] In some embodiments, the immunomodulatory compound is an inhibitor of both the Ikaros (IKZF1) and Aiolos (IKZF3) transcription factors. In some embodiments, theimmunomodulatory compound enhances ubiquitination of both Ikaros and Aiolos. In some embodiments, the immunomodulatory compound enhances the degradation of both Ikaros and Aiolos. In some embodiments, the immunomodulatory compound enhances ubiquitination and degradation of both Ikaros and Aiolos. In some embodiments, administration of theimmunomodulatory compound causes both Aiolos protein levels and Ikaros protein levels to decrease.

[0286] In some embodiments, the immunomodulatory compound is a Selective cytokine inhibitory drug (SelCID). In some embodiments, the immunomodulatory compound inhibit the activity of phosphodiesterase-4 (PDE4). In some embodiments, the immunomodulatory compound suppresses the enzymatic activity of the CDC25 phosphatases. In some embodiments, the immunomodulatory compound alters the intracellular trafficking of CDC25 phosphatases.

[0287] In some embodiments, the immunomodulatory compound in the combination therapy is thalidomide (2-(2,6-dioxopiperidin-3-yl)-lH-isoindole- l,3(2H)-dione) or an analog or derivative of thalidomide. In certain embodiments, a thalidomide derivative includes structural variants of thalidomide that have a similar biological activity. Exemplary thalidomide derivatives include, but are not limited to lenalidomide (REVLIMMUNOMODULATORY COMPOUND™; Celgene Corporation), pomalidomide (also known asACTIMMUNOMODULATORY COMPOUND™ or POMALYST™ (Celgene Corporation)), CC-1088, CDC-501, and CDC- 801, and the compounds disclosed in U.S. Pat. Nos. 5,712,291; 7,320,991; and 8,716,315; U.S. Appl. No. 2016 / 0313300; and PCT Pub. Nos. WO 2002 / 068414 and WO 2008 / 154252.

[0288] In some embodiments, the immunomodulatory compound is l-oxo- and 1,3 dioxo-2- (2,6-dioxopiperldin-3-yl) isoindolines substituted with amino in the benzo ring as described in U.S. Pat. No. 5,635,517 which is incorporated herein by reference.

[0289] In some embodiments, the immunomodulatory compound is a compound of the following formula:

[0290] wherein one of X and Y is -C(O)- and the other of X and Y is -C(O)- or -CH2-, and R5is hydrogen or lower alkyl, or a pharmaceutically acceptable salt thereof. In some embodiments, X is -C(O)- and Y is -CH2-. In some embodiments, both X and Y are -C(O)-. In some embodiments, R5is hydrogen. In other embodiments, R5is methyl.

[0291] In some embodiments, the immunomodulatory compound is a compound that belongs to a class of substituted 2-(2, 6-dioxopiperidin-3-yl)phthalimmunomodulatory compounds and substituted 2-(2,6-dioxopiperldin-3-yl)-l-oxoisoindoles, such as those described in U.S. Pat. Nos. 6,281,230; 6,316,471; 6,335,349; and 6,476,052, and International Patent Application No. PCT / US97 / 13375 (International Publication No. WO 98 / 03502), each of which is incorporated herein by reference.

[0292] In some embodiments, the immunomodulatory compound is a compound of the following formula:whereinone of X and Y is -C(O)- and the other of X and Y is -C(O)- or -CH2-;(1) each of R1, R2, R3, and R4are independently halo, alkyl of 1 to 4 carbon atoms, or alkoxy or 1 to 4 carbon atoms, or(2) one of R1, R3, R4, and R5is -NHRaand the remaining of R1, R2, R3, and R4is are hydrogen, wherein Rais hydrogen or alkyl of 1 to 8 carbon atoms;R5is hydrogen or alkyl of 1 to 8 carbon atoms, benzyl, or halo;provided that R5is other than hydrogen if X and Y are -C(O)- and (i) each of R1, R2, R3, and R4is fluoro; or (ii) one of R1, R2, R3, and R4is amino;or a pharmaceutically acceptable salt thereof.

[0293] In some embodiments, the immunomodulatory compound is a compound that belongs to a class of isoindole-immunomodulatory compounds disclosed in U.S. Pat. No.7,091,353, U.S. Patent Publication No. 2003 / 0045552, and International Application No.PCT / USOI / 50401 (International Publication No. W002 / 059106), each of which are incorporated herein by reference. For example, in some embodiments, the immunomodulatory compound is [2-(2,6-dioxo-piperidin-3-yl)-l,3-dioxo-2, 3-dihydro- lH-isoindol-4-ylmethyl]- amide; (2-(2,6-dioxo-piperidin-3-yl)-l,3-dioxo-2, 3-dihydro- lH-isoindol-4-ylmethyl)-carbamic acid tert-butyl ester; 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))-isoindoline-l,3-dione; N-(2- (2, 6-dioxo-piperidin-3-yl)-l,3-dioxo-2, 3-dihydro- lH-isoindol-4-ylmethyl)-acetamide; N-{(2- (2,6-dioxo(3-piperidyl)-l,3-dioxoisoindolin-4-yl)methyl}cyclopropyl-carboxamide; 2-chloro-N- {(2-(2,6-dioxo(3-piperidyl))-l,3-dioxoisoindolin-4-yl)methyl}acetamide; N-(2-(2,6-dioxo(3- piperidyl))-l,3-dioxoisoindolin-4-yl)-3-pyridylcarboxamide; 3-{ l-oxo-4- (benzylamino)isoindolin-2-yl}piperidine-2,6-dione; 2-(2,6-dioxo(3-piperidyl))-4- (benzylamino)isoindoline-l,3-dione; N-{(2-(2,6-dioxo(3-piperidyl))-l,3-dioxoisoindolin-4- yl)methyl}propanamide; N-{(2-(2,6-dioxo(3-piperidyl))-l,3-dioxoisoindolin-4-yl)methyl}-3- pyridylcarboxamide; N-{(2-(2,6-dioxo(3-piperidyl))-l,3-dioxoisoindolin-4- yl)methyl}heptanamide; N-{(2-(2,6-dioxo(3-piperidyl))-l,3-dioxoisoindolin-4-yl)methyl}-2- furylcarboxamide; {N-(2-(2,6-dioxo(3-piperidyl))-l,3-dioxoisoindolin-4-yl)carbamoyl}methyl acetate; N-(2-(2,6-dioxo(3-piperidyl))-l,3-dioxoisoindolin-4-yl)pentanamide; N-(2-(2,6- dioxo(3-piperidyl))-l,3-dioxoisoindolin-4-yl)-2-thienylcarboxamide; N-{ [2-(2,6-dioxo(3- piperidyl))-l,3-dioxoisoindolin-4-yl]methyl}(butylamino)carboxamide; N-{ [2-(2,6-dioxo(3- piperidyl))-l,3-dioxoisoindolin-4-yl]methyl}(octylamino)carboxamide; or N-{ [2-(2,6-dioxo(3- piperidyl))-l,3-dioxoisoindolin-4-yl]methyl}(benzylamino)carboxamide.

[0294] In some embodiments, the immunomodulatory compound is a compound that belongs to a class of isoindole-immunomodulatory compounds disclosed in U.S. PatentApplication Publication Nos. 2002 / 0045643, International Publication No. WO 98 / 54170, and U.S. Pat. No. 6,395,754, each of which is incorporated herein by reference. In someembodiments, the immunomodulatory compound is a tetra substituted 2-(2,6-dioxopiperdin-3- yl)-l-oxoisoindolines described in U.S. Pat. No. 5,798,368, which is incorporated herein by reference. In some embodiments, the immunomodulatory compound is l-oxo and l,3-dioxo-2- (2,6-dioxopiperidin-3-yl) isoindolines disclosed in U.S. Pat. No. 6,403,613, which isincorporated herein by reference. In some embodiments the immunomodulatory compound is a l-oxo or l,3-dioxoisoindoline substituted in the 4- or 5-position of the indoline ring as described in U.S. Pat. No. 6,380,239 and U.S. Pat. No. 7,244,759, both of which are incorporated herein by reference.

[0295] In some embodiments, the immunomodulatory compound is 2-(4-amino-l-oxo-l,3- dihydro-isoindol-2-yl)-4-carbamoyl-butyric acid or 4-(4-amino-l-oxo-l,3-dihydro-isoindol-2- yl)-4-carbamoyl-butyric acid. In some embodiments, the immunomodulatory compound is 4- carbamoyl-4-{4-[(furan-2-yl-methyl)-amino]-l,3-dioxo-l,3-dihydro-isoindol-2-yl}-butyric acid, 4-carbamoyl-2- {4- [(furan-2-yl-methyl)-amino] - 1 ,3 -dioxo- 1 ,3 -dihydro-isoindol-2-yl } -butyric acid, 2- { 4- [(furan-2-yl-methyl)-amino] - 1 ,3-dioxo- 1 ,3-dihydro-isoindol-2-yl } -4- phenylcarbamoyl-butyric acid, or 2-{4-[(furan-2-yl-methyl)-amino]-l,3-dioxo-l,3-dihydro- isoindol-2-yl } -pentanedioic acid.

[0296] In some embodiments, the immunomodulatory compound is a isoindoline-l-one or isoindoline-l,3-dione substituted in the 2-position with 2,6-dioxo-3-hydroxypiperidin-5-yl as described in U.S. Pat. No. 6,458,810, which is incorporated herein by reference. In some embodiments, the immunomodulatory compound is 3-(5-amino-2-methyl-4-oxo-4H-quinazolin- 3-yl)-piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. In some embodiments, the immunomodulatory compound is 3-[4-(4-morpholin-4-ylmethyl- benzyloxy)- 1 -oxo- 1 ,3 -dihydro-isoindol-2-yl] -piperidine-2, 6-dione.

[0297] In some embodiments, the immunomodulatory compound is a 4’arylmethoxy isoindoline compound, as described in U.S. Pat. No. 9,828,361, which is incorporated herein by reference. In some embodiments, the immunomodulatory compound is a compound of the following formula:or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein:Z is C=0 or CH2;R11is -Z^R13;R12is H or (Ci-C6)alkyl;Z1is 6 to 10 membered aryl, heteroaryl, or heterocycle, each of which may be optionally substituted with one or more halogen; or a bond;R13is -(CH2)n-aryl, -0-(CH2)n-aryl, or -(CH2)n-0-aryl, wherein the aryl is optionally substituted with one or more: (Ci-C6)alkyl; itself optionally substituted with one or more halogen; (Ci-C6)alkoxy, itself substituted with one or more halogen; oxo; amino; carboxyl;cyano; hydroxyl; halogen; deuterium; 6 to 10 membered aryl or heteroaryl, optionally substituted with one or more (Ci-C6)alkyl, (Ci-C6)alkoxy, or halogen; -CONH2; or -COO-(Ci- C6)alkyl, wherein the alkyl may be optionally substituted with one or more halogen; -(CH2)n- heterocycle, -0-(CH2)n-heterocycle or -(CH2)n-0-heterocycle, wherein the heterocycle is optionally substituted with one or more: (Ci-C6)alkyl, itself optionally substituted with one or more halogen; (Ci-C6)alkoxy, itself substituted with one or more halogen; oxo; amino; carboxyl; cyano; hydroxyl; halogen; deuterium; 6 to 10 membered aryl or heteroaryl, optionally substituted with one or more (Ci-C6)alkyl, (Ci-C6)alkoxy or halogen; -CONH2; or -COO-(Ci- C6)alkyl, wherein the alkyl may be optionally substituted with one or more halogen; or -(CH2)n- heteroaryl, -0-(CH2)n-heteroaryl or -(CH2)n-0-heteroaryl, wherein the heteroaryl is optionally substituted with one or more: (Ci-C6)alkyl, itself optionally substituted with one or more halogen; (Ci-C6)alkoxy, itself substituted with one or more halogen; oxo; amino; carboxyl; cyano; hydroxyl; halogen; deuterium; 6 to 10 membered aryl or heteroaryl, optionally substituted with one or more (Ci-C6)alkyl, (Ci-C6)alkoxy or halogen; -CONH2; or -COO-(Ci- C6)alkyl, wherein the alkyl may be optionally substituted with one or more halogen; andn is 0, 1, 2 or 3.

[0298] In some embodiments, the immunomodulatory compound is a (S)-3-[4-(4-morpholin- 4-ylmethyl-benzyloxy)- l-oxo- 1, 3 -dihydro-isoindol-2-yl] -piperidine-2, 6-dione, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. In some embodiments, (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)- l-oxo- 1, 3-dihydro-isoindol-2-yl] -piperidine-2, 6-dione is also called (3S)-3-[7-[[4-(morpholin-4-ylmethyl)phenyl]methoxy]-3-oxo- lH-isoindol-2-yl]piperidine-2, 6-dione, (S)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-l- oxoisoindolin-2-yl)piperidine-2, 6-dione, or iberdomide. In some embodiments, theimmunomodulatory compound is iberdomide or iberdomide hydrochloride.

[0299] In some embodiments, the immunomodulatory compound is an enantiomer or a mixture of enantiomers of (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-l-oxo-l,3-dihydro- isoindol-2-yl] -piperidine-2, 6-dione, or a pharmaceutically acceptable salt, solvate, hydrate, co crystal, clathrate, or polymorph thereof. In some embodiments, the immunomodulatory compound is (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)- l-oxo- 1, 3-dihydro-isoindol-2-yl]- piperidine-2, 6-dione, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. In some embodiments, the immunomodulatory compound is (R)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-l-oxo-l,3-dihydro-isoindol-2-yl]-piperidine-2,6- dione, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof. In some embodiments, the immunomodulatory compound is a solvate of (S)-3-[4-(4- morpholin-4-ylmethyl-benzyloxy)- l-oxo- l,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione. In some embodiments, the immunomodulatory compound is a hydrate of (S)-3-[4-(4-morpholin-4- ylmethyl-benzyloxy)- l-oxo- l,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione. In someembodiments, the immunomodulatory compound is a salt or solid form of 3-(4-((4- (morpholinomethyl)benzyl)oxy)-l-oxoisoindolin-2-yl)piperidine-2,6-dione, or a stereoisomer thereof, as described in U.S. Pat. No. 9,629,849, which is incorporated herein by reference. In some embodiments, the immunomodulatory compound is a pharmaceutically acceptable salt of 3 - [4-(4-morpholin-4-ylmethyl-benzyloxy)- 1 -oxo- 1 ,3 -dihydro-isoindol-2-yl] -piperidine-2, 6- dione. In some embodiments, the immunomodulatory compound is a pharmaceutically acceptable salt of (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)- l-oxo- 1, 3-dihydro-isoindol-2- yl] -piperidine-2, 6-dione. For example, in some embodiments, the immunomodulatory compound is a hydrochloride salt of (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-l-oxo-l,3- dihydro-isoindol-2-yl] -piperidine-2, 6-dione. In certain embodiments, the immunomodulatory compound is the Form A crystal form of the hydrochloride salt of (S)-3-[4-(4-morpholin-4- ylmethyl-benzyloxy)-l-oxo-l,3-dihydro-isoindol-2-yl]-piperidine-2, 6-dione, as disclosed in U.S. Pat. No. 9,629,849. In some embodiments, the Form A crystal form of the hydrochloride salt of (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-l-oxo-l,3-dihydro-isoindol-2-yl]-piperidine-2,6- dione is characterized by XRPD peaks located at t 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 or approximately 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 20. In some embodiments, theimmunomodulatory compound is a salt, hydrate, anhydrate, or solvate of the hydrochloride salt of 3-(4-((4-(morpholinomethyl)benzyl)oxy)-l-oxoisoindolin-2-yl)piperidine-2,6-dione. In some embodiments, the immunomodulatory compound is a polymorph of (S)-3-[4-(4-morpholin-4- ylmethyl-benzyloxy)- l-oxo- l,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione. In someembodiments, the immunomodulatory compound is (S)-3-[4-(4-morpholin-4-ylmethyl- benzyloxy)-l-oxo-l,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione. In some embodiments, theimmunomodulatory compound,acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof (hereinafterCompound 2).

[0300] In some embodiments, the immunomodulatory compound is as described in Oshima, K. et al., Nihon Rinsho., 72(6): 1130-5 (2014); Millrine, D. et al., Trends Mol Med., 23(4):348- 364 (2017); and Collins, et al, Biochem J., 474(7): 1127-1147 (2017).

[0301] In some embodiments, the immunomodulatory compound is an inhibitor of E3 ubiquitin ligase. In some embodiments, the immunomodulatory compound is a derivative of thalidomide. In some embodiments, the immunomodulatory compound is a structural and / or functional analogue of thalidomide. In some embodiments, the immunomodulatory compound is lenalidomide, pomalidomide, avadomide, or a pharmaceutically acceptable salt thereof.

[0302] In some embodiments, the immunomodulatory compound is lenalidomide, pomalidomide, avadomide, a stereoisomer of lenalidomide, pomalidomide, avadomide or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. In some embodiments, the immunomodulatory compound is lenalidomide, a stereoisomer of lenalidomide or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.

[0303] In some embodiments, the immunomodulatory compound is avadomide, which also is known as 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione having thefollowing structure(Formula I), or is an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof (hereinafter Compound 1).

[0304] In some embodiments, the immunomodulatory compound is an enantiomer or a mixture of enantiomers of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6- dione, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. In some embodiments, the immunomodulatory compound is a solvate of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3- yl)-piperidine-2,6-dione. In some embodiments, the immunomodulatory compound is a hydrate of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. In some embodiments, the immunomodulatory compound is a pharmaceutically acceptable salt of 3-(5-amino-2- methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. In some embodiments, theimmunomodulatory compound is a polymorph of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3- yl)-piperidine-2,6-dione. In some embodiments, the immunomodulatory compound is 3-(5- amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. In some embodiments, the immunomodulatory compound has the structure of Formula I.

[0305] In some embodiments, the immunomodulatory compound is lenalidomide, which also is known as 3-(4-amino-l-oxo-l,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione, or is an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. In some embodiments, lenalidomide is 2,6- Piperidinedione, 3-(4-amino-l, 3-dihydro- l-oxo-2H-isoindol-2-yl)-, 3-(4-Amino-l-oxo-l,3- dihydro-2H-isoindol-2-yl)-2,6-piperidinedione, 3-(4-Amino-l-oxo-l,3-dihydro-2H-isoindol-2- yl)-2,6-piperidinedione, 3-(4-Amino-l-oxo-l,3-dihydro-2H-isoindol-2-yl)piperidin-2,6-dion, 3- (4-amino- l-oxo- l,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione, 3-(4-amino-l-oxo-l,3- dihydro-2H-isoindol-2-yl)piperidine-2,6-dione, all of which can be used interchangeably, or is an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.

[0306] In some embodiments, the immunomodulatory compound is (A)-3-(4-amino- 1 -oxo- l,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione. In some embodiments, theimmunomodulatory compound is (S)-3-(4-amino-l-oxo-l,3-dihydro-2H-isoindol-2- yl)piperidine-2,6-dione. In some embodiments, the immunomodulatory compound is a mixture of ( ?)-3-(4-amino-l-oxo-l,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione and (5)-3-(4-amino- l-oxo- l,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione.(Formula II), or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. In some(Formula IIA), or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. Inother embodiments, the immunomodulatory compound i(Formula IIB), or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. In certain embodiments, the immunomodulatory compound comprises a mixture of(Formula IIB), orpharmaceutically acceptable salts, solvates, hydrates, co-crystals, clathrates, or polymorphs thereof.

[0308] In some embodiments, the immunomodulatory compound is an enantiomer or a mixture of enantiomers of 3-(4-Amino-l-oxo-l,3-dihydro-2H-isoindol-2-yl)piperidine-2,6- dione, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph of 3-(4-Amino-l-oxo-l,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione. In some embodiments, the immunomodulatory compound is a solvate of (A)-3-(4-Amino-l -oxo- 1 ,3-dihydro-2H- isoindol-2-yl)piperidine-2,6-dione and / or (S)-3-(4-Amino-l-oxo-l,3-dihydro-2H-isoindol-2- yl)piperidine-2,6-dione. In some embodiments, the immunomodulatory compound is a hydrate of (7?S)-3-(4-Amino-l-oxo-l,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione and / or (5)-3-(4- Amino-l-oxo-l,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione. In some embodiments, the immunomodulatory compound is a pharmaceutically acceptable salt of ( / / )-3-(4-Amino- 1 -oxo-I,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione and / or (5)-3-(4- Amino- 1 -oxo- 1 ,3-dihydro- 2H-isoindol-2-yl)piperidine-2,6-dione. In some embodiments, the immunomodulatory compound is lenalidomide, or 3-(4-amino-l-oxo-l,3-dihydro-2H-isoindol-2-yl)piperidine-2,6- dione. In some embodiments, the immunomodulatory compound has the structure of FormulaII. In some embodiments, the immunomodulatory compound has the structure of Formula IIA or Formula IIB or a mixture thereof.

[0309] In some embodiments, the immunomodulatory compound is pomalidomide, which is also known as 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione, or is an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co crystal, clathrate, or polymorph thereof. In some embodiments, the immunomodulatorycompound(Formula III), or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. In some embodiments, the immunomodulatory compound is(Formula IIIA) , or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. In other embodiments, the immunomodulatorycompound(Formula IIIB), or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. In certain embodiments, theimmunomodulatory compound comprises a mixture(Formula IIIA)(Formula MB) , or pharmaceutically acceptable salts, solvates, hydrates, co-crystals, clathrates, or polymorphs thereof.

[0310] In some embodiments, the immunomodulatory compound is an enantiomer or a mixture of enantiomers of 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline- l,3-dione, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph of 4- amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione. In some embodiments, theimmunomodulatory compound is ( / i)-4-amino-2-(2,6-dioxopipcridin-3-yl)isoindolinc- 1 ,3-dionc and / or (S)-4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph of (7?)-4-amino-2-(2,6- dioxopiperidin-3-yl)isoindoline- l,3-dione and / or (S)-4-amino-2-(2,6-dioxopiperidin-3- yl)isoindoline- l,3-dione. In some embodiments, the immunomodulatory compound is a solvateof (7?)-4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione and / or (S)-4-amino-2-(2,6- dioxopiperidin-3-yl)isoindoline-l,3-dione. In some embodiments, the immunomodulatory compound is a hydrate of (7?)-4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione and / or (S)-4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione. In some embodiments, the immunomodulatory compound is a pharmaceutically acceptable salt of (7?)-4-amino-2-(2,6- dioxopiperidin-3-yl)isoindoline-l,3-dione and / or (S)-4-amino-2-(2,6-dioxopiperidin-3- yl)isoindoline-l,3-dione. In some embodiments, the immunomodulatory compound is (7?)-4- amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione, (S)-4-amino-2-(2,6-dioxopiperidin-3- yl)isoindoline-l,3-dione, or a mixture thereof in any ratio. In some embodiments, the immunomodulatory compound has the structure of Formula III. In some embodiments, the immunomodulatory compound has the structure of Formula IIIA or Formula IIIB or a mixture thereof.

[0311] In some embodiments, the immunomodulatory compound is iberdomide, which also is known as (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-l-oxo-l,3-dihydro-isoindol-2-yl]-piperidine-2, 6-dione, having the following structure(Formula IV), or is an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof (hereinafterCompound 2). In some embodiments, the immunomodulatory compound is iberdomide hydrochloride.

[0312] In some embodiments, the immunomodulatory compound is or comprises lenalidomide. Lenalidomide is FDA approved for the treatment of multiple myeloma, myelodysplastic syndrome associated with deletion 5q, and most recently in relapsed / refractory mantle-cell lymphoma (MCL). Lenalidomide is a synthetic derivative of thalidomide, and is currently understood to have multiple immunomodulatory effects, including enforcement of immune synapse formation between T cell and antigen presenting cells (APCs). For example, in some cases, lenalidomide modulates T cell responses and results in increased interleukin (IL)-2 production in CD4+and CD8+T cells, induces the shift of T helper (Th) responses from Th2 to Thl, inhibits expansion of regulatory subset of T cells (Tregs), and improves functioning of immunological synapses in follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL)(Otahal et al., Oncoimmunology (2016) 5(4):el 115940). Lenalidomide also has direct tumoricidal activity in patients with multiple myeloma (MM) and directly and indirectly modulates survival of CLL tumor cells by affecting supportive cells, such as nurse-like cells found in the microenvironment of lymphoid tissues.I. Compositions and formulations

[0313] In some embodiments of the combination therapy methods, compositions, combinations, kits and uses provided herein, the combination therapy can be administered in one or more compositions, e.g., a pharmaceutical composition containing an immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2.

[0314] In some embodiments, the composition, e.g., a pharmaceutical composition containing the immunomodulatory compound, e.g., lenalidomide or Compound 1, can include carriers such as a diluent, adjuvant, excipient, or vehicle with which the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, and / or the cells are administered. Examples of suitable pharmaceutical carriers are described in“Remington’s Pharmaceutical Sciences” by E. W. Martin. Such compositions will contain a therapeutically effective amount of the immunomodulatory compound, e.g. lenalidomide, Compound 1 or Compound 2, generally in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, and sesame oil. Saline solutions and aqueous dextrose and glycerol solutions also can be employed as liquid carriers, particularly for injectable solutions. The pharmaceutical compositions can contain any one or more of a diluents(s), adjuvant(s), antiadherent(s), binder(s), coating(s), filler(s), flavor(s), color(s), lubricant(s), glidant(s), preservative(s), detergent(s), sorbent(s), emulsifying agent(s), pharmaceutical excipient(s), pH buffering agent(s), or sweetener(s) and a combination thereof. In some embodiments, the pharmaceutical composition can be liquid, solid, a lyophilized powder, in gel form, and / or combination thereof. In some aspects, the choice of carrier is determined in part by the particular inhibitor and / or by the method of administration.

[0315] Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride;benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as 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 dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and / or non-ionic surfactants such as polyethylene glycol (PEG), stabilizers and / or preservatives. The compositions containing the immunomodulatory compound, e.g., lenalidomide or Compound 1 can also be lyophilized.

[0316] In some embodiments, the pharmaceutical compositions can be formulated for administration by any known route including intramuscular, intravenous, intradermal, intralesional, intraperitoneal injection, subcutaneous, intratumoral, epidural, nasal, oral, vaginal, rectal, topical, local, otic, inhalational, buccal (e.g., sublingual), and transdermal administration or any route. In some embodiments, other modes of administration also are contemplated. In some embodiments, the administration is by bolus infusion, by injection, e.g., intravenous or subcutaneous injections, intraocular injection, periocular injection, subretinal injection, intravitreal injection, trans-septal injection, subscleral injection, intrachoroidal injection, intracameral injection, subconjectval injection, subconjuntival injection, sub-Tenon’s injection, retrobulbar injection, peribulbar injection, or posterior juxtascleral delivery. In someembodiments, administration is by parenteral, intrapulmonary, and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, a given dose is administered by a single bolus administration. In some embodiments, it is administered by multiple bolus administrations, for example, over a period of no more than 3 days, or by continuous infusion administration.

[0317] In some embodiments, the administration can be local, topical or systemic depending upon the locus of treatment. In some embodiments local administration to an area in need of treatment can be achieved by, for example, but not limited to, local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant. In someembodiments, compositions also can be administered with other biologically active agents,either sequentially, intermittently or in the same composition. In some embodiments, administration also can include controlled release systems including controlled release formulations and device controlled release, such as by means of a pump. In some embodiments, the administration is oral.

[0318] In some embodiments, pharmaceutically and therapeutically active compounds and derivatives thereof are typically formulated and administered in unit dosage forms or multiple dosage forms. Each unit dose contains a predetermined quantity of therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent. In some embodiments, unit dosage forms, include, but are not limited to, tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil water emulsions containing suitable quantities of the compounds or pharmaceutically acceptable derivatives thereof. Unit dose forms can be contained ampoules and syringes or individually packaged tablets or capsules. Unit dose forms can be administered in fractions or multiples thereof. In some embodiments, a multiple dose form is a plurality of identical unit dosage forms packaged in a single container to be administered in segregated unit dose form. Examples of multiple dose forms include vials, bottles of tablets or capsules or bottles of pints or gallons.

[0319] Active ingredients may be entrapped in microcapsules, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. In certain embodiments, the pharmaceutical composition containing the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, is formulated as an inclusion complex, such as cyclodextrin inclusion complex, or as a liposome. Liposomes can serve to target the host cells (e.g., T-cells or NK cells) to a particular tissue. Many methods are available for preparing liposomes, such as those described in, for example, Szoka et ah, Ann. Rev. Biophys. Bioeng., 9: 467 (1980), and U.S. Patents 4,235,871, 4,501,728, 4,837,028, and 5,019,369.

[0320] The pharmaceutical composition containing the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, in some aspects can employ time-released, delayed release, and sustained release delivery systems such that the delivery of the composition occurs prior to, and with sufficient time to cause, sensitization of the site to be treated. Many types of release delivery systems are available and known. Such systems can avoid repeatedadministrations of the composition, thereby increasing convenience to the subject and the physician.

[0321] The compositions containing the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, can also be lyophilized. The compositions can contain auxiliary substances such as wetting, dispersing, or emulsifying agents (e.g., methylcellulose), pH buffering agents, gelling or viscosity enhancing additives, preservatives, flavoring agents, colors, and the like, depending upon the route of administration and the preparation desired. Standard texts may in some aspects be consulted to prepare suitable preparations.

[0322] Various additives which enhance the stability and sterility of the compositions, including antimicrobial preservatives, antioxidants, chelating agents, and buffers, can be added. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0323] Sustained-release preparations may be prepared. Suitable examples of sustained- release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g. films, or microcapsules.

[0324] In some embodiments, the composition containing the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, are administered in the form of a salt, e.g., a pharmaceutically acceptable salt. Suitable pharmaceutically acceptable acid addition salts include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, and sulphuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, and arylsulphonic acids, for example, p-toluenesulphonic acid.2. Immunomodulatory compoun Dosage Schedule

[0325] In some embodiments, the provided combination therapy method involves administering to the subject a therapeutically effective amount of an immunomodulatory drug (immunomodulatory compound), e.g., lenalidomide, Compound 1 or Compound 2, and the cell therapy, such as a T cell therapy (e.g. CAR-expressing T cells).

[0326] In some embodiments, the administration of the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, is initiated prior to, subsequently to, during, during the course of, simultaneously, near simultaneously, sequentially and / or intermittently with the administration of the cell therapy, such as a T cell therapy (e.g. CAR-expressing T cells). In some embodiments, the method involves initiating the administration of the immunomodulatorycompound, e.g., lenalidomide, Compound 1 or Compound 2 prior to administration of the T cell therapy. In other embodiments, the method involves initiating the administration of the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, after administration of the T cell therapy. In some embodiments, the dosage schedule comprises initiating the administration of the immunomodulatory compound, e.g., lenalidomide,Compound 1 or Compound 2, concurrently or simultaneously with the administration of the T cell therapy.

[0327] In some embodiments, the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, is administered in a cycle. In some embodiments, the cycle comprises an administration period in which the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, is administered followed by a rest period during which the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, is not administered. In some embodiments, the total number of days of the cycle, e.g. from the beginning of initiating administration of the immunomodulatory compound, is greater than or greater than about or is about 21 days, 28 days, 30 days, 40 days, 50 days, 60 days or more.

[0328] In some embodiments, the initiation of the administration of the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, is carried out in at least one cycle and initiation of administration of the T cell therapy are carried out on the same day, optionally concurrently. In some embodiments, the initiation of the administration of theimmunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, in at least one cycle is prior to initiation of administration of the T cell therapy. In some embodiments, the initiation of the administration of the immunomodulatory compound, e.g., lenalidomide,Compound 1 or Compound 2, in at least one cycle is concurrent with or on the same day as initiation of administration of the T cell therapy. In some embodiments, the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, is administered from or from about 0 to 30 days, such as 0 to 15 days, 0 to 6 days, 0 to 96 hours, 0 to 24 hours, 0 to 12 hours,0 to 6 hours, or 0 to 2 hours, 2 hours to 15 days, 2 hours to 6 days, 2 hours to 96 hours, 2 hours to 24 hours, 2 hours to 12 hours, 2 hours to 6 hours, 6 hours to 30 days, 6 hours to 15 days, 6 hours to 6 days, 6 hours to 96 hours, 6 hours to 24 hours, 6 hours to 12 hours, 12 hours to 30 days, 12 hours to 15 days, 12 hours to 6 days, 12 hours to 96 hours, 12 hours to 24 hours, 24 hours to 30 days, 24 hours to 15 days, 24 hours to 6 days, 24 hours to 96 hours, 96 hours to 30 days, 96 hours to 15 days, 96 hours to 6 days, 6 days to 30 days, 6 days to 15 days, or 15 days to30 days prior to initiation of the T cell therapy. In some aspects, the immunomodulatorycompound, e.g., lenalidomide, Compound 1 or Compound 2, is administered no more than about 96 hours, 72 hours, 48 hours, 24 hours, 12 hours, 6 hours, 2 hours or 1 hour prior to initiation of the T cell therapy.

[0329] In some of any such embodiments in which the immunomodulatory compound, e.g., lenalidomide, is given prior to the cell therapy (e.g. T cell therapy, such as CAR-T cell therapy), the administration of the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, continues at regular intervals until the initiation of the cell therapy and / or for a time after the initiation of the cell therapy.

[0330] In some embodiments, the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, is administered, or is further administered, after administration of the cell therapy (e.g. T cell therapy, such as CAR-T cell therapy). In some embodiments, the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, isadministered within or within about 1 hours, 2 hours, 6 hours, 12 hours, 24 hours, 48 hours, 96 hours, 4 days, 5 days, 6 days or 7 days, 14 days, 15 days, 21 days, 24 days, 28 days, 30 days, 36 days, 42 days, 60 days, 72 days or 90 days after initiation of administration of the cell therapy (e.g. T cell therapy). In some embodiments, the provided methods involve continued administration, such as at regular intervals, of the immunomodulatory compound after initiation of administration of the cell therapy.

[0331] In some embodiments, the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, is administered up to or up to about 1 day, up to or up to about 2 days, up to or up to about 3 days, up to or up to about 4 days, up to or up to about 5 days, up to or up to about 6 days, up to or up to about 7 days, up to or up to about 12 days, up to or up to about 14 days, up to or up to about 21 days, up to or up to about 24 days, up to or up to about 28 days, up to or up to about 30 days, up to or up to about 35 days, up to or up to about 42 days, up to or up to about 60 days or up to or up to about 90 days, up to or up to about 120 days, up to or up to about 180 days, up to or up to about 240 days, up to or up about 360 days, or up to or up to about 720 days or more after the initiation of administration of the cell therapy (e.g. T cell therapy, such as CAR-T cell therapy).

[0332] In some of any such above embodiments, the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, is administered prior to and after initiation of administration of the cell therapy (e.g. T cell therapy, such as CAR-T cell therapy).

[0333] In some embodiments, the initiation of the administration of the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, is carried out at or after, optionallyimmediately after or within 1 to 3 days after: (i) peak or maximum level of the cells of the T cell therapy are detectable in the blood of the subject; (ii) the number of cells of the T cell therapy detectable in the blood, after having been detectable in the blood, is not detectable or is reduced, optionally reduced compared to a preceding time point after administration of the T cell therapy; (iii) the number of cells of the T cell therapy detectable in the blood is decreased by or more than 1.5-fold, 2.0-fold, 3.0-fold, 4.0-fold, 5.0-fold, lO-fold or more the peak or maximum number cells of the T cell therapy detectable in the blood of the subject after initiation of administration of the T cell therapy; (iv) at a time after a peak or maximum level of the cells of the T cell therapy are detectable in the blood of the subject, the number of cells of or derived from the T cells detectable in the blood from the subject is less than less than 10%, less than 5%, less than 1% or less than 0.1% of total peripheral blood mononuclear cells (PBMCs) in the blood of the subject; (v) the subject exhibits disease progression and / or has relapsed following remission after treatment with the T cell therapy; and / or (iv) the subject exhibits increased tumor burden as compared to tumor burden at a time prior to or after administration of the T cells and prior to initiation of administration of the immunomodulatory compound.

[0334] In some embodiments, the initiation of the administration of the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, in at least one cycle is after initiation of administration of the T cell therapy. In some embodiments, the initiation of the administration of the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, is at least or about at least 1 day, at least or about at least 2 days, at least or about at least 3 days, at least or about at least 4 days, at least or about at least 5 days, at least or about at least 6 days, at least or about at least 7 days, at least or about at least 8 days, at least or about at least 9 days, at least or about at least 10 days, at least or at least about 12 days, at least or about at least 14 days, at least or at least about 15 days, at least or about at least 21 days, at least or at least about 24 days, at least or about at least 28 days, at least or about at least 30 days, at least or about at least 35 days or at least or about at least 42 days, at least or about at least 60 days, or at least or about at least 90 days after initiation of the administration of the T cell therapy. In some embodiments, the initiation of the administration of the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, is carried out at least 2 days after, at least 1 week after, at least 2 weeks after, at least 3 weeks after, or at least 4 weeks after, the initiation of the administration of the T cell therapy. In some embodiments, the initiation of the administration of the immunomodulatory compound, e.g., lenalidomide, Compound 1 orCompound 2, is carried out 2 to 28 days or 7 to 21 days after initiation of administration of the Tcell therapy. In some embodiments, the initiation of the administration of theimmunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, is carried out at a time that is greater than or greater than about 14 days, 15 days, 16 days, 17 days, 18 days,19, days, 20 days, 21 days, 24 days, or 28 days after initiation of the administration of the T cell therapy. In some embodiments, the immunomodulatory compound, e.g., lenalidomide,Compound 1 or Compound 2, is administered several times a day, twice a day, daily, every other day, three times a week, twice a week, or once a week after initiation of the cell therapy. In some embodiments, the immunomodulatory compound, e.g., lenalidomide, Compound 1 orCompound 2, is administered daily. In some embodiments the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, is administered twice a day. In some embodiments, the immunomodulatory compound, e.g., lenalidomide, Compound 1 orCompound 2, is administered three times a day. In other embodiments, the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, is administered every other day.In some embodiments, the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, is administered daily. In some embodiments, the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, is administered during the administration period for a plurality of consecutive days, such as for up to about 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more than 30 consecutive days. In some embodiments, the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, is administered for greater than or greater than about 7 consecutive days, greater than or greater than about 14 consecutive days, greater than or greater than about 21 consecutive days, greater than or greater than about 21 consecutive days, or greater than or greater than about 28 consecutive days. In some embodiments, the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, is administered during the administration period for up to 21 consecutive days. In some embodiments, the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, is administered during the administration period for up to 21 consecutive days, wherein the cycle comprises greater than 30 days beginning upon initiation of the administration of the immunomodulatory compound.

[0335] In some embodiments, the immunomodulatory compound, e.g., lenalidomide orCompound 1, is administered during the administration period for no more than about 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or no more than30 consecutive days. In certain embodiments, the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, is administered once daily for 14 days over a 21day treatment cycle. In certain embodiments, the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, is administered once daily for 21 days over a 28 day treatment cycle. In some embodiments, the immunomodulatory compound, e.g.,lenalidomide, Compound 1 or Compound 2, is administered during the administration period for no more than 14 consecutive days.

[0336] In some embodiments, the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, is administered in a cycle, wherein the cycle comprises the administration of the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2 for a plurality of consecutive days followed by a rest period during which the immunomodulatory compound is not administered. In some embodiments, the rest period is greater than about 1 day, greater than about 3 consecutive days, greater than about 5 consecutive days, greater than about 7 consecutive days, greater than about 8 consecutive days, greater than about 9 consecutive days, greater than about 10 consecutive days, greater than about 11 consecutive days, greater than about 12 consecutive days, greater than about 13 consecutive days, greater than about 14 consecutive days, greater than about 15 consecutive days, greater than about 16 consecutive days, greater than about 17 consecutive days, greater than about 18 consecutive days, greater than about 19 consecutive days, greater than about 20 consecutive days, or greater than about 21 or more consecutive days. In some embodiments, the rest period is greater than 7 consecutive days, greater than 14 consecutive days, greater than 21 days, or greater than 28 days. In some embodiments, the rest period is greater than about 14 consecutive days. In some embodiments, the cycle of administration of the immunomodulatory compound does not contain a rest period.

[0337] In some embodiments, the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, is administered in a cycle, wherein the cycle is repeated at least one time. In some embodiments, the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, is administered for at least 2 cycles, at least 3 cycles, at least 4 cycles, at least 5 cycles, at least 6 cycles, at least 7 cycles, at least 8 cycles, at least 9 cycles, at least 10 cycles, at least 11 cycles, or at least 12 cycles. In some embodiments, theimmunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, isadministered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 cycles.

[0338] In some embodiments, the immunomodulatory compound, e.g., lenalidomide,Compound 1 or Compound 2, is administered six times daily, five times daily, four times daily,three times daily, twice daily, once daily, every other day, every three days, twice weekly, once weekly or only one time prior to or subsequently to initiation of administration of the T cell therapy. In some embodiments, the immunomodulatory compound, e.g., lenalidomide or Compound 1, is administered in multiple doses in regular intervals prior to, during, during the course of, and / or after the period of administration of the T cell therapy. In some embodiments, the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, is administered in one or more doses in regular intervals prior to the administration of the T cell therapy. In some embodiments, the immunomodulatory compound, e.g., lenalidomide or Compound 1, is administered in one or more doses in regular intervals after the administration of the T cell therapy. In some embodiments, one or more of the doses of the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, can occur simultaneously with the administration of a dose of the T cell therapy.

[0339] In some embodiments, the dose, frequency, duration, timing and / or order of administration of the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, is determined, based on particular thresholds or criteria of results of the screening step and / or assessment of treatment outcomes described herein, e.g., those described in Section III herein.

[0340] In some embodiments, the method involves administering the cell therapy to a subject that has been previously administered a therapeutically effective amount of the immunomodulatory compound. In some embodiments, the immunomodulatory compound is administered to a subject before administering a dose of cells expressing a recombinant receptor to the subject. In some embodiments, the treatment with the immunomodulatory compound occurs at the same time as the administration of the dose of cells. In some embodiments, the immunomodulatory compound is administered after the administration of the dose of cells.

[0341] In some embodiments, the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, is administered daily for 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or more than 21 days. In some embodiments, the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, is administered twice a day for 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or more than 21 days. In some embodiments, the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, isadministered three times a day for 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or more than 21 days. In some embodiments, the immunomodulatory compound, e.g., lenalidomide,Compound 1 or Compound 2, is administered every other day for 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or more than 21 days.

[0342] In some embodiments of the methods provided herein, the immunomodulatory compound, e.g., lenalidomide, Compound 1 or Compound 2, and the T cell therapy are administered simultaneously or near simultaneously.

[0343] In some embodiments, immunomodulatory compound, e.g. lenalidomide,Compound 1 or Compound 2, is administered at a dose of from or from about 0.1 mg to about 100 mg, from or from about 0.1 mg to 50 mg, from or from about 0.1 mg to 25 mg, from or from about 0.1 mg to 10 mg, from or from about 0.1 mg to 5 mg, from or from about 0.1 mg to 1 mg, from or from about 1 mg to 100 mg, from or from about 1 mg to 50 mg, from or from about 1 mg to 25 mg, from or from about 1 mg to 10 mg, from or from about 1 mg to 5 mg, from or from about 5 mg to 100 mg, from or from about 5 mg to 50 mg, from or from about 5 mg to 25 mg, from or from about 5 mg to 10 mg, from or from about 10 mg to 100 mg, from or from about 10 mg to 50 mg, from or from 10 mg to 25 mg, from or from about 25 mg to 100 mg, from or from about 25 mg to 50 mg or from or from about 50 mg to 100 mg, each inclusive. In some embodiments, the amount is a once daily amount of the immunomodulatory compound, e.g. lenalidomide, Compound 1 or Compound 2.

[0344] In some embodiments, the immunomodulatory compound, e.g. lenalidomide, Compound 1, is administered at a dosage of from about 1 mg to about 20 mg, e.g., from about 1 mg to about 10 mg, from about 2.5 mg to about 7.5 mg, from about 5 mg to about 15 mg, such as about 5 mg, 10 mg, 15 mg or 20 mg. In some embodiments, the immunomodulatory compound, e.g. lenalidomide or Compound 1 is administered at a dose of from about 10 pg / kg to 5 mg / kg, e.g., about 100 pg / kg to about 2 mg / kg, about 200 pg / kg to about 1 mg / kg, about 400 pg / kg to about 600 pg / kg, such as about 500 pg / kg. In some embodiments, the amount is a once daily amount of the immunomodulatory compound, e.g. lenalidomide or Compound 1. In some embodiments, the immunomodulatory compound is Compound l.In some embodiments, the immunomodulatory compound, e.g., lenalidomide, Compound 1, or Compound 2, is administered at a total daily dosage amount of at least or at least about 0.1 mg per day, 0.5 mg per day, 1.0 mg per day, 2.5 mg per day, 5 mg per day, 10 mg per day, 25 mg per day, 50 mg per day or 100 mg per day. In some embodiments, the dose of the immunomodulatory compound, e.g. lenalidomide or Compound 1 is or is about 25 mg per day. In particular embodiments, the dose of the immunomodulatory compound, e.g. lenalidomide or Compound 1 is or is aboutlO mg per day. In some embodiments, the immunomodulatory compound is Compound 1.

[0345] In some embodiments, the immunomodulatory compound, e.g. lenalidomide or Compound 1, is administered in an amount greater than or greater than about 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg and less than 25 mg. In some embodiments, the immunomodulatory compound, e.g. lenalidomide or Compound 1, is administered in an amount greater than or greater than about 1 mg per day, 2.5 mg per day, 5 mg per day, 7.5 mg per day, 10 mg per day,15 mg per day and less than 25 mg per day. In some embodiments, the immunomodulatory compound is Compound 1.

[0346] In some embodiments, the provided methods include administering an effective amount of Compound 2 per day to a subject to modulate activity and / or function of the T cell therapy. In some embodiments, Compound 2 is administered at a dosage of from or from about 0.1 mg to at or about 1 mg. In some embodiments, the amount is at or about 0.1 mg, at or about 0.2 mg, at or about 0.3 mg, at or about 0.4 mg, at or about 0.5 mg, at or about 0.6 mg, at or about 0.7 mg, at or about 0.8 mg, at or about 0.9 mg or at or about 1.0 mg, or any value between any of the foregoing. In some embodiments, the amount of Compound 2 is administered in a cycling regimen involving daily administration for three weeks in a four week period or cycle. The administration of Compound 2 is carried out for a period of time, such as generally for more than one week, such as for at or greater than one month, at or greater than two months, at or greater than three months, at or greater than four months, at or greater than five months or at or greater than six months. Exemplary dosing regimens are described herein. In someembodiments, the provided methods include administering an effective amount of Compound 1 per day to a subject to modulate activity and / or function of the T cell therapy. In some embodiments, the effective amount is no more than 3 mg per day. In some embodiments, the effective amount is from or from about 1 mg to about 3 mg per day for the extent of the period, such as is at or about 1 mg per day, 1.5 mg per day, 2.0 mg per day, 2.5 mg per day or 3 mg per day. In some embodiments, the amount of Compound 1 is administered in a cycling regimen involving daily administration for no more than 5 days per week. The administration ofCompound 1 is carried out for a period of time, such as generally for more than one week, such as for at or greater than one month, at or greater than two months, at or greater than three months, at or greater than four months, at or greater than five months or at or greater than six months. Exemplary dosing regimens are described herein. In some embodiments, for each week of a cycling regimen, or for at least one week of the cycling regimen, Compound 1 isadministered for consecutive days in a week (e.g. each of 3, 4 or 5 days) followed by several days of rest during which the compound is not administered. In some embodiments, Compound1 is administered in a cycling regimen, or at least one week of the cycling regimen, in the amount (e.g. 1 mg to 3 mg per day) for 5 days followed by a rest period of two days during which the compound is not administered (5 / 7 day per week).

[0347] In some aspects, the provided methods minimize or avoid toxicity following administration of the T cell therapy and / or immunomodulatory compound, e.g. lenalidomide or Compound 1, to a subject. In some aspects, the methods provided herein involve administering doses that are substantially lower than doses identified to be the MTD for the compound.

[0348] For example, it has been reported that for Compound 1 a starting dose of 2 mg given 5 / 7 days is 2 times lower than the MTD when 3 mg Compound 1 is given 5 / 7 days (Carpio el al. (2015). In some aspects, the provided methods are carried out by administering an amount of the compound that is or is less than 3 mg per day given 5 / 7 days, such as is or is about 2.5 mg, 2.0 mg, 1.5 mg, 1.0 mg given 5 / 7 days per week. In some embodiments, Compound 1 is administered to the subject a sufficient time after receiving a lymphodepleting therapy, such that myelosuppressive effects of Compound 1 and the lymphodepleting therapy are minimized. In some embodiments, the administration of Compound 1 is initiated at a time after, or that is suspected or likely to be after, peak CAR-T cells are present in the blood of the subject, e.g. at or after 14 days after initiation of administration of the T cell, such as 14 to 28 days, e.g. at or about 21 days or 28 days after initiation of administration of the cell therapy. In some embodiments, Compound 1 is administered at a time when the subject does not exhibit a severe toxicity following the administration of the cell therapy.

[0349] In some of any of the embodiments, the methods and uses include administration ofCompound 1. In some embodiments, the administration of Compound 1 is initiated after(subsequent to) the initiation of the cell therapy, such as a T cell therapy (e.g., CAR-expressingT cells). In some embodiments, administration of Compound 1 is initiated at or after peak or maximum level of the cells of the T cell therapy is detectable in the blood of the subject. In some cases, initiation of administration Compound 1 is carried out at or within a week, such as within 1, 2 or 3 days after (i) a time in which peak or maximum level of the cells of the T cell therapy are detectable in the blood of the subject; (ii) the number of cells of the T cell therapy detectable in the blood, after having been detectable in the blood, is not detectable or is reduced, optionally reduced compared to a preceding time point after administration of the T cell therapy;(iii) the number of cells of the T cell therapy detectable in the blood is decreased by or more than 1.5-fold, 2.0-fold, 3.0-fold, 4.0-fold, 5.0-fold, lO-fold or more the peak or maximum number cells of the T cell therapy detectable in the blood of the subject after initiation ofadministration of the T cell therapy; (iv) at a time after a peak or maximum level of the cells of the T cell therapy are detectable in the blood of the subject, the number of cells of or derived from the cells detectable in the blood from the subject is less than less than 10%, less than 5%, less than 1% or less than 0.1% of total peripheral blood mononuclear cells (PBMCs) in the blood of the subject; (v) the subject exhibits disease progression and / or has relapsed following remission after treatment with the T cell therapy; and / or (iv) the subject exhibits increased tumor burden as compared to tumor burden at a time prior to or after administration of the cells and prior to initiation of administration of Compound 1. In certain aspects, the provided methods are carried out to enhance, increase or potentiate T cell therapy in subjects in which a peak response to the T cell therapy has been observed but in which the response, e.g. presence of T cells and / or reduction in tumor burden, has become reduced or is no longer detectable.

[0350] In some embodiments, the administration of Compound 1 is initiated at or about 14 to about 35 days after initiation of administration of the T cell therapy. In some embodiments, the administration of Compound 1 is initiated about 21 to about 35 days after initiation of administration of the T cell therapy. In some embodiments, the administration of Compound 1 is initiated about 21 to about 28 days after initiation of administration of the T cell therapy. In some embodiments, the administration of Compound 1 is initiated at or about 14 days, at or about 15 days, at or about 16 days, at or about 17 days, at or about 18 days, at or about 19 days, at or about 20 days, at or about 21 days, at or about 22 days, at or about 23 days, at or about 24 days, at or about 25 days, at or about 26 days, at or about 27 days, at or about 28 days, at or about 29 days, at or about 30 days, at or about 31 days, at or about 32 days, at or about 33 days, at or about 34 days, or at or about 35 days after initiation of administration of the T cell therapy.

[0351] In some embodiments, at the time at which the subject is first administeredCompound 1 and / or at any subsequent time after initiation of the administration, the subject does not exhibit a sign or symptom of a severe toxicity, such as severe cytokine release syndrome(CRS) or severe toxicity. In some embodiments, the administration of Compound 1 is at a time at which the subject does not exhibit a sign or symptom of severe CRS and / or does not exhibit grade 3 or higher CRS, such as prolonged grade 3 CRS or grade 4 or 5 CRS. In someembodiments, the administration of Compound 1 is at a time at which the subject does not exhibit a sign or symptom of severe neurotoxicity and / or does not exhibit grade 3 or higher neurotoxicity, such as prolonged grade 3 neurotoxicity or grade 4 or grade 5 neurotoxicity. In some aspects, between the time of the initiation of the administration of the T cell therapy and the time of the administration of Compound 1, the subject has not exhibited severe CRS and / orhas not exhibited grade 3 or higher CRS, such as prolonged grade 3 CRS or grade 4 or 5 CRS.In some instances, between the time of the initiation of the administration of the T cell therapy and the time of the administration of Compound 1, the subject has not exhibited severe neurotoxicity and / or does not exhibit grade 3 or higher neurotoxicity, such as prolonged grade 3 neurotoxicity or grade 4 or 5 neurotoxicity.

[0352] In some embodiments, administration of Compound 1 per day it is administered is at an amount of from or from about 0.1 mg to 5 mg. In some embodiments, administration of Compound 1 per day it is administered is at an amount of about 0.1 mg to about 5 mg, about 0.5 mg to about 5 mg, about 1 mg to about 5 mg, about 1.5 mg to about 5 mg, about 2 mg to about 5 mg, about 2.5 mg to about 5 mg, about 3 mg to about 5 mg, about 0.1 mg to about 4 mg, about 0.1 mg to about 4 mg, about 1 mg to about 4 mg, about 1.5 mg to about 4 mg, about 2 mg to about 4 mg, about 2.5 mg to about 4 mg, about 3 mg to about 4 mg, about 0.1 mg to about 3.5 mg, about 0.5 mg to about 3.5 mg, about 1 mg to about 3.5 mg, about 1.5 mg to about 3.5 mg, about 2 mg to about 3.5 mg, about 2.5 mg to about 3.5 mg, about 3 mg to about 3.5 mg, about 0.1 mg to about 3 mg, about 0.5 mg to about 3 mg, about 1 mg to about 3 mg, about 1.5 mg to about 3 mg, about 2 mg to about 3 mg, about 2.5 mg to about 3 mg, about 0.1 mg to about 2.5 mg, about 0.5 mg to about 2.5 mg, about 1 mg to about 2.5 mg, about 1.5 mg to about 2.5 mg, about 2 mg to about 2.5 mg, about 0.1 mg to about 2 mg, about 0.5 mg to about 2 mg, about 1 mg to about 2 mg, about 1.5 mg to about 2 mg, about 0.1 mg to about 1.5 mg, about 0.5 mg to about 1.5 mg, about 1 mg to about 1.5 mg, about 0.1 mg to about 1 mg, or about 0.5 mg to about 1 mg.

[0353] In some embodiments, administration of Compound 1 per day it is administered is at an amount of about or at least about, or at or at least at 0.5 mg. In some embodiments, administration of Compound 1 per day it is administered is at an amount of about or at least about, or at or at least at 1 mg. In some embodiments, administration of Compound 1 per day it is administered is at an amount of about or at least about, or at or at least at 1.5 mg. In some embodiments, administration of Compound 1 per day it is administered is at an amount of about or at least about, or at or at least at 2 mg. In some embodiments, administration of Compound 1 per day it is administered is at an amount of about or at least about, or at or at least at 2.5 mg. In some embodiments, administration of Compound 1 per day it is administered is at an amount of about or at least about, or at or at least at 3 mg. In some of any such embodiments,administration of Compound 1 per day it is administered is at an amount of no more than about5 mg. In some embodiments, administration of Compound 1 per day it is administered is at anamount of no more than about 4.5 mg. In some embodiments, administration of Compound 1 per day it is administered is at an amount of no more than about 4 mg. In some embodiments, administration of Compound 1 per day it is administered is at an amount of no more than about 3.5 mg. In some embodiments, administration of Compound 1 per day it is administered is at an amount of no more than about 3 mg . In some embodiments, administration of Compound 1 per day it is administered is at an amount of no more than about 2.5 mg. In some embodiments, administration of Compound 1 per day it is administered is at an amount of no more than about 2 mg. In some embodiments, administration of Compound 1 per day it is administered is at an amount of no more than about 1.5 mg. In some embodiments, administration of Compound 1 per day it is administered is at an amount of no more than about 1 mg.

[0354] In some embodiments, administration of Compound 1 per day it is administered is at an amount of at or about 3 mg. In some embodiments, administration of Compound 1 per day it is administered is at an amount of at or about 2.5 mg. In some embodiments, administration of Compound 1 per day it is administered is at an amount of at or about 2 mg. In someembodiments, administration of Compound 1 per day it is administered is at an amount of at or about 1.5 mg. In some embodiments, administration of Compound 1 per day it is administered is at an amount of at or about 1 mg per day.

[0355] In some embodiments, Compound 1 is administered in an amount that achieves a maximum concentration (Cmax) of Compound 1 in the blood, such as for each week of a cycling regimen or for at least one week of a cycling regimen, in a range of about 10 nM to about 500 nM, about 40 nM to about 500 nM, about 60 nM to about 500 nM, about 80 nM to about 500 nM, about 100 nM to about 500 nM, about 150 nM to about 500 nM, about 200 nM to about500 nM, about 250 nM to about 500 nM, about 300 nM to about 500 nM, about 350 nM to about 500 nM, about 400 nM to about 500 nM, 10 nM to about 400nM, about 40 nM to about400 nM, about 60 nM to about 400 nM, about 80 nM to about 400 nM, about 100 nM to about400 nM, about 150 nM to about 400 nM, about 200 nM to about 400 nM, about 250 nM to about 400 nM, about 300 nM to about 400 nM, about 350 nM to about 400 nM, 10 nM to about350 nM, about 40 nM to about 350 nM, about 60 nM to about 350 nM, about 80 nM to about350 nM, about 100 nM to about 350 nM, about 150 nM to about 350 nM, about 200 nM to about 350 nM, about 250 nM to about 350 nM, about 300 nM to about 350 nM, about 10 nM to about 300 nM, about 40 nM to about 300 nM, about 60 nM to about 300 nM, about 80 nM to about 300 nM, about 100 nM to about 300 nM, about 150 nM to about 300 nM, about 200 nM to about 300 nM, about 250 nM to about 250 nM, about 10 nM to about 250 nM, about 40 nMto about 250 nM, about 60 nM to about 250 nM, about 80 nM to about 250 nM, about 100 nM to about 250 nM, about 150 nM to about 250 nM, about 200 nM to about 250 nM, about 10 nM to about 200 nM, about 40 nM to about 200 nM, about 60 nM to about 200 nM, about 80 nM to about 200 nM, about 100 nM to about 200 nM, about 150 nM to about 200 nM, about 10 nM to about 150 nM, about 40 nM to about 150 nM, about 60 nM to about 150 nM, about 80 nM to about 150 nM, about 100 nM to about 150 nM, about 10 nM to about 100 nM, about 40 nM to about 100 nM, about 60 nM to about 100 nM, or about 80 nM to about 100 nM. In some embodiments, Compound 1 is administered at an amount that maintains the Cmaxin the range for at least about 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 16 hours or 24 hours

[0356] In some embodiments, Compound 1 is administered at an amount that achieves a Cmaxof Compound 1 in the blood at about or at least about 40 nM. In some embodiments, Compound 1 is administered at an amount that achieves a Cmaxof Compound 1 in the blood at about or at least about 60 nM. In some embodiments, Compound 1 is administered at an amount that achieves a Cmax of Compound 1 in the blood, such as for each week of a cycling regimen or for at least one week of a cycling regimen, of at about or at least about 80 nM. In some embodiments, Compound 1 is administered at an amount that achieves a Cmax of Compound 1 in the blood, such as for each week of a cycling regimen or for at least one week of a cycling regimen, of at about or at least about 90 nM. In some embodiments, Compound 1 isadministered at an amount that achieves a Cmax of Compound 1 in the blood, such as for each week of a cycling regimen or for at least one week of a cycling regimen, of at about or at least about 100 nM. In some embodiments, Compound 1 is administered at an amount that maintains the Cmax for at least about 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 16 hours or 24 hours.

[0357] In some embodiments, Compound 1 is administered at an amount that achieves aCmaxof Compound 1 in the blood, such as for each week of a cycling regimen or for at least one week of a cycling regimen, of at no more than about 500 nM. In some embodiments, Compound1 is administered at an amount that achieves a Cmax of Compound 1 in the blood, such as for each week of a cycling regimen or for at least one week of a cycling regimen, of at no more than about 400 nM. In some embodiments, Compound 1 is administered at an amount that achieves aCmaxof Compound 1 in the blood, such as for each week of a cycling regimen or for at least one week of a cycling regimen, of at no more than about 350 nM. In some embodiments, Compound1 is administered at an amount that achieves a Cmax of Compound 1 in the blood, such as for each week of a cycling regimen or for at least one week of a cycling regimen, of at no more than about 300 nM. In some embodiments, Compound 1 is administered at an amount that achieves aCmaxof Compound 1 in the blood, such as for each week of a cycling regimen or for at least one week of a cycling regimen, of at no more than about 250 nM. In some embodiments, Compound 1 is administered at an amount that achieves a Cmaxof Compound 1 in the blood, such as for each week of a cycling regimen or for at least one week of a cycling regimen, of at no more than about 200 nM. In some embodiments, Compound 1 is administered at an amount that achieves a Cmaxof Compound 1 in the blood, such as for each week of a cycling regimen or for at least one week of a cycling regimen, of at no more than about 150 nM.

[0358] In some embodiments, Compound 1 is administered in a cycling regimen that involves repeated dosing of the compound for a specified period or duration. In some embodiments, Compound 1 is administered in a cycling regimen in which, for each week of the cycling regimen or for at least one week of the cycling regimen, the compound is administered in an effective amount, such as an amount described above, on each of no more than 5 days per week for a period of more than one week. In some embodiments, the amount of Compound 1 for each administration or per day it is administered is no more than 3 mg (e.g., no more than 3mg, 2.5 mg, 2 mg, l.5mg, lmg, 0.5 mg). In some embodiments, the amount of Compound 1 for each administration or per day it is administered is at or about 3mg, at or about 2.5mg, at or about 2mg, at or about l.5mg, at or about lmg, at or about 0.5 mg. In some embodiments, the amount of Compound 1 for each administration or per day it is administered is about lmg to about 2mg (e.g., at or about lmg, at or about 2mg).

[0359] In some embodiments, each week of a cycling regimen comprises administering Compound 1 each of no more than 5 days per week. In some embodiments, each week of a cycling regimen comprises administering Compound 1 for each of no more than 4 days per week. In some embodiments, each week of a cycling regimen comprises administeringCompound 1 for each of no more than 3 days per week.

[0360] In some embodiments, each week of a cycling regimen comprises administering Compound 1 for 3 to 5 days per week. In some embodiments, each week of a cycling regimen comprises administering Compound 1 for 4 to 5 days per week. In some embodiments, each week of a cycling regimen comprises administering Compound 1 for 3 to 4 days per week.

[0361] In some embodiments, the each week of a cycling regimen, or at least one week of a cycling regimen, comprises administering Compound 1 on each of no more than 5 consecutive days per week followed by a rest period for the remainder of the week during which the compound is not administered. In some embodiments, each week of a cycling regimen, or at least one week of a cycling regimen, comprises administering Compound 1 for 3 to 5consecutive days per week followed by a rest period for the remainder of the week during which the compound is not administered. In some embodiments, each week of the cycling regimen, or at least one week of the cycling regimen, comprises administering Compound 1 on each of 3 consecutive days per week followed by a rest period of 4 days during which the compound is not administered. In some embodiments, each week of a cycling regimen, or at least one week of a cycling regimen, comprises administering Compound 1 on each of 4 consecutive days per week followed by a rest period of 3 days during which the compound is not administered. In some embodiments, each week of a cycling regimen, or at least one week of a cycling regimen, comprises administering Compound 1 one each of 5 consecutive days per week followed by a rest period of 2 days during which the compound is not administered.

[0362] In some embodiments, the cycling regimen for administering Compound 1 is carried out for a period of time subsequent to initiation of administration of the T cell therapy. In some embodiments, administration of Compound 1 extends for a period of more than one week after initiation of administration of the T cell therapy. In some embodiments, administration of Compound 1 extends for a period of about or at least about one month after initiation of administration of the T cell therapy. In some embodiments, administration of Compound 1 extends for a period of about or at least about two months after initiation of administration of the T cell therapy. In some embodiments, administration of Compound 1 extends for a period of about or at least about three months after initiation of administration of the T cell therapy. In some embodiments, administration of Compound 1 extends for a period of about or at least about four months after initiation of administration of the T cell therapy. In some embodiments, administration of Compound 1 extends for a period of about or at least about five months after initiation of administration of the T cell therapy.

[0363] In some embodiments, administration of Compound 1 extends for a period of at least three months. In some embodiments, administration of Compound 1 extends for a period of at or about 90 days, at or about 100 days, at or about 105 days, at or about 110 days, at or about 115 days, at or about 120 days, at or about 125 days, at or about 130 days, at or about 135 days, at or about 140 days, at or about 145 days, at or about 150 days, at or about 155 days, at or about 160 days, at or about 165 days, at or about 170 days, at or about 175 days, at or about 180 days, at or about 185 days, at or about 190 days, at or about 195 days, at or about 200 days or more after initiation of administration of the T cell therapy.

[0364] In some embodiments, administration of Compound 1 extends for a period of at or about 90 days or at or about three months after initiation of administration of the T cell therapy( e.g ., CAR T cell therapy). In some embodiments, administration of Compound 1 extends for a period of at or about 120 days or four months after initiation of administration of the T cell therapy (e.g., CAR T cell therapy). In some embodiments, administration of Compound 1 extends for a period of at or about 150 days or five months after initiation of administration of the T cell therapy (e.g., CAR T cell therapy). In some embodiments, administration ofCompound 1 extends for a period of at or about 180 days or six months after initiation of administration of the T cell therapy (e.g., CAR T cell therapy).

[0365] In some embodiments, administration of Compound 1 is ended or stopped at the end of the period (e.g. at or about 3, 4, 5, or 6 months) after initiation of administration of the T cell therapy (e.g., CAR T cell therapy) if the subject has, prior to or at or about 6 months, achieved a complete response (CR) following the treatment or the cancer (e.g. B cell malignancy) has progressed or relapsed following remission after the treatment. In some embodiments, the period is of a fixed duration such that the administration of Compound 1 is continued for the period even if the subject has achieved a complete response (CR) at a time point prior to the end of the period. In some embodiments the subject is has a CR with minimal residual disease (MRD). In some embodiments, the subject has a CR that is MRD-.

[0366] In some embodiments, administration of Compound 1 is continued after the end of the period, e.g. continued for longer than at or about 3, 4, 5 or 6 months after initiation of administration of the T cell therapy (e.g. CAR T cells), if the subject exhibits a partial response (PR) or stable disease (SD) after the treatment. In some embodiments, administration of Compound 1 is continued for greater than 6 months after initiation of administration of the T cell therapy (e.g., CAR T cell therapy). In some embodiments, for subjects that exhibited a PR or SD at the end of the initial period, administration of Compound 1 is continued until the subject has achieved a complete response (CR) following the treatment or until the cancer (e.g.B cell malignancy, such as an NHL, e.g. DLBCL) has progressed or relapsed following...

Claims

WHAT IS CLAIMED:

1. A method for or rescuing T cell activity, the method comprising exposing a plurality of T cells having an exhausted phenotype to an effective amount of animmunomodulatory 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).

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

3. A method for increasing T cell activity or potency and preventing or inhibiting, reducing or delaying the onset of T cell exhaustion, the 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 ubiquitination, depletion and / or degradation of Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein at least a portion of the exposing is carried out during conditions that induce, or are capable of inducing, an exhausted phenotype in T cells of the plurality in the absence of the compound.

4. A method for reducing or delaying the onset of T cell exhaustion, the 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 ubiquitination, depletion and / or degradation of Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein at least a portion of the exposing is carriedout during conditions that induce, or are capable of inducing, an exhausted phenotype in T cells of the plurality in the absence of the compound.

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 stimulatory agent that is capable of stimulating a signal in T cells of the plurality, said signal optionally including a primary and / or costimulatory signal.

6. The method of claim 5, wherein the conditions comprise persistent, repeat, prolonged or long term exposure to the at least one T cell stimulatory agent.

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

8. The method of claim 5-7, wherein the at least one T cell stimulatory agent comprises an anti-CD3 antibody.

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-l-BB), 0X40, CD40L or ICOS.

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

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

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

13. The method of claim 12, wherein the at least one T cell stimulatory agent is or comprises an anti-idioptypic antibody specific to the recombinant antigen receptor.

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

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

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

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

18. The method of any of claims 1-17, wherein the exposing is carried out ex vivo.

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

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

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

22. The method of any of claims 19-21, wherein said exposing comprises administration of said plurality of T cells to a subject, optionally wherein, where the T cells are from the subject, wherein the administration of the compound is to said subject.

23. The method of claim 22, wherein: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, wherein, prior to the exposing, said subject has been administered said compound; orsaid 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 comprises administration of said compound to said subject.

24. A method of treatment, the method comprising administering, to a subject, an immunomodulatory compound, wherein said 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), wherein, (a) said subject, prior to the administration of the compound, has been administered a T cell therapy comprising a dose of T cells expressing a recombinant antigen receptor that binds a target antigen, or (b) prior to or at the time of administration of said compound, said subject or a blood sample from the subject contains, or has been confirmed to contain, one or more T cells expressing a recombinant antigen receptor,wherein at the time of the administration of the compoundone or more of therecombinant receptor-expressing T cells in the subject has an exhausted phenotype.

25. The method of claim 24, wherein at the time of the administration of the compoundan exhausted phenotype of one or more of the 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 from the subject.

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

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

28. A method of treatment, the method comprising:(a) selecting a subject as a candidate for administration of an immunomodulator compound, said selected subject having exhausted recombinant receptor-expressing T cells; and(b) administering to the subject the immunomodulatory compound, 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).

29. The method of claim 28, wherein a tissue, tumor, biological fluid or biological sample of or from said selected subjectcomprises one or more T cells that express a recombinant antigen receptor that binds to a target antigen and that have an exhausted phenotype.

30. The method of claim 29, wherein 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, wherein at least at or about 10%, at least at or about 20%, at least at or about 30%, at least at or about 40%, at least at or about 50%, at least at or about 60 %, at least at or about 70 % or at least at or about 80 %, of the T cells in said tissue, fluid, tumor or sample expressing the recombinant receptor have an exhausted phenotype.

31. The method of claim 29 or claim 30, wherein the tissue, tumor, biological fluid or biological samplecomprises a plurality of T cells that express a recombinant antigen receptor that binds to a target antigen, wherein greater than at or about 10% more, greater than at or about20% more, greater than at or about 30% more, greater than at or about 40% more, or greater than at or about 50% more, or greater than 2-fold more, or greater than 3-fold more, or greater than 5-fold more, or greater than lO-fold more, of the T cells in the tissue, tumor, fluid or sample of or from the selected subject that express the recombinant antigen receptor have an exhausted phenotype, as compared to the percentage or number of T cells expressing the recombinant receptor in the, or in a comparable, fluid, tissue, tumor or sample from said subject at earlier time point had said exhausted phenotype.

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

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

34. The method of claim 27 or claim 30 or claim 33, wherein the prior time point is a time:subsequent to the administration of T cells expressing said recombinant receptor to said selected subject and is at or before a peak or maximum level of T cells expressing recombinant receptor are detectable in the blood of the subject;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 prior to said determination or selection.

35. The method of any of claims 24-34, wherein:at the time of the administration of the T cell therapy the subject had a disease or condition; orat the time of the administration of the T cell therapy and at the time of theadministration of the compound the subject has a disease or condition.

36. The method of any of claims 20-35, wherein at the time of the administration of the T cell therapy the subject had a disease or condition and at the time of the administration ofthe compound the disease or condition has relapsed or progressed or been deemed non- responsive to said compound in the subject following the administration of the T cell therapy.

37. The method of any of claims 1-36, wherein the exhaustion phenotype, with reference to a T cell or population of T cells, comprises:an increase in the level or degree of surface expression on the T cell or T cells, or in the percentage of T said population of T cells exhibiting surface expression, of one or more exhaustion marker, optionally 2, 3, 4, 5 or 6 exhaustion markers, compared to a reference T cell population under the same conditions; ora decrease in the level or degree of an activity exhibited by said T cells 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.

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

39. The method of claim 37, wherein the decrease in the level, degree or percentage is by greater than at or about 1.2-fold, at or about 1.5-fold, at or about 2.0-fold, at or about 3- fold, at or about 4-fold, at or about 5-fold, at or about 6-fold, at or about 7-fold, at or about 8- fold, at or about 9-fold, at or about lO-fold or more.

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

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

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

43. The method of any of claims 37-42, wherein one or more of the one or more exhaustion marker is an inhibitory receptor.

44. The method of any of claims 37-43, wherein one or more of the one or more exhaustion marker is selected from among PD-l, CTLA-4, TIM-3, LAG-3, BTLA, 2B4, CD 160, CD39, VISTA, and TIGIT.

45. The method of any of claims 37-44, wherein the activity or 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. The method of any of claims 37-45, wherein the exposure to said antigen or antigen receptor- specific agent comprises incubation with the antigen or antigen receptor- specific agent, optionally an agent that binds the recombinant receptor, wherein said antigen is optionally the target antigen.

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

48. The method of any of claims 2 and 11—47, wherein the target antigen is associated with, specific to, and / or expressed on a cell or tissue of a disease, disorder or condition.

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

50. The method of any of claims 2 and 11-48, wherein the target antigen is selected from among anbό integrin (avb6 integrin), B cell maturation antigen (BCMA), BAFF-R, B7-H3,B7-H6, carbonic anhydrase 9 (CA9, also known as CAIX or G250), a cancer-testis antigen, cancer / testis antigen 1B (CTAG, also known as NY-ESO-l and LAGE-2), carcinoembryonic antigen (CEA), a cyclin, cyclin A2, C-C Motif Chemokine Ligand 1 (CCL-l), CD19, CD20,CD22, CD23, CD24, CD30, CD33, CD38, CD44, CD44v6, CD44v7 / 8, CD123, CD133, CD138,CD 171, CS-l, chondroitin sulfate proteoglycan 4 (CSPG4), epidermal growth factor protein(EGFR), truncated epidermal growth factor protein (tEGFR), type III epidermal growth factor receptor mutation (EGFR vIII), epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40(EPG-40), ephrinB2, ephrine receptor A2 (EPHa2), estrogen receptor, Fc receptor like 5(FCRL5; also known as Fc receptor homolog 5 or FCRH5), fetal acetylcholine receptor (fetalAchR), a folate binding protein (FBP), folate receptor alpha, ganglioside GD2, O-acetylatedGD2 (OGD2), ganglioside GD3, glycoprotein 100 (gplOO), glypican-3 (GPC3), G ProteinCoupled Receptor 5D (GPCR5D), Her2 / neu (receptor tyrosine kinase erb-B2), Her3 (erb-B3),Her4 (erb-B4), erbB dimers, Human high molecular weight-melanoma-associated antigen(HMW-MAA), hepatitis B surface antigen, Human leukocyte antigen Al (HLA-A1), Human leukocyte antigen A2 (HLA-A2), IL-22 receptor alpha(IL-22Ra), IL-13 receptor alpha 2 (IL- l3Ra2), kinase insert domain receptor (kdr), kappa light chain, Ll cell adhesion molecule (Ll-CAM), CE7 epitope of Ll-CAM, Leucine Rich Repeat Containing 8 Family Member A(LRRC8A), Lewis Y, Melanoma-associated antigen (MAGE)-Al, MAGE-A3, MAGE-A6,MAGE-A10, mesothelin (MSLN), c-Met, murine cytomegalovirus (CMV), mucin 1 (MUC1),MUC16, natural killer group 2 member D (NKG2D) ligands, melan A (MART-l), neural cell adhesion molecule (NCAM), oncofetal antigen, Preferentially expressed antigen of melanoma(PRAME), progesterone receptor, a prostate specific antigen, prostate stem cell antigen(PSCA), prostate specific membrane antigen (PSMA), Receptor Tyrosine Kinase Like OrphanReceptor 1 (ROR1), survivin, TACI, Trophoblast glycoprotein (TPBG also known as 5T4), tumor-associated glycoprotein 72 (TAG72), Tyrosinase related protein 1 (TRP1, also known asTYRP1 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-l), a pathogen-specific or pathogen-expressed antigen, or an antigen associated with a universal tag, and / or biotinylated molecules, and / or molecules expressed by HIV, HCV, HBV or other pathogens.

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

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

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

54. The method of any of claims 1-51, wherein the disease or condition is a multiple myeloma.

55. The method of any of claims 2 and 11-51 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-l, syndecan, SYN-l), CS-l (CS1, CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24), BAFF-R, TACI or FcRH5.

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

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

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

59. A method of treatment, the method comprising:(a) administering a T cell therapy to a subject having a cancer, said T cell therapy comprising a dose of T cells expressing a recombinant antigen receptor that binds to a target antigen; and(b) administering to the subject an immune modulatory 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), at an amount, duration and / or frequency effective to:(1) effect an increase in antigen- specific or antigen receptor-driven activity of naive or non-exhausted T cells in the subject, which optionally comprise T cells expressing said recombinant receptor, following exposure of the T cells to antigen or to an antigen receptor- specific agent as compared to the absence of said administration of said compound; or(2) prevent, inhibit or delay the onset of an exhaustion phenotype, in naive or non- exhausted T cells T cells in the subject, which optionally comprise T cells expressing said recombinant receptor, following exposure of the T cells to antigen or to an antigen receptor- specific agent, as compared to the absence of said administration of said compound; or(3) reverse an exhaustion phenotype in exhausted T cells, optionally comprising T cells expressing said recombinant receptor, in the subject, as compared to the absence of said administration of said subject.

60. The method of claim 59, wherein the amount, duration and / or frequency is effective (i) to effect said increase in antigen- specific or antigen receptor-driven activity and (ii) to prevent, inhibit or delay said onset of exhaustion phenotype and / or to reverse said exhaustion phenotype.

61. The method of claim 59 or claim 60, wherein the amount, duration and / or frequency is effective (i) to effect said increase in antigen-specific or antigen receptor-driven activity and (ii) to prevent, inhibit or delay said onset of exhaustion phenotype.

62. The method of claim 59 or claim 60, wherein the amount, duration and / or frequency is effective (i) to effect said increase in antigen-specific or antigen receptor-driven activity and (ii) to prevent, inhibit or delay said onset of exhaustion phenotype and to reverse said exhaustion phenotype.

63. A method of treatment, the method comprising:(a) administering a T cell therapy to a subject having a cancer, said T cell therapy comprising a dose of T cells expressing a recombinant antigen receptor that binds to a target antigen; and(b) administering to the subject an immune modulatory 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), at an amount, duration and / or frequency effective to:(1) effect an increase in antigen- specific or antigen receptor-driven activity of naive or non-exhausted T cells in the subject, which optionally comprise T cells expressing said recombinant receptor, following exposure of the T cells to antigen or to an antigen receptor- specific agent as compared to the absence of said administration of said compound; or(2) prevent, inhibit or delay the onset of an exhaustion phenotype, in naive or non- exhausted T cells T cells in the subject, which optionally comprise T cells expressing said recombinant receptor, following exposure of the T cells to antigen or to an antigen receptor- specific agent, as compared to the absence of said administration of said compound; or(3) reverse an exhaustion phenotype in exhausted T cells, optionally comprising T cells expressing said recombinant receptor, in the subject, as compared to the absence of said administration of said subject.

64. The method of claim 63, wherein the amount, duration and / or frequency is effective (i) to effect said increase in antigen- specific or antigen receptor-driven activity and (ii) to prevent, inhibit or delay said onset of exhaustion phenotype and / or to reverse said exhaustion phenotype.

65. The method of claim 63 or claim 64, wherein the amount, duration and / or frequency is effective (i) to effect said increase in antigen-specific or antigen receptor-driven activity and (ii) to prevent, inhibit or delay said onset of exhaustion phenotype.

66. The method of claim 63 or claim 64, wherein the amount, duration and / or frequency is effective (i) to effect said increase in antigen-specific or antigen receptor-drivenactivity and (ii) to prevent, inhibit or delay said onset of exhaustion phenotype and to reverse said exhaustion phenotype.

67. The method of any of claims 1-66, wherein the compound depletes or degrade Ikaros (IKZF1).

68. The method of any of claims 1-67, wherein the compound is a compound of the following structure:whereinone of X and Y is -C(O)- and the other of X and Y is -C(O)- or -CH2-;(1) each of R1, R2, R3, and R4are independently halo, alkyl of 1 to 4 carbon atoms, or alkoxy or 1 to 4 carbon atoms, or(2) one of R1, R3, R4, and R5is -NHRaand the remaining of R1, R2, R3, and R4is are hydrogen, wherein Rais hydrogen or alkyl of 1 to 8 carbon atoms;R5is hydrogen or alkyl of 1 to 8 carbon atoms, benzyl, or halo;provided that R5is other than hydrogen if X and Y are -C(O)- and (i) each of R1, R2, R3, and R4is fluoro; or (ii) one of R1, R2, R3, and R4is amino;or a pharmaceutically acceptable salt thereof.

69. The method of any of claims 1-68, wherein the compound is a compound of the following structure:wherein one of X and Y is -C(O)- and the other of X and Y is -C(O)- or -CH2-, and R5is hydrogen or lower alkyl, or a pharmaceutically acceptable salt thereof.

70. The method of any of claims 1-69, wherein the compound that is or comprises 3- (4-amino-l-oxo-l,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione having the following structure:or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.

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

72. The method of any of claims 1-67, wherein the compound is a compound that is or comprises 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione having the following structure:or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.

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

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

75. The method of any of claims 1-67, wherein the compound is a compound of the following structure:or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein:Z is C=0 or CH2;R11is -Z^R13;R12is H or (Ci-C6)alkyl;Z1is 6 to 10 membered aryl, heteroaryl, or heterocycle, each of which may be optionally substituted with one or more halogen; or a bond;R13is -(CH2)n-aryl, -0-(CH2)n-aryl, or -(CH2)n-0-aryl, wherein the aryl is optionally substituted with one or more: (Ci-C6)alkyl; itself optionally substituted with one or more halogen; (Ci-C6)alkoxy, itself substituted with one or more halogen; oxo; amino; carboxyl; cyano; hydroxyl; halogen; deuterium; 6 to 10 membered aryl or heteroaryl, optionally substituted with one or more (Ci-C6)alkyl, (Ci-C6)alkoxy, or halogen; -CONH2; or -COO-(Ci- C6)alkyl, wherein the alkyl may be optionally substituted with one or more halogen; -(CH2)n- heterocycle, -0-(CH2)n-heterocycle or -(CH2)n-0-heterocycle, wherein the heterocycle is optionally substituted with one or more: (Ci-C6)alkyl, itself optionally substituted with one or more halogen; (Ci-C6)alkoxy, itself substituted with one or more halogen; oxo; amino; carboxyl; cyano; hydroxyl; halogen; deuterium; 6 to 10 membered aryl or heteroaryl, optionally substituted with one or more (Ci-C6)alkyl, (Ci-C6)alkoxy or halogen; -CONH2; or -COO-(Ci- C6)alkyl, wherein the alkyl may be optionally substituted with one or more halogen; or -(CH2)n- heteroaryl, -0-(CH2)n-heteroaryl or -(CH2)n-0-heteroaryl, wherein the heteroaryl is optionally substituted with one or more: (Ci-C6)alkyl, itself optionally substituted with one or more halogen; (Ci-C6)alkoxy, itself substituted with one or more halogen; oxo; amino; carboxyl; cyano; hydroxyl; halogen; deuterium; 6 to 10 membered aryl or heteroaryl, optionally substituted with one or more (Ci-C6)alkyl, (Ci-C6)alkoxy or halogen; -CONH2; or -COO-(Ci- C6)alkyl, wherein the alkyl may be optionally substituted with one or more halogen; andn is 0, 1, 2 or 3.

76. The method of any of claims 1-67 and 75, wherein the compound isor a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

77. The method of any of claims 1-67, 75 and 76, wherein the compound is the FormA crystal form of the hydrochloride salt78. The method of claim 77, wherein the XRPD pattern of the Form A crystal formof the hydrochloride saltcharacterized by XRPD peaks located at 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 or approximately 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 2Q.

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

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

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

82. The method of any of claims 59-81, wherein the target antigen is a tumor antigen, optionally wherein the target antigen is associated with, specific to, and / or expressed on a cell or tissue of the cancer,83. The method of any of claims 59-82, wherein the target antigen is selected from B cell maturation antigen (BCMA), anbό integrin (avb6 integrin), BAFF-R, B7-H3, B7-H6, carbonic anhydrase 9 (CA9, also known as CAIX or G250), a cancer-testis antigen, cancer / testis antigen 1B (CTAG, also known as NY-ESO-l and LAGE-2), carcinoembryonic antigen (CEA), a cyclin, cyclin A2, C-C Motif Chemokine Ligand 1 (CCL-l), CD5, CD19, CD20, CD21,CD22, CD23, CD24, CD30, CD38, CD44, CD44v6, CD44v7 / 8, CD45, CD79a, CD79b, CD123,CD133, CD138, CD171, CS-l, chondroitin sulfate proteoglycan 4 (CSPG4), epidermal growth factor protein (EGFR), truncated epidermal growth factor protein (tEGFR), type III epidermal growth factor receptor mutation (EGFR vIII), epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), ephrinB2, ephrine receptor A2 (EPHa2), estrogen receptor, Fc receptor like 5 (FCRL5; also known as Fc receptor homolog 5 or FCRH5), fetal acetylcholine receptor (fetal AchR), a folate binding protein (FBP), folate receptor alpha, ganglioside GD2, O- acetylated GD2 (OGD2), ganglioside GD3, glycoprotein 100 (gplOO), glypican-3 (GPC3), GProtein Coupled Receptor 5D (GPCR5D), Her2 / neu (receptor tyrosine kinase erb-B2), Her3(erb-B3), Her4 (erb-B4), erbB dimers, Human high molecular weight-melanoma-associated antigen (HMW-MAA), hepatitis B surface antigen, Human leukocyte antigen Al (HLA-A1),Human leukocyte antigen A2 (HLA-A2), Igkappa, Iglambda, IL-22 receptor alpha(IL-22Ra),IL-13 receptor alpha 2 (IL-l3Ra2), kinase insert domain receptor (kdr), Ll cell adhesion molecule (Ll-CAM), CE7 epitope of Ll-CAM, Leucine Rich Repeat Containing 8 FamilyMember A (LRRC8A), Lewis Y, Melanoma-associated antigen (MAGE)-Al, MAGE-A3,MAGE-A6, MAGE-A10, mesothelin (MSLN), c-Met, murine cytomegalovirus (CMV), mucin 1(MUC1), MUC16, natural killer group 2 member D (NKG2D) ligands, melan A (MART-l), neural cell adhesion molecule (NCAM), oncofetal antigen, Preferentially expressed antigen of melanoma (PRAME), progesterone receptor, a 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-l), a pathogen- specific or pathogen- expressed antigen.

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

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

86. The method of claim 85, wherein the NHL comprises aggressive NHL, diffuse large B cell lymphoma (DLBCL), DLBCL-NOS, optionally transformed indolent; 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 BCL6rearrangements with DLBCL histology (double / triple hit).

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

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

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

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

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

92. The method of any 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-l, syndecan, SYN-l), CS-l (CS1, CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24), BAFF-R, TACI or FcRH5.

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

94. The method of any of claims 20-93, wherein the administration of the compound continues for a period that extends for at or about or greater than three months after the initiation of the administration of the T cell therapy.

95. The method of claim 74, wherein the effective amount is no more than at or about 4 mg per day.

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

97. The method of claim 74, wherein the effective amount is no more than at or about 3 mg per day.

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

99. The method of claim 74, wherein the effective amount is no more than at or about 2.5 mg per day.

100. The method of any of claims 74 and 95-99, wherein, for each week of the cycling regimen, or for at least one week of the cycling regimen, the administration of the compound comprises administering the compound on each of no more than 5 consecutive days of the week followed by a rest period for the remainder of the week, during which the compound is not administered.

101. The method of claim 100, wherein the no more than 5 consecutive days is 3 consecutive days per week followed by a rest period of 4 days, during which the compound is not administered.

102. The method of claim 100, wherein the no more than 5 consecutive days is 4 consecutive days per week followed by a rest period of 3 days, during which the compound is not administered.

103. The method of claim 100, wherein the no more than 5 consecutive days is 5 consecutive days per week followed by a rest period of 2 days, during which the compound is not administered.

104. The method of any one of claims 20-103, wherein the administration continues for a period that extends for at or about or greater than four months after the initiation of the administration of the T cell therapy.

105. The method of any of claims 20-104, wherein the administration continues for a period that extends for at or about or greater than five months after the initiation of the administration of the T cell therapy.

106. The method of any of claims 20-105, wherein the administration continues for a period that extends for at or about or greater than six months after the initiation of the administration of the T cell therapy.

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

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

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

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

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

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

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

114. The method of any of claims 20-113, wherein the administration of the compound continues for a period that extends for from or from at or about three months to at or six months.

115. The method of any of claims 20-114, wherein the administration of the compound continues for a period that extends for at or about three months after initiation of administration of the T cell therapy.

116. The method of any of claims 20-114, wherein the administration of the compound continues for a period that extends for at or about 3 months after initiation of administration of the T cell therapy if the subject has, prior to at or about 3 months, achieved a complete response (CR) following the treatment or the cancer has progressed or relapsed following remission after the treatment.

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

118. The method of any of claims 20-114, wherein the administration of the compound continues for a period that extends for at or about six months after initiation of administration of the T cell therapy.

119. The method of any of claims 20-118, wherein the administration of the compound continues for a period that extends for at or about 6 months after initiation of administration of the T cell therapy if the subject has, prior to at or about 6 months, achieved a complete response (CR) following the treatment or the cancer has progressed or relapsed following remission after the treatment.

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

121. The method of any of claims 20-120, wherein the administration is continued for the duration of the period even if the subject has achieved a complete response (CR) at a time point prior to the end of the period.

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

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

125. The method of claim 123 or claim 124, wherein the administration is continued until the subject has achieved a complete response (CR) following the treatment or until the cancer has progressed or relapsed following remission after the treatment.

126. The method of any of claims 20-125, wherein the administration of the compound is initiated at or after peak or maximum level of the cells of the T cell therapy are detectable in the blood of the subject.

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

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

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

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

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

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

133. The method of claim 132, wherein:the severe toxicity is severe cytokine release syndrome (CRS), optionally grade 3 or higher, prolonged grade 3 or higher or grade 4 or 5 CRS; and / orthe severe toxicity is severe neurotoxicity, optionally grade 3 or higher, prolonged grade 3 or higher or grade 4 or 5 neurotoxicity.

134. The method of any one of claims 20-133, wherein the administration of the compound is suspended and / or the administration is modified if the subject exhibits a toxicity following the administration of the compound, optionally a hematologic toxicity.

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

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

137. The method of claim 136, wherein the administration is modified after the administration of the compound is restarted.

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

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

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

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

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

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

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

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

148. The method of any of claims 1-74 and 80-140, 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 of claims 20-148, wherein the compound is administered orally.

150. The method of any of claims 20-149, wherein the administration of the compound:reverses an exhaustion phenotype in recombinant receptor-expressing T cells in the subject;prevents, inhibits or delays the onset of an exhaustion phenotype in recombinant receptor-expressing T cells in the subject;or reduces the level or degree of an exhaustion phenotype in recombinant receptor expressing T cells in the subject; orreduces the percentage, of the total number of recombinant receptor-expressing T cells in the subject, that have an exhaustion phenotype.

151. The method of any of claims 3-149, wherein the initiation of the administration of the compound is carried out subsequently to the administration of the T cell therapy and, following administration of the compound or initiation thereof, the subject exhibits a restoration or rescue of an antigen- or tumor- specific activity or function of recombinant receptor expressing T cells in said subject, optionally wherein said restoration, rescue, and / or initiation of administration of said compound, is at a point in time after recombinant receptor-expressing T cells in the subject or the in the blood of the subject have exhibited an exhausted phenotype.

152. The method of any of claims 3-149, wherein the administration of the compound comprises administration at an amount, frequency and / or duration effective to:(a) effect an increase in antigen- specific or antigen receptor-driven activity of naive or non-exhausted T cells in the subject, which optionally comprise T cells expressing said recombinant receptor, following exposure of the T cells to antigen or to an antigen receptor- specific agent as compared to the absence of said administration of said compound; or(b) prevent, inhibit or delay the onset of an exhaustion phenotype, in naive or non- exhausted T cells T cells in the subject, which optionally comprise T cells expressing said recombinant receptor, following exposure of the T cells to antigen or to an antigen receptor- specific agent, as compared to the absence of said administration of said compound; or(c) reverse an exhaustion phenotype in exhausted T cells, optionally comprising T cells expressing said recombinant receptor, in the subject, as compared to the absence of said administration of said subject.

153. The method of claim 152, wherein the administration of the compound comprises administration at an amount, frequency and / or duration effective (i) to effect said increase in activity and (ii) to prevent, inhibit or delay said onset of said exhaustion phenotype and / or reverse said exhaustion phenotype.

154. The method of claims 152 or 153, wherein the T cells in the subject comprise T cells expressing said recombinant receptor and / or said antigen is the target antigen.

155. The method of any of claims 150-154,wherein the exhaustion phenotype, with reference to a T cell or population of T cells, comprises: an increase in the level or degree of surface expression on the T cell or T cells, or in the percentage of T said population of T cells exhibiting surface expression, of one or more exhaustion marker, optionally 2, 3, 4, 5 or 6 exhaustion markers, compared to a reference T cell population under the same conditions; ora decrease in the level or degree of an activity exhibited by said T cells 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.

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

157. The method of claim 155, wherein the decrease in the level, degree or percentage is by greater than at or about 1.2-fold, at or about 1.5-fold, at or about 2.0-fold, at or about 3- fold, at or about 4-fold, at or about 5-fold, at or about 6-fold, at or about 7-fold, at or about 8- fold, at or about 9-fold, at or about lO-fold or more.

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

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

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

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

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

163. The method of any of claims 155-162, wherein the activity or 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. The method of any of claims 155-163,wherein the exposure to said antigen or antigen receptor- specific agent comprises incubation with the antigen or antigen receptor- specific agent, optionally an agent that binds the recombinant receptor, wherein said antigen is optionally the target antigen.

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

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

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

168. The method of any of claims 1-167, wherein the recombinant antigen receptor is a chimeric antigen receptor that specifically binds the 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 comprising an IT AM.

170. The method of claim 169, wherein the intracellular signaling domain comprises a signaling domain of a CD3-zeta (€ϋ3z) chain, optionally a human CD3-zeta chain.

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

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

174. The method of any of claims 16 and 168-173, wherein:the CAR comprises an scFv specific for the target antigen; a transmembrane domain,; a cytoplasmic signaling domain derived from a costimulatory molecule, which optionally is or comprises a 4-1BB, optionally human 4-1BB; and a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule, which optionally is or comprises a CD3zeta signaling domain, optionally a human CD3zeta signaling domain; and optionally wherein the CAR further comprises a spacer between the transmembrane domain and the scFv;the CAR comprises, in order, an scFv specific for the target antigen; a transmembrane domain; a cytoplasmic signaling domain derived from a costimulatory molecule, which optionally is or comprises a 4-1BB signaling domain, optionally a human 4-1BB signaling domain; and a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule, which optionally is a CD3zeta signaling domain, optionally human CD3zeta signaling domain; orthe CAR comprises, in order, an scFv specific for the target antigen; a spacer; a transmembrane domain, a cytoplasmic signaling domain derived from a costimulatory molecule, which optionally is a 4-1BB signaling domain, and a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule, which optionally is or comprises a CD3zeta signaling domain.

175. The method of any of claims 21-174, wherein the dose of genetically engineered T cells comprises from or from about 1 x 105to 5 x 108total CAR-expressing T cells, 1 x 106to 2.5 x 108total CAR-expressing T cells, 5 x 106to 1 x 108total CAR-expressing T cells, 1 x 107to 2.5 x 108total CAR-expressing T cells, 5 x 107to 1 x 108total CAR-expressing T cells, each inclusive.

176. The method of any of claims 21-175, wherein the dose of genetically engineered T cells comprises at least or at least about 1 x 105CAR-expressing cells, at least or at least about 2.5 x 105CAR-expressing cells, at least or at least about 5 x 105CAR-expressing cells, at least or at least about 1 x 106CAR-expressing cells, at least or at least about 2.5 x 106CAR- expressing cells, at least or at least about 5 x 106CAR-expressing cells, at least or at least about 1 x 107CAR-expressing cells, at least or at least about 2.5 x 107CAR-expressing cells, at least or at least about 5 x 107CAR-expressing cells, at least or at least about 1 x 108CAR-expressing cells, at least or at least about 2.5 x 108CAR-expressing cells, or at least or at least about 5 x 108CAR-expressing cells.

177. The method of any of claims 21-176, wherein the dose of genetically engineered T cells comprises at or about 5 x 107total CAR-expressing T cells.

178. The method of any of claims 21-177, wherein the dose of genetically engineered T cells comprises at or about 1 x 108CAR-expressing cells.

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

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

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

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

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

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

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

186. The method of claim 184 or claim 185, wherein the lymphodepleting therapy comprises administration of cyclophosphamide at about 200-400 mg / m2, optionally at or about 300 mg / m2, inclusive, and / or fludarabine at about 20-40 mg / m2, optionally 30 mg / m2, daily for 2-4 days, optionally for 3 days, or wherein the lymphodepleting therapy comprisesadministration of cyclophosphamide at about 500 mg / m2.

187. The method of any one of claims 184-186, wherein:the lymphodepleting therapy comprises administration of cyclophosphamide at or about 300 mg / m2and fludarabine at about 30 mg / m2daily for 3 days; and / orthe lymphodepleting therapy comprises administration of cyclophosphamide at or about500 mg / m2and fludarabine at about 30 mg / m2daily for 3 days.

188. The method of any of claims 20-187, wherein: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, or is durable in at least 60, 70, 80, 90, or 95 % of subjects achieving the CR, for at or greater than 6 months or at or greater than 9 months; and / orwherein at least 60, 70, 80, 90, or 95 % of subjects achieving a CR by six months remain in response, remain in CR, and / or survive or survive without progression, for greater at or greater than 3 months and / or at or greater than 6 months and / or at greater than nine months; and / orat least 50%, at least 60% or at least 70% of the subjects treated according to the method achieve objective response (OR) optionally wherein the OR is durable, or is durable in at least 60, 70, 80, 90, or 95 % of subjects achieving the OR, for at or greater than 6 months or at or greater than 9 months; and / orwherein at least 60, 70, 80, 90, or 95 % of subjects achieving an OR by six months remain in response or surviving for greater at or greater than 3 months and / or at or greater than 6 months.

189. 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 immune modulatory 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 the methods of any of claims 1-187.