Compositions and methods for immunotherapy

Abstract

This invention relates generally to compositions and methods for increasing the efficacy of immunotherapies, such as T cell therapy. In particular, the present invention relates to compositions comprising 3,4-dihydroxybenzoate (derivatives, prodrugs, or pharmaceutical salts thereof), related methods of increasing the efficacy of immunotherapies (e.g., T cell therapies) through administration of such compositions, and related methods for manufacturing a population of T cells through expanding a population of genetically engineered T cells with such compositions.

Description

Attorney Docket No. UM-43996.601COMPOSITIONS AND METHODS FOR IMMUNOTHERAPYCROSS REFERENCE TO RELATED APPLICATIONThe present application claims priority to U.S. Provisional Application No. 63 / 730,785, filed December 11, 2024, which is incorporated herein by reference in its entirety.FIELD OF THE INVENTIONThis invention relates generally to compositions and methods for increasing the efficacy of immunotherapies, such as T cell therapy. In particular, the present invention relates to compositions comprising 3,4-dihydroxybenzoate (derivatives, prodrugs, or pharmaceutical salts thereof), related methods of increasing the efficacy of immunotherapies (e.g., T cell therapies) through administration of such compositions, and related methods for manufacturing a population of T cells through expanding a population of genetically engineered T cells with such compositions.INTRODUCTIONImmunotherapy of cancer has become an increasingly promising avenue in the treatment of cancer, but has also revealed the complexity of generating an immune response to a diseased tissue that is immunologically derived from a healthy tissue. These difficulties are compounded by the relatively low frequency of immunogenic cancer neoepitopes, insufficient co-stimulation, and inhibitory molecules produced by many cancer cells.T-cells play an important role in controlling the development of cancer- related lesions in vivo. T-cells are activated via their T-cell receptor that binds to short antigen peptides presented on major histocompatibility complex class molecules (MHCs). Upon recognition of peptides presented by the MHC I complex, CD8+ cytotoxic T-cells (CTLs) are activated and can destroy target cells presenting the peptides using certain ligands (e.g., via TRAIL, TNF- related apoptosis-inducing ligand) or via lysis using perforin / granzyme. In addition, CD4+ T- cells recognize foreign or disease-associated peptides presented by the MHCII complex and improve the capacity of dendritic cells (DCs) to induce CTLs by crosslinking the costimulatory molecule CD40 on DCs with the CD40 ligand on activated CD4+ T-cells. Furthermore, by secreting cytokines such as interleukin-2 (IL-2), activated CD4+ T-cells support the clonal expansion of activated CTLs. Besides this, activated CD4+ T-cells can significantly boost cellular components of the innate immunity, such as macrophages and NK cells by enhanced IFN-y secretion. Concomitantly, increased IFN-y levels improve theAttorney Docket No. UM-43996.601 recognition capacity of T-cells through induction of higher expression levels of MHCI molecules on the target cells.Unfortunately, these processes can be modulated by cancer cells, and it has been shown that some cancer cells have evaded immune recognition by loss or downregulation of TAP and MHC components, and apoptosis mediators, or by various metabolic mechanism (e.g., arginine or tryptophan depletion). In still other cases, tumors have expressed increased quantities of cytokines (e.g., IL- 10, TGF-beta) or other regulator factors (e.g., MIT), and especially factors for T-cells (e.g., Fas-ligand, PD-L1, MICA). In addition, Tregs (regulatory T-cells, or suppressor T-cells, many of which are CTLA-4 positive) can accumulate at a tumor site, leading to additional immune evasion.

[0008] Therefore, there is still a need for improved treatment systems and methods to increase efficacy of immunotherapy and to improve memory T-cell formation.The present invention addresses this urgent need.SUMMARY OF THE INVENTIONThis invention relates generally to compositions and methods for increasing the efficacy of immunotherapies, such as T cell therapy. In particular, the present invention relates to compositions comprising 3,4-dihydroxybcnzoatc (derivatives, prodrugs, or pharmaceutical salts thereof), related methods of increasing the efficacy of immunotherapies (e.g., T cell therapies) through administration of such compositions, and related methods for manufacturing a population of T cells through expanding a population of genetically engineered T cells with such compositions.In certain embodiments, the present invention provides a method for treating an immune system related condition or disease in a subject comprising administering to the subject genetically engineered T cells and a therapeutically effective amount of 3,4- dihydroxybenzoate (DHB) (derivatives, prodrugs, or pharmaceutical salts thereof). In some embodiments, the DIIB (derivatives, prodrugs, or pharmaceutical salts thereof) and the genetically engineered T cells are administered simultaneously and / or at different time points.In some embodiments, the DHB is the following prodrugAttorney Docket No. UM-43996.601In some embodiments, the immune system related condition or disease is selected from cancer or an autoimmune disease or condition.In some embodiments, the genetically engineered T cells are selected from CAR T cells, genetically engineered TCR expressing T cells, genetically engineered T cells configured for tumor infiltrating lymphocyte (TIL) therapy, genetically engineered T cells configured for transduced T-cell therapy, and / or viral specific T cells reengineered with a TCR or CAR.In some embodiments, the method further comprises administering to said subject one or more anticancer agents. In some embodiments, the one or more anticancer agents is selected from a chemotherapeutic agent and radiation therapy.In some embodiments, the anticancer agent is one or more immune checkpoint inhibitors (ICIs). In some embodiments, the one or more ICIs are selected from atezolizumab, avelumab, bevacizumab, cemiplimab, cetuximab, daratumumab, dinutuximab, durvalumab, elotuzumab, ipilimumab, isatuximab, mogamulizumab, necitumumab, nivolumab, obitunuzumab, ofatumumab, oralatumab, panitumumab, pembrolizumab, pertuzumab, ramucirumab, rituximab, trastuzumab, gemtuzumab ozogamicin, bentruximab vedotin, trastuzumab emtansine, inotuzumab ozogamicin, polatuzumab vedotin, efortumab vedotin, trastuzumab dcruxtccan, Sacituzumab govitccan, moxetumuomab pasudotox, ibritumomab tiuxetan, iodine tositumuomab, and blatinumomab. In some embodiments, the one or more ICIs is an inhibitor of CTLA-4, PD-1, PDL-1, Lag3, LAIR1, or LAIR 2.In some embodiments, the genetically engineered T cell population, wherein the genetically engineered T cell population was expanded in the presence of DHB (derivatives, prodrugs, or pharmaceutical salts thereof). In some embodiments, the DHB is the following prodrugIn certain embodiments, the present invention provides a composition comprising a genetically engineered T cell population, wherein the genetically engineered T cell population was expanded in the presence of DHB. In some embodiments, the genetically engineered T cell population is selected from CAR T cell population, a population of genetically engineered TCR expressing T cells, a population of genetically engineered T cells configured for tumor infiltrating lymphocyte (TIL) therapy, a population of geneticallyAttorney Docket No. UM-43996.601 engineered T cells configured for transduced T-cell therapy, and / or a population of viral specific T cells reengineered with a TCR or CAR.In certain embodiments, the present invention provides a method of generating a population of genetically engineered T cells, comprising expanding a population of genetically engineered T cells in the presence of DHB.In some embodiments, population of genetically engineered T cells is selected from CAR T cell population, a population of genetically engineered TCR expressing T cells, a population of genetically engineered T cells configured for tumor infiltrating lymphocyte (TIL) therapy, a population of genetically engineered T cells configured for transduced T-cell therapy, and / or a population of viral specific T cells reengineered with a TCR or CAR.In certain embodiments, the present invention provides a method of treating an immune system related condition or disease, comprising administering to the subject a genetically engineered T cell population that were expanded in the presence of DHB.In some embodiments, the genetically engineered T cell population is selected from CAR T cell population, a population of genetically engineered TCR expressing T cells, a population of genetically engineered T cells configured for tumor infiltrating lymphocyte (TIL) therapy, a population of genetically engineered T cells configured for transduced T-cell therapy, and / or a population of viral specific T cells reengineered with a TCR or CAR.In some embodiments, the subject is undergoing an adoptive T cell therapy. In some embodiments, the adoptive T cell therapy is a CAR T-cell therapy. In some embodiments, the adoptive T cell therapy is a transduced T-cell therapy. In some embodiments, the adoptive T cell therapy is a tumor infiltrating lymphocyte (TIL) therapy.In some embodiments, the immune system related condition or disease is selected from cancer or an autoimmune disease or condition.In some embodiments, the method further comprises administering to said subject one or more anticancer agents. In some embodiments, the one or more anticancer agents is selected from a chemotherapeutic agent and radiation therapy.In some embodiments, the anticancer agent is one or more immune checkpoint inhibitors (ICIs). In some embodiments, the one or more ICIs are selected from atezolizumab, avelumab, bevacizumab, cemiplimab, cetuximab, daratumumab, dinutuximab, durvalumab, elotuzumab, ipilimumab, isatuximab, mogamulizumab, necitumumab, nivolumab, obitunuzumab, ofatumumab, oralatumab, panitumumab, pembrolizumab, pertuzumab, ramucirumab, rituximab, trastuzumab, gemtuzumab ozogamicin, bentruximab vedotin, trastuzumab emtansine, inotuzumab ozogamicin, polatuzumab vedotin, efortumab vedotin,Attorney Docket No. UM-43996.601 trastuzumab deruxtecan, Sacituzumab govitecan, moxetumuomab pasudotox, ibritumomab tiuxetan, iodine tositumuomab, blatinumomab. In some embodiments, the one or more ICIs is an inhibitor of CTLA-4, PD- 1 , PDL- 1 , Lag3 , LAIR 1 , or LAIR 2.In certain embodiments, the present invention provides a composition comprising the following prodrugIn certain embodiments, the present invention provides a composition comprising a genetically engineered T cell population, wherein the genetically engineered T cell population was expanded in the presence of the following prodrug of DHB:some embodiments, the genetically engineered T cell population is selected from CAR T cell population, a population of genetically engineered TCR expressing T cells, a population of genetically engineered T cells configured for tumor infiltrating lymphocyte (TIL) therapy, a population of genetically engineered T cells configured for transduced T-cell therapy, and / or a population of viral specific T cells reengineered with a TCR or CAR.In certain embodiments, the present invention provides a method of generating a population of genetically engineered T cells, comprising expanding a population of genetically engineered T cells in the presence of the following prodrug of DHB:In some embodiments, population of genetically engineered T cells is selected from CAR T cell population, a population of genetically engineered TCR expressing T cells, a population of genetically engineered T cells configured for tumor infiltrating lymphocyteAttorney Docket No. UM-43996.601(TIL) therapy, a population of genetically engineered T cells configured for transduced T-cell therapy, and / or a population of viral specific T cells reengineered with a TCR or CAR.In certain embodiments, the present invention provides a method of treating an immune system related condition or disease, comprising administering to the subject a genetically engineered T cell population that were expanded in the presence of DHB.In some embodiments, the genetically engineered T cell population is selected from CAR T cell population, a population of genetically engineered TCR expressing T cells, a population of genetically engineered T cells configured for tumor infiltrating lymphocyte (TIL) therapy, a population of genetically engineered T cells configured for transduced T-cell therapy, and / or a population of viral specific T cells reengineered with a TCR or CAR.In some embodiments, the subject is undergoing an adoptive T cell therapy. In some embodiments, the adoptive T cell therapy is a CAR T-cell therapy. In some embodiments, the adoptive T cell therapy is a transduced T-cell therapy. In some embodiments, the adoptive T cell therapy is a tumor infiltrating lymphocyte (TIL) therapy.In some embodiments, the immune system related condition or disease is selected from cancer or an autoimmune disease or condition.In some embodiments, the method further comprises administering to said subject one or more anticanccr agents. In some embodiments, the one or more anticanccr agents is selected from a chemotherapeutic agent and radiation therapy.In some embodiments, the anticancer agent is one or more immune checkpoint inhibitors (ICIs). In some embodiments, the one or more ICIs are selected from atezolizumab, avelumab, bevacizumab, cemiplimab, cetuximab, daratumumab, dinutuximab, durvalumab, elotuzumab, ipilimumab, isatuximab, mogamulizumab, necitumumab, nivolumab, obitunuzumab, ofatumumab, oralatumab, panitumumab, pembrolizumab, pertuzumab, ramucimmab, rituximab, trastuzumab, gemtuzumab ozogamicin, bentruximab vedotin, trastuzumab emtansine, inotuzumab ozogamicin, polatuzumab vedotin, efortumab vedotin, trastuzumab deruxtecan, Sacituzumab govitecan, moxetumuomab pasudotox, ibritumomab tiuxetan, iodine tositumuomab, blatinumomab. In some embodiments, the one or more ICIs is an inhibitor of CTLA-4, PD-1, PDL-1, Lag3, LAIR1, or LAIR 2.BRIEF DESCRIPTION OF THE DRAWINGSFIG. 1A-G. 1. Ex vivo treatment of CD8+ T cells with DHB enhanced the anti-tumor efficacy of adoptively transferred T cells. OT-I CD8+T cells were isolated from splenocytes from OT-I mice and cultured with SIINFEKL peptide (4 nM) and DHB for 3 days, then cellsAttorney Docket No. UM-43996.601 were washed twice and further cultured with DHB in presence of IL-2 (10 ng / mL) for 5 days. Shown are the frequencies of (a) CD127+PD-1 CD8+T cells, (b) FoxoU, (c) TcfU, and (d) Ki67+among CD127+PD-1 CD8+T cells, (e) Therapeutic regimen of the adoptive cell therapy of DHB or PBS treated OT-I CD8+T cells for the B16F10-OVA tumor model, and the average tumor growth curves. (f,g) Analyses of CD8+T cells in tumor tissues on day 21. Shown are the frequencies of (f) Thyl.l+CD8+T cells, and (g) Ki 67 MFI values among Thyl.UCD8+T cells. Data represent the mean ± s.e.m. (n = 16 (a-d). 8-10 (e-g) biologically independent samples). Data were analyzed using a two-sided, unpaired Student’s t-test (a-d), two-way ANOVA with Bonferroni’s multiple comparisons test (e), or a one-way ANOVA with Bonferroni’s multiple comparisons test (f,g).FIG. 2A-I. Oral administration of DHB Prodrug 201 enhanced the antitumor activity of adoptively transferred T cells, a) Schematic diagram of the overall therapy schedule. Five days after inoculation with B16F10-OVA cancer cells, OT-I T cells were adoptively transferred into the tumor-bearing mice. Prodrug 201 was administered orally starting on day 5 and continued every other day thereafter, b) Average B16F10-OVA tumor growth curves, c) Average tumor volume on day 21 . d-i) Tumor tissues were harvested on day 21 to analyze adoptively transferred T cells by flow cytometry. Percentage of adoptively transferred Thyl.U OT-I CD8+T cells (d) and endogenous Thyl.2+CD8+T cells (c). The populations of Thyl.U cells expressing TCF1 (f) and TOX (g). Expression levels of TCF1 (h) and TOX (i) among Thyl.U cells. MFI, median fluorescence intensity. Data are presented as means ± S.E.M. (*P<0.05, **P<0.01, *** <0.001; one-way ANOVA with post-hoc Tukey’s test).FIG. 3A-C. A) To evaluate the in vivo antitumor efficacy of adoptive cell therapy, activated CD8+T cells generated ex vivo were adoptively transferred into NOOC1-OVA- bearing mice. B) Ex vivo treatment of activated OT-I CD8+T cells with DHB significantly enhanced the antitumor efficacy compared with control OT-I CD8+T cells. C) Phenotypic analysis of PBMCs isolated from the mice on day 30, and observed higher frequencies of TcfU CD8+T cells, and CD44+CD62L+CD8+T cells among tumor antigen-specific CD8+T cells in the DHB-trained OT-I ACT group.DEFINITIONSIt must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "a T cell" includes two or more T cells, and the like.Attorney Docket No. UM-43996.601The term "about," particularly in reference to a given quantity, is meant to encompass deviations of plus or minus five percent.The term "chimeric antigen receptor" or "CAR," as used herein, refers to an artificial T cell receptor that is engineered to be expressed on an immune effector cell and specifically bind an antigen. CARs may be used as a therapy with adoptive cell transfer. T cells arc removed from a patient and modified so that they express the receptors specific to a particular form of antigen. In some embodiments, the CARs have been expressed with specificity to a tumor associated antigen, for example. CARs may also comprise an intracellular activation domain, a transmembrane domain and an extracellular domain comprising a tumor associated antigen binding region. The specificity of CAR designs may be derived from ligands of receptors (e.g., peptides). In some embodiments, a CAR can target cancers by redirecting the specificity of a T cell expressing the CAR specific for tumor associated antigens."Pharmaceutically acceptable excipient or carrier" refers to an excipient that may optionally be included in the compositions of the invention and that causes no significant adverse toxicological effects to the patient."Pharmaceutically acceptable salt" includes, but is not limited to, amino acid salts, salts prepared with inorganic acids, such as chloride, sulfate, phosphate, diphosphate, bromide, and nitrate salts, or salts prepared from the corresponding inorganic acid form of any of the preceding, e.g., hydrochloride, etc., or salts prepared with an organic acid, such as malate, maleate, fumarate, tartrate, succinate, ethylsuccinate, citrate, acetate, lactate, methanesulfonate, benzoate, ascorbate, para-toluenesulfonate, palmoate, salicylate and stearate, as well as estolate, gluceptate and lactobionate salts. Similarly, salts containing pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium (including substituted ammonium).The term “T cell” refers to T lymphocytes as defined in the art and is intended to include thymocytes, immature T lymphocytes, mature T lymphocytes, resting T lymphocytes, or activated T lymphocytes. The T cells can be CD4+T cells, CD8+T cells, CD4+CD8+T cells, or CD4“CD8“ cells. The T cells can also be T helper cells, such as T helper 1 (TH1), or T helper 2 (TH2) cells, or TH17 cells, as well as cytotoxic T cells, regulatory T cells, natural killer T cells, naive T cells, memory T cells, or gamma delta T cells.The T cells can be a purified population of T cells, or alternatively the T cells can be in a population with cells of a different type, such as B cells and / or other peripheral blood cells. The T cells can be a purified population of a subset of T cells, such as CD4+T cells, or they can be a population of T cells comprising different subsets of T cells. In anotherAttorney Docket No. UM-43996.601 embodiment of the invention, the T cells are T cell clones that have been maintained in culture for extended periods of time. T cell clones can be transformed to different degrees. In a specific embodiment, the T cells are a T cell clone that proliferates indefinitely in culture.In some embodiments, the T cells are primary T cells. The term “primary T cells” is intended to include T cells obtained from an individual, as opposed to T cells that have been maintained in culture for extended periods of time. Thus, primary T cells are particularly peripheral blood T cells obtained from a subject. A population of primary T cells can be composed of mostly one subset of T cells. Alternatively, the population of primary T cells can be composed of different subsets of T cells.The T cells can be from previously stored blood samples, from a healthy individual, or alternatively from an individual affected with a condition. The condition can be an infectious disease, such as a condition resulting from a viral infection, a bacterial infection or an infection by any other microorganism, or a hypeiproliferative disease, such as cancer like melanoma. In yet another embodiment of the invention, the T cells are from a subject suffering from or susceptible to an autoimmune disease or T-cell pathologies. The T cells can be of human origin, murine origin or any other mammalian species.The terms "subject," "individual," and "patient," are used interchangeably herein and refer to any vertebrate subject, including, without limitation, humans and other primates, including non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, sheep, pigs, goats and horses; domestic mammals such as dogs and cats; laboratory animals including rodents such as mice, rats and guinea pigs; birds, including domestic, wild and game birds such as chickens, turkeys and other gallinaceous birds, ducks, geese, and the like. The term does not denote a particular age. Thus, both adult and newborn individuals are intended to be covered.DETAILED DESCRIPTION OF THE INVENTIONThe provided methods are based on experiments conducted during the course of developing embodiments for the present invention wherein it was determined that ex vivo treatment of CD8 T cells with 3,4-dihydroxybenzoate (DHB) resulted in increased CD8 T cell memory phenotype. Additional experiments determined that infusion of DHB into tumorbearing mice resulted in improved anti-tumor efficacy.Accordingly, the present invention provides combination therapies involving administration of an immunotherapy involving T cell function or activity, such as a T cell therapy, and an immunomodulatory compound, such as a structural or functionalAttorney Docket No. UM-43996.601 analog or derivative of 3,4-dihydroxybenzoate (DHB). In some aspects, the provided methods enhance or modulate proliferation and / or activity of T cell activity associated with administration 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 a composition comprising DHB (derivatives, prodrugs, or pharmaceutical salts thereof), 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).As such, the present invention contemplates that exposure of animals (e.g., humans) undergoing adoptive T cell therapies (e.g., a CAR T-cell therapy, a transduced T-cell therapy, and a tumor infiltrating lymphocyte (TIL) therapy) with genetically engineered T cell populations to compositions comprising DHB (derivatives, prodrugs, or pharmaceutical salts thereof) will result in improved therapy outcome as such improved T cell memory phenotype (e.g., improved CD8 T cell memory phenotype), and improved anti-tumor efficacy. Indeed, the present invention contemplates that the use of DHB (derivatives, prodrugs, or pharmaceutical salts thereof) within adoptive T cell therapies satisfies an unmet need as the effectiveness of such therapies are frequently experiencing compromised T cell memory phenotype, and compromised anti-tumor efficacy. Thus, the present invention provides methods for treating an immune system related condition or disease (e.g., cancer) in a subject comprising administering to the subject (e.g., simultaneously and / or at different time points) genetically engineered T cells and DHB (derivatives, prodrugs, or pharmaceutical salts thereof).Such methods are not limited to a specific type or kind of genetically engineered T cells. In some embodiments, the genetically engineered T cells are manufactured (e.g., expanded) in the presence of DHB (derivatives, prodmgs, or pharmaceutical salts thereof). In some embodiments, the genetically engineered T cells include, but are not limited to, CAR T cells, genetically engineered TCR expressing T cells, genetically engineered T cells configured for tumor infiltrating lymphocyte (TIL) therapy, genetically engineered T cells configured for transduced T-cell therapy, and / or viral specific T cells reengineered with a TCR or CAR.DHB (derivatives, prodmgs, or pharmaceutical salts thereof) may be administered by any suitable mode of administration, but is typically administered orally. Multiple cycles of treatment may be administered to a subject. In certain embodiments, the DHB is administered according to a daily dosing regimen or intermittently. In another embodiment,Attorney Docket No. UM-43996.601 the DHB is administered for a period of time sufficient to improve T cell memory phenotype (e.g., improved CD8 T cell memory phenotype) and / or anti-tumor efficacy, then discontinued.The present invention contemplates that ex vivo expansion of a population of T cells with DHB will result in a population T cells with improved T cell memory phenotype (e.g., improved CD8 T cell memory phenotype) and / or improved anti-tumor efficacy. Thus, the present invention provides compositions comprising a population of T cells that were expanded in the presence DHB. Thus, the present invention provides methods of expanding a population of T cells to generate T cell populations with improved T cell memory phenotype (e.g., improved CD8 T cell memory phenotype) and / or improved anti-tumor efficacy through expanding such T cells in the presence of DHB. Thus, the present invention provides kits comprising T cell populations that were expanded in the presence of DHB and additional agents (e.g., additional agents useful in expanding T cells) (e.g., additional agents useful in adoptive T cell therapies (e.g., a CAR T-cell therapy, a transduced T-cell therapy, and a tumor infiltrating lymphocyte (TIL) therapy). Such methods are not limited to a specific type or kind of genetically engineered T cells. In some embodiments, the genetically engineered T cells include, but are not limited to, CAR T cells, genetically engineered TCR expressing T cells, genetically engineered T cells configured for tumor infiltrating lymphocyte (TIL) therapy, genetically engineered T cells configured for transduced T-cell therapy, and / or viral specific T cells reengineered with a TCR or CAR.The present invention contemplates that ex vivo expansion of a population of genetically engineered T cells (e.g., genetically engineered for use within adoptive T cell therapies (e.g., a CAR T-cell therapy, a transduced T-cell therapy, and a tumor infiltrating lymphocyte (TIL) therapy)) with DHB will result in genetically engineered T cells with improved T cell memory phenotype (e.g., improved CD8 T cell memory phenotype) and / or improved anti-tumor efficacy. Thus, the present invention provides compositions comprising a population of genetically engineered T cells that were expanded in the presence of DHB. Thus, the present invention provides methods of expanding a population of genetically engineered T cells to generate genetically engineered T cell populations with improved T cell memory phenotype (e.g., improved CD8 T cell memory phenotype) and / or improved antitumor efficacy through expanding such T cells in the presence of DHB. Thus, the present invention provides kits comprising genetically engineered T cell populations that were expanded in the presence of DHB. Such methods are not limited to a specific type or kind of genetically engineered T cells. In some embodiments, the genetically engineered T cellsAttorney Docket No. UM-43996.601 include, but are not limited to, CAR T cells, genetically engineered TCR expressing T cells, genetically engineered T cells configured for tumor infiltrating lymphocyte (TIL) therapy, genetically engineered T cells configured for transduced T-cell therapy, and / or viral specific T cells reengineered with a TCR or CAR.The present invention contemplates that exposure of animals (e.g., humans) undergoing adoptive T cell therapies (e.g., a CAR T-cell therapy, a transduced T-cell therapy, and a tumor infiltrating lymphocyte (TIL) therapy) with genetically engineered T cell populations that were expanded in the presence of DHB will result in improved therapy outcome as such genetically engineered T cell populations with improved T cell memory phenotype (e.g., improved CD8 T cell memory phenotype) and / or improved anti-tumor efficacy. Thus, the present invention provides methods of treating an immune system related condition or disease (e.g., cancer) in a subject comprising administering a population of genetically engineered T cells expanded in the presence of DHB. Such methods are not limited to a specific type or kind of genetically engineered T cells. In some embodiments, the genetically engineered T cells include, but are not limited to, CAR T cells, genetically engineered TCR expressing T cells, genetically engineered T cells configured for tumor infiltrating lymphocyte (TIL) therapy, genetically engineered T cells configured for transduced T-cell therapy, and / or viral specific T cells reengineered with a TCR or CAR.Such embodiments are not limited to a particular type or kind of an immune system related condition or disease.For example, in some embodiments, the immune system related condition or disease is an autoimmune disease or condition (e.g., Acquired Immunodeficiency Syndrome (AIDS), alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune lymphoproliferative syndrome (ALPS), autoimmune thrombocytopenic purpura (ATP), Behcet's disease, cardiomyopathy, celiac sprue-dermatitis hepetiformis; chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy (CIPD), cicatricial pemphigoid, cold agglutinin disease, crest syndrome, Crohn's disease, Degos' disease, dermatomyositis-juvenile, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, insulin-dependent diabetes mellitus, juvenile chronic arthritis (Still's disease), juvenile rheumatoid arthritis, Meniere's disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pernacious anemia,Attorney Docket No. UM-43996.601 polyarteritis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, Raynaud's phenomena, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma (progressive systemic sclerosis (PSS), also known as systemic sclerosis (SS)), Sjogren's syndrome, stiff-man syndrome, systemic lupus erythematosus, Takayasu arteritis, temporal arteritis / giant cell arteritis, ulcerative colitis, uveitis, vitiligo, Wegener's granulomatosis, and any combination thereof).For example, in some embodiments, the immune system related condition or disease is cancer (e.g., breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, renal cancer, liver cancer, brain cancer, lymphoma, leukemia, lung cancer, and thyroid carcinoma).The present invention contemplates that the use of genetically engineered T cell populations that were expanded in the presence of DHB within adoptive T cell therapies (e.g., a CAR T-cell therapy, a transduced T-cell therapy, and a tumor infiltrating lymphocyte (TIL) therapy) satisfies an unmet need as such therapies are frequently compromised by such T cell populations experiencing diminished T cell memory phenotype (e.g., improved CD8 T cell memory phenotype) and / or diminished anti-tumor efficacy.Such methods arc not limited to a specific type or kind of genetically engineered T cells. In some embodiments, the genetically engineered T cells include, but are not limited to, CAR T cells, genetically engineered TCR expressing T cells, genetically engineered T cells configured for tumor infiltrating lymphocyte (TIL) therapy, genetically engineered T cells configured for transduced T-cell therapy, and / or viral specific T cells reengineered with a TCR or CAR.The embodiments of the present invention are not limited to a specific type of DHB (jQ someembodiments, the DHB is a structurally related derivative of DHB with similar functional properties. In some embodiments, the DHB is a pharmaceutical salt.Attorney Docket No. UM-43996.601In some embodiments, DHB is provided in a prodrug form. In some embodiments, theIn some embodiments, the DHB is the following prodrug of DHB:In some embodiments, the DHB (derivatives, prodrugs, or pharmaceutical salts thereof) is associated with a biodegradable agent (e.g., a microparticle or a nanoparticle). For example, in some embodiments, the present invention provides compositions comprising biodegradable agents (e.g., microparticles or a nanoparticles) associated with (e.g., complexed, conjugated, encapsulated, absorbed, adsorbed, admixed) DHB (derivatives, prodrugs, or pharmaceutical salts thereof).In some embodiments, biodegradable agent is a microparticle or nanoparticle.In some embodiments, the size of the microparticle is between 0.5 microns to 100 microns.In some embodiments, the average size of the nanoparticle is between 6 to 500 nm.Attorney Docket No. UM-43996.601In some embodiments, the nanoparticle is selected from the group consisting of sHDL nanoparticle, fullerenes, endohedral metallofullerenes buckyballs, trimetallic nitride templated endohedral metallofullerenes, single-walled and multi-walled carbon nanotubes, branched and dendritic carbon nanotubes, gold nanorods, silver nanorods, single-walled and multi-walled boron / nitratc nanotubcs, carbon nanotubc peapods, carbon nanohoms, carbon nanohorn peapods, liposomes, nanoshells, dendrimers, any nanostructures, microstructures, or their derivatives formed using layer-by-layer processes, self-assembly processes, or polyelectrolytes, microparticles, quantum dots, superparamagnetic nanoparticles, nanorods, cellulose nanopaiticles, glass and polymer micro- and nano-spheres, biodegradable PLGA micro- and nano-spheres, gold nanoparticles, silver nanopaiticles, carbon nanoparticles, iron nanoparticles, a modified micelle, metal-polyhistidine-DOPE@liposome, metal- polyhistidine-PEG, 4arm-PEG-polyhistidine-metal hydrogels, and sHDL-polyhistidine, and metal-organic framework (MOF) coordination polymer (CP).In some embodiments, the nanoparticle is a sIIDL nanoparticle. In some embodiments, the sHDL nanoparticle comprises a mixture of at least one phospholipid and at least one HDL apolipoprotein or apolipoprotein mimetic. In some embodiments, the average particle size of the sHDL nanoparticle is between 6-70 nm.In some embodiments, the HDL apolipoprotein is selected from the group consisting of apolipoprotein A-I (apo A-I), an ApoA-I mimetic, apolipoprotein A-II (apo A-II), apolipoprotein A-II xxx (apo A-II-xxx), apolipoprotein A4 (apo A4), apolipoprotein Cs (apo Cs), apolipoprotein E (apo E), apolipoprotein A-I milano (apo A-I-milano), apolipoprotein A- I parts (apo A-Lparis), apolipoprotein M (apo M), an HDL apolipoprotein mimetic, preproapoliprotein, preproApoA-I, proApoA I, preproApoA-II, proApoA II, preproApoA-IV, proApoA-IV, ApoA-V, preproApoE, proApoE, preproApoA iMiiano, proApoA-Ixniano, preproApoA-Iparis, proApoA-Ipms, and mixtures thereof.In some embodiments, the phospholipid is selected from the group consisting of dipalmitoylphosphatidylcholine (DPPC), dioleoyl-sn-glycero-3-phosphoethanolamine-N-[3- (2-pyridyldithio) propionate] (DOPE- PDF), 1 ,2-dipalmitoyl-5n-glycero-3- phosphothioethanol, l,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphoethanolamine-N-[4-(p- maleimidophenyl)butyramide], l,2-dihexadecanoyL.sn-glycero-3-phosphoethanolamine-N-[4- (p-maleimidophenyl)butyramide], l,2-dihexadecanoyl-57i-glycero-3-phosphoethanolamine-N- [4-(p-nialeirnidomethyl)cyclohexane-carboxamide], l,2-di-(9Z-octadecenoyl)-.sn-glycero-3- phosphoethanolamine-N-f4-(p-maleimidomethyl)cyclohexane-carboxamide],Attorney Docket No. UM-43996.601 phosphatidylcholine, phosphatidylinositol, phosphatidylserine, phosphatidylethanolamine, and combinations thereof.Some embodiments of the present invention provide for administering such methods (e.g., adoptive T cell therapies with genetically engineered T cell populations and compositions comprising DHB (derivatives, prodrugs, or pharmaceutical salts thereof)) (e.g., adoptive T cell therapies with genetically engineered T cell populations that were expanded in the presence of DHB) in combination with an effective amount of at least one additional therapeutic agent (including, but not limited to, chemotherapeutic antineoplastics, apoptosismodulating agents, antimicrobials, antivirals, antifungals, and anti-inflammatory agents) and / or therapeutic technique e.g., surgical intervention, and / or radiotherapies). In a particular embodiment, the additional therapeutic agent(s) is an anticancer agent.DHB can be formulated into pharmaceutical compositions optionally comprising one or more pharmaceutically acceptable excipients. Exemplary excipients include, without limitation, carbohydrates, inorganic salts, antimicrobial agents, antioxidants, surfactants, buffers, acids, bases, and combinations thereof. Excipients suitable for injectable compositions include water, alcohols, polyols, glycerine, vegetable oils, phospholipids, and surfactants. A carbohydrate such as a sugar, a derivatized sugar such as an alditol, aldonic acid, an cstcrificd sugar, and / or a sugar polymer may be present as an excipient. Specific carbohydrate excipients include, for example: monosaccharides, such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xy litol, sorbitol (glucitol), pyranosyl sorbitol, myoinositol, and the like. The excipient can also include an inorganic salt or buffer such as citric acid, sodium chloride, potassium chloride, sodium sulfate, potassium nitrate, sodium phosphate monobasic, sodium phosphate dibasic, and combinations thereof.A surfactant can be present as an excipient. Exemplary surfactants include: polysorbates, such as "Tween 20" and "Tween 80," and pluronics such as F68 and F88 (BASF, Mount Olive, New Jersey); sorbitan esters; lipids, such as phospholipids such as lecithin and other phosphatidylcholines, phosphatidylethanolamines (although preferably not in liposomal form), fatty acids and fatty esters; steroids, such as cholesterol; chelating agents, such as EDTA; and zinc and other such suitable cations.Acids or bases can be present as an excipient in the pharmaceutical composition. Nonlimiting examples of acids that can be used include those acids selected from the groupAttorney Docket No. UM-43996.601 consisting of hydrochloric acid, acetic acid, phosphoric acid, citric acid, malic acid, lactic acid, formic acid, trichloroacetic acid, nitric acid, perchloric acid, phosphoric acid, sulfuric acid, fumaric acid, and combinations thereof. Examples of suitable bases include, without limitation, bases selected from the group consisting of sodium hydroxide, sodium acetate, ammonium hydroxide, potassium hydroxide, ammonium acetate, potassium acetate, sodium phosphate, potassium phosphate, sodium citrate, sodium formate, sodium sulfate, potassium sulfate, potassium fumerate, and combinations thereof.The amount of DHB (derivatives, prodrugs, or pharmaceutical salts thereof) (e.g., when contained in a drug delivery system) in the pharmaceutical composition will vary depending on a number of factors, but will optimally be a therapeutically effective dose when the composition is in a unit dosage form or container (e.g., a vial). A therapeutically effective dose can be determined experimentally by repeated administration of increasing amounts of the composition in order to determine which amount produces a clinically desired endpoint.The amount of any individual excipient in the pharmaceutical composition will vary depending on the nature and function of the excipient and particular needs of the composition. Typically, the optimal amount of any individual excipient is determined through routine experimentation, i.e., by preparing compositions containing varying amounts of the excipient (ranging from low to high), examining the stability and other parameters, and then determining the range at which optimal performance is attained with no significant adverse effects. Generally, however, the excipient(s) will be present in the composition in an amount of about 1% to about 99% by weight, preferably from about 5% to about 98% by weight, more preferably from about 15 to about 95% by weight of the excipient, with concentrations less than 30% by weight most preferred. These foregoing pharmaceutical excipients along with other excipients are described in "Remington: The Science & Practice of Pharmacy", 19thed., Williams & Williams, (1995), the "Physician’s Desk Reference", 52nded., Medical Economics, Montvale, NJ (1998), and Kibbe, A.H., Handbook of Pharmaceutical Excipients, 3rdEdition, American Pharmaceutical Association, Washington, D.C., 2000.The pharmaceutical compositions encompass all types of formulations and in particular those that are suited for injection, e.g., powders or lyophilates that can be reconstituted with a solvent prior to use, as well as ready for injection solutions or suspensions, dry insoluble compositions for combination with a vehicle prior to use, and emulsions and liquid concentrates for dilution prior to administration. Examples of suitable diluents for reconstituting solid compositions prior to injection include bacteriostatic waterAttorney Docket No. UM-43996.601 for injection, dextrose 5% in water, phosphate buffered saline, Ringer’s solution, saline, sterile water, deionized water, and combinations thereof. With respect to liquid pharmaceutical compositions, solutions and suspensions are envisioned. Additional preferred compositions include those for oral, ocular, or localized delivery.The pharmaceutical preparations herein can also be housed in a syringe, an implantation device, or the like, depending upon the intended mode of delivery and use. Preferably, the pharmaceutical compositions comprising DHB described herein are in unit dosage form, meaning an amount of a conjugate or composition of the invention appropriate for a single dose, in a premeasured or pre-packaged form.The pharmaceutical compositions herein may optionally include one or more additional agents, or may be combined with one or more additional agents, such as other drugs for improving T cell memory and / or anti -tumor efficacy (e.g., anti-PD-1 checkpoint inhibitor, such as nivolumab), or other medications used to treat a subject for an infection or disease associated with compromised T cells (e.g., antiviral, antibiotic, or anti-cancer drugs and therapies, including adoptive T cell therapies). Compounded preparations may be used including DHB and one or more other agents, such as other drugs for improving T cell memory and / or improving anti-tumor efficacy . Alternatively, such agents can be contained in a separate composition from the composition comprising DHB and co-administcrcd concurrently, before, or after the composition comprising DHB.At least one therapeutically effective cycle of treatment with DHB will be administered to a subject for treatment of compromised T cell memory. By “therapeutically effective cycle of treatment” is intended a cycle of treatment that when administered, brings about a positive therapeutic response with respect to treatment of an individual. Of particular interest is a cycle of treatment with DHB that, when administered transiently as described herein, improves T cell memory.In certain embodiments, multiple therapeutically effective doses of pharmaceutical compositions comprising DHB, and / or one or more other therapeutic agents (e.g., anti-PD-1 checkpoint inhibitor, such as nivolumab) (e.g., antiviral, antibiotic, or anti-cancer drugs and therapies, including adoptive T cell therapies) will be administered.In some embodiments, the one or more additional therapeutic agents are immune checkpoint inhibitors or immune checkpoint blockers. In some embodiments, the immune checkpoint inhibitor or blocker comprises an inhibitor of CTLA-4, PD-1, PDL-1, Lag3, LAIR1, or LAIR 2. In some embodiments, the immune checkpoint inhibitor or blocker comprises an anti-CTLA-4 antibody, an anti-PD-1 antibody, an anti-PDL-1 antibody, an anti-Attorney Docket No. UM-43996.601Lag3 antibody, an anti-LAIRl antibody, or an anti-LAIR 2 antibody. In some embodiments, the immune checkpoint inhibitor or blocker comprises an anti-PD-1 antibody, or an anti- PDL- 1 antibody. In some embodiments, the immune checkpoint inhibitor or blocker is selected from nivolumab, pembrolizumab, ipilimumab, atezolizumab, avelumab, and durvalumab. As another example, the immune checkpoint inhibitor or blocker may be a monoclonal antibody (e.g. atezolizumab, avelumab, bevacizumab, cemiplimab, cetuximab, daratumumab, dinutuximab, durvalumab, elotuzumab, ipilimumab, isatuximab, mogamulizumab, necitumumab, nivolumab, obitunuzumab, ofatumumab, oralatumab, panitumumab, pembrolizumab, pertuzumab, ramucirumab, rituximab, trastuzumab, gemtuzumab ozogamicin, bentruximab vedotin, trastuzumab emtansine, inotuzumab ozogamicin, polatuzumab vedotin, efortumab vedotin, trastuzumab deruxtecan, Sacituzumab govitecan, moxetumuomab pasudotox, ibritumomab tiuxetan, iodine tositumuomab, blatinumomab).In some embodiments, the one or more additional therapeutic agents are selected from an apoptotic agent, a mitotic inhibitor (e.g., monomethyl auristatin E (MMAE), monomethyl auristatin F(MMAF), mertansine (DM1), and ravtansine (DM4)), an anti -tumor antibiotic, an immunomodulating agent, a nucleic acid for gene therapy, an anti-angiogenic agent, an anti- mctabolitc, a boron-containing agent, a chcmoprotcctivc agent, a hormone agent, an antihormone agent, a DNA damaging agent (e.g., psilocybin, gliclazomycin, streptomycin, pyrrolobenzodiazepine (PBD), doxorubicin, and adrianmycin), a corticosteroid, a photoactive therapeutic agent, an oligonucleotide, a radionuclide agent, a radiosensitizer, a topoisomerase inhibitor, and a tyrosine kinase inhibitor.In some embodiments, the one or more additional therapeutic agents are selected from a disease-modifying antirheumatic drug (e.g., leflunomide, methotrexate, sulfasalazine, hydroxychloroquine), a biologic agent (e.g., rituximab, infliximab, etanercept, adalimumab, golimumab), a nonsteroidal anti-inflammatory drug (e.g., ibuprofen, celecoxib, ketoprofen, naproxen, piroxicam, diclofenac), an analgesic (e.g., acetaminophen, tramadol), an immunomodulator (e.g., anakinra, abatacept), and a glucocorticoid (e.g., prednisone, methylprednisone).In some embodiments, the one or more additional therapeutic agents are selected from a chemotherapeutic agent. Examples of chemotherapeutic agents include, but are not limited to, abiraterone acetate, methotrexate, paclitaxel albumin-stabilized nanoparticle formulation, ABVC (doxorubicin hydrochloride, bleomycin, vinblastine sulfate, dacarbazine combination), ABVE (doxorubicin hydrochloride, bleomycin, vinblastine sulfate, etoposideAttorney Docket No. UM-43996.601 combination), ABVE-PC (doxorubicin hydrochloride, bleomycin, vinblastine sulfate, etoposide, prednisone, cyclophosphamide combination), AC (doxorubicin hydrochloride and cyclophosphamide combination), AC-T (doxorubicin hydrochloride, cyclophosphamide, paclitaxel combination), brentuximab vedotin, ADE (cytarabine, daunorubicin hydrochloride, etoposide combination), ado-trastuzumab cmtansinc, doxorubicin hydrochloride, fluorouracil, afatinib dimaleate, everolimus, imiquimod, aldesleukin, alemtuzumab, pemetrexed disodium, palonosetron hydrochloride, chlorambucil, aminolevulinic acid, anastrozole, aprepitant, pamidronate disodium, exemestane, nelarabine, arsenic trioxide, ofatumumab, asparaginase erwinia chrysanthemi, bevacizumab, axitinib, azacitidine, BEACOPP (bleomycin, etoposide, doxorubicin hydrochloride, cyclophosphamide, vincristine sulfate, procarbazine hydrochloride, prednisone combination), carmustine, belinostat, bendamustine hydrochloride, BEP (bleomycin, etoposide, cisplatin combination), bevacizumab, bexarotene, tositumomab, 1 131 Iodine tositumomab, bicalutamide, carmustine, bleomycin, bortezomib, bosutinib, busulfan, cabazitaxel, cabozantinib-S-malate, CAF (cyclophosphamide, doxorubicin hydrochloride, fluorouracil combination), irinotecan hydrochloride, capecitabine, CAPOX (capecitabine, oxaliplatin combination), carboplatin, carboplatin-taxol combination, carfilzomib, carmustine implant, lomustine, ceritinib, daunorubicin hydrochloride, recombinant HPV bivalent vaccine, cetuximab, chlorambucil, chlorambucil-prcdnisonc combination, CHOP (cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone combination), cisplatin, cyclophosphamide, clofarabine, CMF (cyclophosphamide, methotrexate, fluorouracil combination), COPP (cyclophosphamide, vincristine sulfate, procarbazine hydrochloride, prednisone combination), COPP- ABV (cyclophosphamide, vincristine sulfate, procarbazine hydrochloride, prednisone, doxorubicin hydrochloride, bleomycin, vinblastine sulfate combination), dactinomycin, crizotinib, CVP (cyclophosphamide, vincristine sulfate, prednisone combination), ifosfamide, ramucirumab, cytarabine, liposomal cytarabine, dabrafenib, dacarbazine, decitabine, dactinomycin, dasatinib, degarelix, denileukin diftitox, denosumab, dexrazoxane hydrochloride, docetaxel, doxorubicin hydrochloride liposome, fluorouracil, rasburicase, epirubicin hydrochloride, oxaliplatin, eltrombopag olamine, enzalutamide, EPOCH (etoposide, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride combination), eribulin mesylate, vismodegib, erlotinib hydrochloride, etoposide phosphate, etoposide, everolimus, raloxifene hydrochloride, torernifene, fulvestrant, FEC (fluorouracil, epirubicin hydrochloride, cyclophosphamide combination), letrozole, filgrastim, fludarabine phosphate, fluorouracil, FOLFIRI (leucovorin calcium, fluorouracil, irinotecan hydrochloride combination),Attorney Docket No. UM-43996.601FOLFIRI-bevacizumab combination, FOLFIRI-cetuximab combination, FOLFIRINOX (leucovorin calcium, fluorouracil, irinotecan hydrochloride, oxaliplatin combination), FOLFOX (leucovorin calcium, fluorouracil, oxaliplatin combination), pralatrexate, FU-LV (fluorouracil, leucovorin calcium combination), recombinant HPV quadrivalent vaccine, obinutuzumab, gcfitinib, gemcitabine hydrochloride, gemcitabine-cisplatin combination, gemcitabine-oxaliplatin combination, gemtuzumab ozogamicin, imatinib mesylate, glucarpidase, goserelin acetate, trastuzumab, topotecan hydrochloride, hyper-CVAD (cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone combination), ibritumomab tiuxetan, ibrutinib, ICE (ifosfamide, carboplatin, etoposide combination), ponatinib hydrochloride, idarubicin hydrochloride, idelalisib, ifosamide, axitinib, recombinant interferon a- 2b, ipilimumab, irinotecan hydrochloride, romidepsin, ixabepilone, mxolitinib phosphate, palifermin, pembrolizumab, lapatinib ditosylate, lenalidomide, letrozole, leucovorin calcium, leuprolide acetate, vincristine sulfate liposome, procarbazine hydrochloride, mechlorethamine hydrochloride, megestrol acetate, trametinib, mercaptopurine, mesna, temozolomide, mitomycin C, mitoxantrone hydrochloride, MOPP (mechlorethamine hydrochloride, vincristine sulfate, procarbazine hydrochloride, prednisone combination), plerixafor, vinorelbine tartrate, nelarabine, sorafenib tosylate, nilotinib, tamoxifen citrate, romiplostim, obinutuzumab, ofatumumab, omacctaxinc mcpcsuccinatc, pegaspargase, OEPA (vincristine sulfate, etoposide, prednisone, doxorubicin hydrochloride combination), OFF (oxaliplatin, fluorouracil, leucovorin calcium combination), OPPA (vincristine sulfate, procarbazine hydrochloride, prednisone, doxorubicin hydrochloride combination), paclitaxel, PAD (bortezomib, doxorubicin hydrochloride, dexamethasone combination), palifermin, palonosetron hydrochloride, pamidronate e disodium, panitumumab, pazopanib hydrochloride, peginterferon a- 2b, pembrolizumab, pemetrexed disodium, pertuzumab, plerixafor, pomalidomide, ponatinib hydrochloride, pralatrexate, prednisone, procarbazine hydrochloride, sipuleuceLT, radium 223 dichloride, R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone combination), R-CVP (rituximab, cyclophosphamide, vincristine sulfate, prednisone combination), reforafenib, rituximab, romidepsin, ruxolitinib phosphate, talc, siltuximab, sipuleuceLT, sorafenib tosylate, STANFORD V (mechlorethamine hydrochloride, doxorubicin hydrochloride, vinblastine sulfate, vincristine sulfate, bleomycin, etoposide, prednisone combination), sunitinib malate, thalidomide, TAG (docetaxel, doxorubicin hydrochloride, cyclophosphamide combination), temozolomide, temsirolimus, topotecan hydrochloride, toremifene, TPF (docetaxel, cisplatin, fluorouracil combination), trametinib,Attorney Docket No. UM-43996.601 trastuzumab, vandetanib, VAMP (vincristine sulfate, doxorubicin hydrochloride, methotrexate, prednisone combination), VelP (vinblastine sulfate, ifosamide, cisplatin combination), vinblastine sulfate, vemurafenib, vincristine sulfate, vincristine sulfate liposome, vinorelbine tartrate, VIP (etoposide, ifosfamide, cisplatin combination), vismodcgib, vorinostat, XELOX (capccitabinc, oxaliplatin combination), ziv-aflibcrccpt, zoledronic acid, QBECO, QBKPN, QBSAU, QBECP, and combinations thereof.In some embodiments, the one or more additional therapeutic agents are capable of or suspected of being capable of treating a disease or condition related to atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious disease; HIV; Aids; infection with sars virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (chicken) flu vims, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterized by benign or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin's lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, so gall bladder, spleen, brain, lymphatic system, bones, skin or pancreas.In some embodiments, the one or more additional therapeutic agents are capable of or suspected of being capable of treating a disease or condition related to a neoplastic disease, selected from, but not limited to, leukemia, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia, chronic leukemia, chronic myelocytic, (granulocytic) leukemia, chronic lymphocytic leukemia, Polycythemia vera, lymphoma, Hodgkin's disease, non-Hodgkin's disease, Multiple myeloma, Waldenstrom's macroglobulinemia, Heavy chain disease, solid tumors, sarcomas and carcinomas, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma,Attorney Docket No. UM-43996.601 adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, and neuroblastomaretinoblastoma. In some embodiments, the disease is an inflammatory disease selected from the group consisting of, but not limited to, eczema, inflammatory bowel disease, rheumatoid arthritis, asthma, psoriasis, ischemia / reperfusion injury, ulcerative colitis and acute respiratory distress syndrome.In some embodiments, the one or more additional therapeutic agents are capable of or suspected of being capable of treating a disease or condition related to a viral disease selected from the group consisting of, but not limited to, viral disease caused by hepatitis B, hepatitis C, rotavirus, human immunodeficiency virus type I (HIV-I), human immunodeficiency virus type II (HIV-II), human T-cell lymphotropic virus type I (HTLV-I), human T-cell lymphotropic virus type II (HTLV-II), AIDS, DNA viruses such as hepatitis type B and hepatitis type C vims; parvoviruses, such as adcno-associatcd vims and cytomegalovirus; papovavimses such as papilloma vims, polyoma vimses, and SV40; adenovimses; herpes vimses such as herpes simplex type I (HSV-I), herpes simplex type II (HSV-II), and Epstein- Barr vims; poxvimses, such as variola (smallpox) and vaccinia vims; and RNA vimses, such as human immunodeficiency vims type I (HIV-I), human immunodeficiency vims type II (HIV-II), human T-cell lymphotropic vims type I (HTLV-I), human T-cell lymphotropic vims type II (HTLV-II), influenza vims, measles vims, rabies vims, Sendai vims, picomaviruses such as poliomyelitis vims, coxsackieviruses, rhino vimses, reovimses, togavimses such as rubella vims (German measles) and Semliki forest vims, arboviruses, and hepatitis type A vims.In some embodiments, the one or more additional therapeutic agents are capable of or suspected of being capable of treating a disease or condition related to Gram-positive and / or Gram-negative bacteria and / or dmg resistant Gram-positive and / or Gram-negative bacteria. Examples of such diseases or conditions include, but are not limited to, pneumonia, endocarditis, bacteremia, sepsis and other forms of toxemia caused by Gram-positive and / or Gram-negative bacteria.Attorney Docket No. UM-43996.601In some embodiments, the one or more additional therapeutic agents are capable of or suspected of being capable of treating a disease or condition related to an autoimmune disorder and / or inflammatory disease. Examples of autoimmune disorders and / or inflammatory diseases include, but are not limited to, arthritis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, degenerative arthritis, polymyalgia rheumatic, ankylosing spondylitis, reactive arthritis, gout, pseudogout, inflammatory joint disease, systemic lupus erythematosus, polymyositis, and fibromyalgia. Additional types of arthritis include achilles tendinitis, achondroplasia, acromegalic arthropathy, adhesive capsulitis, adult onset Still's disease, anserine bursitis, avascular necrosis, Behcet's syndrome, bicipital tendinitis, Blount's disease, brucellar spondylitis, bursitis, calcaneal bursitis, calcium pyrophosphate dihydrate deposition disease (CPPD), crystal deposition disease, Caplan's syndrome, carpal tunnel syndrome, chondrocalcinosis, chondromalacia patellae, chronic synovitis, chronic recurrent multifocal osteomyelitis, Churg-Strauss syndrome, Cogan's syndrome, corticosteroid-induced osteoporosis, costostemal syndrome, CREST syndrome, cryoglobulinemia, degenerative joint disease, dermatomyositis, diabetic finger sclerosis, diffuse idiopathic skeletal hyperostosis (DISH), discitis, discoid lupus erythematosus, drug-induced lupus, Duchenne's muscular dystrophy, Dupuytren's contracture, Ehlers-Danlos syndrome, enteropathic arthritis, epicondylitis, erosive inflammatory osteoarthritis, exercise-induced compartment syndrome, Fabry's disease, familial Mediterranean fever, Farber’s lipogranulomatosis, Felty's syndrome, Filth's disease, flat feet, foreign body synovitis, Freiberg's disease, fungal arthritis, Gaucher's disease, giant cell arteritis, gonococcal arthritis, Goodpasture's syndrome, granulomatous arteritis, hemarthrosis, hemochromatosis, Henoch-Schonlein purpura, Hepatitis B surface antigen disease, hip dysplasia, Hurler syndrome, hypermobility syndrome, hypersensitivity vasculitis, hypertrophic osteoarthropathy, immune complex disease, impingement syndrome, laccoud's arthropathy, juvenile ankylosing spondylitis, juvenile dermatomyositis, juvenile rheumatoid arthritis, Kawasaki disease, Kienbock’s disease, Legg-Calve-Perthes disease, Lesch-Nyhan syndrome, linear scleroderma, lipoid dermatoarthritis, Lofgren's syndrome, Lyme disease, malignant synovioma, Marfan's syndrome, medial plica syndrome, metastatic carcinomatous arthritis, mixed connective tissue disease (MCTD), mixed cryoglobulinemia, mucopolysaccharidosis, multicentric reticulohistiocytosis, multiple epiphyseal dysplasia, mycoplasmal arthritis, myofascial pain syndrome, neonatal lupus, neuropathic arthropathy, nodular panniculitis, ochronosis, olecranon bursitis, Osgood-Schlatter's disease, osteoarthritis, osteochondromatosis, osteogenesis imperfecta, osteomalacia, osteomyelitis, osteonecrosis, osteoporosis, overlap syndrome, pachydermoperiostosis Paget's disease of bone, palindromicAttorney Docket No. UM-43996.601 rheumatism, patellofemoral pain syndrome, Pellegrini-Stieda syndrome, pigmented villonodular synovitis, piriformis syndrome, plantar fasciitis, polyarteritis nodus, Polymyalgia rheumatic, polymyositis, popliteal cysts, posterior tibial tendinitis, Pott's disease, prepatellar bursitis, prosthetic joint infection, pseudoxanthoma elasticum, psoriatic arthritis, Raynaud's phenomenon, reactive arthritis / Rcitcr's syndrome, reflex sympathetic dystrophy syndrome, relapsing polychondritis, retrocalcaneal bursitis, rheumatic fever, rheumatoid vasculitis, rotator cuff tendinitis, sacroiliitis, salmonella osteomyelitis, sarcoidosis, saturnine gout, Scheuermann's osteochondritis, scleroderma, septic arthritis, seronegative arthritis, shigella arthritis, shoulder-hand syndrome, sickle cell arthropathy, Sjogren's syndrome, slipped capital femoral epiphysis, spinal stenosis, spondylolysis, staphylococcus arthritis, Stickler syndrome, subacute cutaneous lupus, Sweet's syndrome, Sydenham's chorea, syphilitic arthritis, systemic lupus erythematosus (SLE), Takayasu's arteritis, tarsal tunnel syndrome, tennis elbow, Tietse's syndrome, transient osteoporosis, traumatic arthritis, trochanteric bursitis, tuberculosis arthritis, arthritis of Ulcerative colitis, undifferentiated connective tissue syndrome (UCTS), urticarial vasculitis, viral arthritis, Wegener's granulomatosis, Whipple's disease, Wilson's disease, and yersinial arthritis.The pharmaceutical compositions of the present invention are typically, although not necessarily, administered orally, via injection (subcutaneously, intravenously, or intramuscularly), by infusion, or locally. Additional modes of administration are also contemplated, such as topical, intralesion, intracerebral, intracerebroventricular, intraparenchymatous, pulmonary, rectal, transdermal, transmucosal, intrathecal, pericardial, intra-arterial, intraocular, intraperitoneal, and so forth.The pharmaceutical preparation can be in the form of a liquid solution or suspension immediately prior to administration, but may also take another form such as a syrup, cream, ointment, tablet, capsule, powder, gel, matrix, suppository, or the like. The pharmaceutical compositions comprising DHB and other agents may be administered using the same or different routes of administration in accordance with any medically acceptable method known in the art.In another embodiment, the pharmaceutical compositions comprising DHB and / or other agents are administered prophylactically. Such prophylactic uses will be of particular value for subjects with a chronic infection or cancer, who are at risk of developing compromised T cells (e.g., T cells with compromised T cell memory).In another embodiment of the invention, the pharmaceutical compositions comprising DHB and / or other agents are in a sustained-release formulation, or a formulation that isAttorney Docket No. UM-43996.601 administered using a sustained-release device. Such devices are well known in the art, and include, for example, transdermal patches, and miniature implantable pumps that can provide for drug delivery over time in a continuous, steady-state fashion at a variety of doses to achieve a sustained-release effect with a non-sustained-release pharmaceutical composition.The invention also provides a method for administering a conjugate comprising DHB as provided herein to a patient suffering from a condition that is responsive to treatment with DHB contained in the conjugate or composition. The method comprises administering, via any of the herein described modes, a therapeutically effective amount of the conjugate or drug delivery system, preferably provided as part of a pharmaceutical composition. The method of administering may be used to treat any condition that is responsive to treatment with DHB. More specifically, the pharmaceutical compositions herein are effective in improving T cell memory and / or improving anti-tumor efficacy.Those of ordinary skill in the art will appreciate which conditions DHB can effectively treat. The actual dose to be administered will vary depending upon the age, weight, and general condition of the subject as well as the severity of the condition being treated, the judgment of the health care professional, and conjugate being administered. Therapeutically effective amounts can be determined by those skilled in the art, and will be adjusted to the particular requirements of each particular case.Generally, a therapeutically effective amount will range from about 0.50 mg to 5 grams of a DHB daily, more preferably from about 5 mg to 2 grams daily, even more preferably from about 7 mg to 1 .5 grams daily. Preferably, such doses are in the range of 10- 600 mg four times a day (QID), 200-500 mg QID, 25- 600 mg three times a day (TID), 25-50 mg TID, 50-100 mg TID, 50-200 mg TID, 300-600 mg TID, 200-400 mg TID, 200-600 mg TID, 100 to 700 mg twice daily (BID), 100-600 mg BID, 200-500 mg BID, or 200-300 mg BID. The amount of compound administered will depend on the potency of the DHB and the magnitude or effect desired and the route of administration.A purified DHB (again, preferably provided as part of a pharmaceutical preparation) can be administered alone or in combination with one or more other therapeutic agents, such as other drugs (e.g., anti-PD-1 checkpoint inhibitor, such as nivolumab), or other medications used to treat a subject for an infection or disease associated with compromised T cell activity (e.g., compromised T cell memory) (e.g., antiviral, antibiotic, or anti-cancer drugs); or adoptive T cell therapies (e.g., a CAR T-cell therapy, a transduced T-cell therapy, and a tumor infiltrating lymphocyte (TIL) therapy); or other medications used to treat a particular condition or disease according to a variety of dosing schedules depending on the judgment ofAttorney Docket No. UM-43996.601 the clinician, needs of the patient, and so forth. The specific dosing schedule will be known by those of ordinary skill in the art or can be determined experimentally using routine methods. Exemplary dosing schedules include, without limitation, administration five times a day, four times a day, three times a day, twice daily, once daily, three times weekly, twice weekly, once weekly, twice monthly, once monthly, and any combination thereof. Preferred compositions are those requiring dosing no more than once a day.DHB can be administered prior to, concurrent with, or subsequent to other agents or therapies. If provided at the same time as other agents or therapies, DHB can be provided in the same or in a different composition. Thus, DHB and other agents can be presented to the individual by way of concurrent therapy. By “concurrent therapy” is intended administration to a subject such that the therapeutic effect of the combination of the substances is caused in the subject undergoing therapy. For example, concurrent therapy may be achieved by administering a dose of a pharmaceutical composition comprising DHB and a dose of a pharmaceutical composition comprising at least one other agent, such as another drug for treating compromised T cells, which in combination comprise a therapeutically effective dose, according to a particular dosing regimen. Similarly, DHB and one or more other therapeutic agents can be administered in at least one therapeutic dose. Administration of the separate pharmaceutical compositions or therapies can be performed simultaneously or at different times (i.e., sequentially, in either order, on the same day, or on different days), as long as the therapeutic effect of the combination of these substances is caused in the subject undergoing therapy.The invention also provides kits comprising one or more containers holding compositions comprising DHB and optionally one or more other agents for treating or preventing compromised T cells. Compositions can be in liquid form or can be lyophilized. Suitable containers for the compositions include, for example, bottles, vials, syringes, and test tubes. Containers can be formed from a variety of materials, including glass or plastic. A container may have a sterile access port (for example, the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodemric injection needle).The kit can further comprise a second container comprising a pharmaceutically- acceptable buffer, such as phosphate-buffered saline, Ringer's solution, or dextrose solution. It can also contain other materials useful to the end-user, including other pharmaceutically acceptable formulating solutions such as buffers, diluents, filters, needles, and syringes or other delivery devices. The delivery device may be pre-filled with the compositions. The kit can also comprise a package insert containing written instructions for methods of using DHB.Attorney Docket No. UM-43996.601The package insert can be an unapproved draft package insert or can be a package insert approved by the Food and Drug Administration (FDA) or other regulatory body.One of ordinary skill in the art will readily recognize that the foregoing represents merely a detailed description of certain preferred embodiments of the present invention. Various modifications and alterations of the compositions and methods described above can readily be achieved using expertise available in the art and are within the scope of the invention.EXAMPLESThe following examples are illustrative, but not limiting, of the compounds, compositions, and methods of the present invention. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in clinical therapy and which are obvious to those skilled in the art are within the spirit and scope of the invention.Example I.This example demonstrates that ex vivo treatment of CD8+ T cells with DHB enhances the anti-tumor efficacy of adoptively transferred T cells.MethodsDHB treatment induces stem-like memory CD8+T cell differentiation. Splenocytes from OT-I mice were obtained aseptically. CD8+T cells were isolated using CD8+T cell isolation kit (Stemcell) and activated with SIINFEKL (4 nM) in the presence of DHB (100 pM) for 3 days. Then cells were washed twice with T-cell medium and further cultured with IL-2 (10 ng / mL; Pepro Tech) in the presence of DHB for 5 days. The cells were collected, blocked with CD16 / 32 antibody and stained with BV570-anti-mouse CD8a Antibody (Biolegend, Clone 53-6.7), PerCP-Cy5.5-anti-mouse CD127 Antibody (Fisher Scientific, Clone A7R34), and FITC-anti-mouse CD279 (PD-1) Antibody (eBioscience, Clone RMP1 30). Cells were washed twice in FACS buffer, fixed, permeabilized using the Foxp3 Transcription Factor Staining Buffer Kit (eBioscience) and stained with PE-anti-mouse / human / rat Foxol Antibody (Cell Signaling, Clone C29H4), APC-anti-mouse / human Tcfl / Tcf7 Antibody (Cell Signaling, Clone C63D9), AF700-anti-mouse Ki-67 Antibody (Biolegend, Clone 16A8), Live / Dead fixable Near-IR (Invitrogen, no. L10119). Cells were analyzed with Cylek Aurora using SpectroFlo v.3.1.0.Attorney Docket No. UM-43996.601Evaluation of adoptive cell therapy in mice. To generate OVA-specific CD8+T cells for adoptive cell therapy (ACT), OT-I CD8+T cells were isolated from spleens of OT-I mice using CD8+T cell isolation kit (Stemcell) and treated with SIINFEKL peptide (4 nM) and DHB (100 pM) for 3 days. Cells were washed twice with T-cell medium and further expanded with IL-2 (10 ng / mL; Pcpro Tech) in the presence of DHB for 5 days. Female C57BL / 6 mice of age 7-8 weeks (Jackson Laboratories) were inoculated with 1.5xl05B16F10-OVA cancer cells subcutaneously in the right flank. Five days after tumor inoculation, mice were retro-orbitally injected with 3x106activated OT-I CD8+T cells in 100 pL of sterile PBS. Tumor size and body weight was monitored every 2 days. Tumor size was calculated based on the equation: volume = length x width2x 0.5. On day 21, tumor tissues were collected for tumor infiltrating T cell analysis.ResultsFoxol plays a critical role in promoting T cell longevity through memory programming, underscoring its importance in optimizing CAR T-cell therapy. Ex vivo treatment of activated OT-I CD8+T cells with DHB significantly increased the frequency of CD127+PD-1‘CD8+T cells, representing long-lived memory T cells (Fig. la). Within this immune cell subset, DHB enhanced the expression of memory-associated markers (Foxol and Tcfl) (Fig. lb,c), and concomitantly upregulated proliferation marker (Ki67) (Fig. Id).Based on these results, we next evaluated whether ex vivo treatment of CD8+T cells with DHB might enhance T cell persistence and survival, leading to long-lasting antitumor efficacy after adoptive cell therapy (ACT) of CD8+T cells. In order to test whether DHB could improve the potency of T cell therapy, we established an ACT model where in vitro- activated OT-I CD8+T cells were adoptively transferred into B16F10-OVA-bearing mice (Fig. le). Compared with control OT-I ACT, DHB-treated OT-I CD8+T cells significantly delayed tumor growth, and 2 of 10 mice achieved complete tumor regression (Fig. le). We further analyzed the tumor-infiltrating T cells on day 21 and observed prominent accumulation of transferred (Thyl.U) CD8+T cells and Ki67+CD8+T cells for the DHB- treated OT-I ACT group (Fig. lf,g). Taken together, ex vivo treatment of T cells with DHB endows T cells with a persistent memory phenotype, enhancing their survival and promoting the anti-tumor activity of adoptively transferred T cells. These results suggest that DHB treatments during the production of CAR-T cells may endow CAR-T cells with durable memory phenotype, thus enhancing its therapeutic efficacy.Attorney Docket No. UM-43996.601Example ILThis example demonstrates that in vivo administration of DHB Prodrug 201 improves the anti-tumor efficacy of adoptively transferred T cells.MethodEnhancement of adoptive OT-I T cell transfer therapy after Prodrug 201 administration. CD8+T cells were isolated from spleens and lymph nodes of Thy 1. 1+OT-1 transgenic mice by negative selection using EasySep Mouse CD8+T Cell Isolation Kit (STEMCELL Technologies). To activate and expand OT-I CD8+T cells in vitro, purified OT-I T cells were cultured in RPML1640 medium supplemented with 10% heat-inactivated FBS, 1% penicillin / streptomycin, 1 mM sodium pyruvate, 10 mM HEPES, lx non-essential amino acids, 50 pM P-mercaptoethanol, recombinant mouse interleukin-2 (10 ng / mL; Peprotech), and Dynabeads™ Mouse T-Activator CD3 / CD28 (at a bead-to-cell ratio of 1: 1; Gibco) for 5 days in a humidified CO2 incubator at 37°C. We next evaluated the ability of Prodrug 201 to enhance adoptive T cell transfer therapy in vivo. Female C57BL / 6 (Thyl.2+) mice were inoculated with 2xl05B16F10-OVA cancer cells on their right flanks. Five days after tumor inoculation, mice were randomly divided into three treatment groups, and retro-orbitally injected with 5xl06activated OT-I CD8+T cells in 100 pL of sterile PBS. Oral administration of Prodrug 201 was initiated on day 5 after tumor inoculation and was given every other day. Tumor growth was monitored every other day. Tumor volume was calculated as 0.5 x (length) x (width)2. On day 21, tumor tissues were collected, single-cell suspensions were prepared, and tumor-infiltrating T cells were analyzed by flow cytometry.ResultsThe chemical structure of DHB oral Prodrug 201 is shown here:We investigated whether oral administration of Prodrug 201 could enhance the antitumor activity of adoptively transferred T cells. To this end, on day 5 post-B16F10-OVA inoculation, we performed adoptive transfer of activated Thyl.U OT-I T cells, followed by the initiation of oral Prodrug 201 administration (Fig. 2a). While adoptive cell therapy (ACT)Attorney Docket No. UM-43996.601 alone did not significantly suppress the aggressive tumor growth of B16F10-OVA, oral administration of Prodrug 201 markedly enhanced the antitumor activity of the adoptively transferred T cells (Fig. 2b, c).Subsequently, we conducted a detailed flow cytometry analysis of tumor-infiltrating adoptively transferred T cells by preparing single-cell suspensions from tumor tissues. Although there were no significant changes in the populations of tumor-infiltrating adoptively transferred T cells or endogenous Thyl.2+CD8 T cells following Prodrug 201 administration, we observed that Prodrug 201 administration increased the proportion of TCF1 -expressing adoptively transferred T cells and decreased the proportion of TOX- expressing adoptively transferred T cells (Fig. 2f-i). This suggests that Prodrug 201 reduces T cell exhaustion and promotes the development of a stem-like memory phenotype in T cells in vivo. Therefore, systemic administration of Prodrug 201 shows the potential to enhance the therapeutic efficacy of ACT.Example III.This example demonstrates that ex vivo treatment of CD8+ T cells with DHB promotes stem-like phenotype and persistent antitumor efficacy in vivo.MethodsEvaluation of adoptive cell therapy in mice. To generate OVA-specific CD8+T cells for adoptive cell therapy (ACT), OT-I CD8+T cells were isolated from spleens of OT-I mice using CD8+T cell isolation kit (Stemcell) and treated with SIINFEKL peptide (4 nM) and DHB (100 pM) for 3 days. Cells were washed twice with T-cell medium and further expanded with IL-2 (10 ng / mL; Pepro Tech) in the presence of DHB for 5 days. Female C57BL / 6 mice of age 7-8 weeks (Jackson Laboratories) were inoculated with 2xl06NOOCL OVA cancer cells subcutaneously in the right flank. Seven days after tumor inoculation, mice were retro-orbitally injected with 3xl06activated OT-I CD8+T cells in 100 pL of sterile PBS. Tumor size and body weight was monitored every 2 days. Tumor size was calculated based on the equation: volume = length x width2x 0.5. On day 30, peripheral blood mononuclear cells (PBMCs) were collected for immunophenotyping investigation.ResultsTo evaluate the in vivo antitumor efficacy of adoptive cell therapy, activated CD8+T cells generated ex vivo were adoptively transferred into NOOCl-OVA-bearing mice (Fig. 3a). ExAttorney Docket No. UM-43996.601 vivo treatment of activated OT-I CD8+T cells with DHB significantly enhanced the antitumor efficacy compared with control OT-I CD8+T cells (Fig. 3b). We further conducted phenotypic analysis of PBMCs isolated from the mice on day 30, and observed higher frequencies of Tcfl+CD8+T cells, and CD44+CD62L+CD8+T cells among tumor antigenspecific CD8+T cells in the DHB-traincd OT-I ACT group (Fig. 3c). These findings support that DHB reprograms tumor antigen-specific CD8+T cells toward a stem-like phenotype, promoting persistent antitumor immunity in vivo.Having now fully described the invention, it will be understood by those of skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations, and other parameters without affecting the scope of the invention or any embodiment thereof. All patents, patent applications and publications cited herein are fully incorporated by reference herein in their entirety.INCORPORATION BY REFERENCEThe entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes.EQUIVALENTSThe invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

Attorney Docket No. UM-43996.601What Is Claimed Is:

1. A method for treating an immune system related condition or disease in a subject comprising administering to the subject genetically engineered T cells and a therapeutically effective amount of 3,4-dihydroxybenzoate (DIIB) (derivatives, prodrugs, or pharmaceutical salts thereof).

2. The method of claim 1, wherein the DHB (derivatives, prodrugs, or pharmaceutical salts thereof) and the genetically engineered T cells are administered simultaneously and / or at different time points.

3. The method of claim 1 , wherein the immune system related condition or disease is selected from cancer or an autoimmune disease or condition.

4. The method of claim 1, wherein the genetically engineered T cells are selected from CAR T cells, genetically engineered TCR expressing T cells, genetically engineered T cells configured for tumor infiltrating lymphocyte (TIL) therapy, genetically engineered T cells configured for transduced T-cell therapy, and / or viral specific T cells reengineered with a TCR or CAR.

5. The method of claim 1, further comprising administering to said subject one or more anticancer agents.

6. The method of claim 5, wherein the one or more anticancer agents is selected from a chemotherapeutic agent and radiation therapy.

7. The method of claim 5, wherein the anticancer agent is one or more immune checkpoint inhibitors (ICTs).

8. The method of claim 7, wherein the one or more ICIs are selected from atezolizumab, avelumab, bevacizumab, cemiplimab, cetuximab, daratumumab, dinutuximab, durvalumab, elotuzumab, ipilimumab, isatuximab, mogamulizumab, necitumumab, nivolumab, obitunuzumab, ofatumumab, oralatumab, panitumumab, pembrolizumab, pertuzumab,Attorney Docket No. UM-43996.601 ramucirumab, rituximab, trastuzumab, gemtuzumab ozogamicin, bentruximab vedorin, trastuzumab emtansine, inotuzumab ozogamicin, polatuzumab vedotin, efortumab vedotin, trastuzumab deruxtecan, Sacituzumab govitecan, moxetumuomab pasudotox, ibritumomab tiuxetan, iodine tositumuomab, and blatinumomab.

9. The method of claim 7, wherein the one or more ICIs is an inhibitor of CTLA-4, PD-1, PDL-1, Lag3, LAIR1, or LAIR 2.

10. The method of claim 1, wherein the genetically engineered T cell population, wherein the genetically engineered T cell population was expanded in the presence of DHB.1 1 . The method of claim 1 , wherein the DHB is the following prodrug of DHB:

12. A composition comprising a genetically engineered T cell population, wherein the genetically engineered T cell population was expanded in the presence of DHB .

13. The composition of claim 12, wherein the genetically engineered T cell population is selected from CAR T cell population, a population of genetically engineered TCR expressing T cells, a population of genetically engineered T cells configured for tumor infiltrating lymphocyte (TIL) therapy, a population of genetically engineered T cells configured for transduced T-cell therapy, and / or a population of viral specific T cells reengineered with a TCR or CAR.

14. A method of generating a population of genetically engineered T cells, comprising expanding a population of genetically engineered T cells in the presence of DHB.

15. The method of claim 14, wherein the population of genetically engineered T cells is selected from CAR T cell population, a population of genetically engineered TCR expressingAttorney Docket No. UM-43996.601T cells, a population of genetically engineered T cells configured for tumor infiltrating lymphocyte (TIL) therapy, a population of genetically engineered T cells configured for transduced T-cell therapy, and / or a population of viral specific T cells reengineered with a TCR or CAR.

16. A method of treating an immune system related condition or disease, comprising administering to the subject a genetically engineered T cell population that were expanded in the presence of DHB.

17. The method of claim 16, wherein the genetically engineered T cell population is selected from CAR T cell population, a population of genetically engineered TCR expressing T cells, a population of genetically engineered T cells configured for tumor infiltrating lymphocyte (TIL) therapy, a population of genetically engineered T cells configured for transduced T-cell therapy, and / or a population of viral specific T cells reengineered with a TCR or CAR.

18. The method of claim 16, wherein the subject is undergoing an adoptive T cell therapy.

19. The method of claim 18, wherein the adoptive T cell therapy is a CAR T-cell therapy.

20. The method of claim 18, wherein the adoptive T cell therapy is a transduced T-cell therapy.

21. The method of claim 18, wherein the adoptive T cell therapy is a tumor infiltrating lymphocyte (TIL) therapy.

22. The method of claim 18, wherein the immune system related condition or disease is selected from cancer or an autoimmune disease or condition.

23. The method of claim 18, further comprising administering to said subject one or more anticancer agents.Attorney Docket No. UM-43996.60124. The method of claim 23, wherein the one or more anticancer agents is selected from a chemotherapeutic agent and radiation therapy.

25. The method of claim 23, wherein the anticancer agent is one or more immune checkpoint inhibitors (ICIs).

26. The method of claim 25, wherein the one or more ICIs are selected from atezolizumab, avelumab, bevacizumab, cemiplimab, cetuximab, daratumumab, dinutuximab, durvalumab, elotuzumab, ipilimumab, isatuximab, mogamulizumab, necitumumab, nivolumab, obitunuzumab, ofatumumab, oralatumab, panitumumab, pembrolizumab, pertuzumab, ramucirumab, rituximab, trastuzumab, gemtuzumab ozogamicin, bentruximab vedotin, trastuzumab emtansine, inotuzumab ozogamicin, polatuzumab vedotin, efortumab vedotin, trastuzumab deruxtecan, Sacituzumab govitecan, moxetumuomab pasudotox, ibritumomab tiuxetan, iodine tositumuomab, blatinumomab.

27. The method of claim 25, wherein the one or more ICIs is an inhibitor of CTLA-4, PD-1, PDL-1, Lag3, LAIR1, or LAIR 2.

28. A composition comprising the following prodrug29. A method of generating a population of genetically engineered T cells, comprising expanding a population of genetically engineered T cells in the presence of the following prodrugAttorney Docket No. UM-43996.60130. The method of claim 29, wherein the population of genetically engineered T cells is selected from CAR T cell population, a population of genetically engineered TCR expressing T cells, a population of genetically engineered T cells configured for tumor infiltrating lymphocyte (TIL) therapy, a population of genetically engineered T cells configured for transduced T-cell therapy, and / or a population of viral specific T cells reengineered with a TCR or CAR.

31. A method of treating an immune system related condition or disease, comprising administering to the subject a genetically engineered T cell population that were expanded in the presence of the following prodrug32. The method of claim 31, wherein the genetically engineered T cell population is selected from CAR T cell population, a population of genetically engineered TCR expressing T cells, a population of genetically engineered T cells configured for tumor infiltrating lymphocyte (TIL) therapy, a population of genetically engineered T cells configured for transduced T-cell therapy, and / or a population of viral specific T cells reengineered with a TCR or CAR.

33. The method of claim 31, wherein the subject is undergoing an adoptive T cell therapy.

34. The method of claim 33, wherein the adoptive T cell therapy is a CAR T-cell therapy.

35. The method of claim 33, wherein the adoptive T cell therapy is a transduced T-cell therapy.

36. The method of claim 33, wherein the adoptive T cell therapy is a tumor infiltrating lymphocyte (TIL) therapy.Attorney Docket No. UM-43996.60137. The method of claim 33, wherein the immune system related condition or disease is selected from cancer or an autoimmune disease or condition.

38. The method of claim 33, further comprising administering to said subject one or more anticancer agents.

39. The method of claim 38, wherein the one or more anticancer agents is selected from a chemotherapeutic agent and radiation therapy.

40. The method of claim 38, wherein the anticancer agent is one or more immune checkpoint inhibitors (ICIs).

41. The method of claim 40, wherein the one or more ICIs are selected from atezolizumab, avelumab, bevacizumab, cemiplimab, cetuximab, daratumumab, dinutuximab, durvalumab, elotuzumab, ipilimumab, isatuximab, mogamulizumab, necitumumab, nivolumab, obitunuzumab, ofatumumab, oralatumab, panitumumab, pembrolizumab, pertuzumab, ramucirumab, rituximab, trastuzumab, gemtuzumab ozogamicin, bentruximab vedotin, trastuzumab emtansine, inotuzumab ozogamicin, polatuzumab vedotin, efortumab vedotin, trastuzumab deruxtecan, Sacituzumab govitecan, moxetumuomab pasudotox, ibritumomab tiuxetan, iodine tositumuomab, blatinumomab.

42. The method of claim 40, wherein the one or more ICIs is an inhibitor of CTLA-4, PD- 1, PDL-1, Lag3, LAIR1, or LAIR 2.

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