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SUMMARY
T cells represent an important component of the host response to pathogens and tumors. Adoptive T-cell therapy, in which T cells are isolated or engineered to be specific for molecules expressed on diseased cells and administered to patients, has shown efficacy in infections and malignancy. Clinical applications of T-cell therapy have been facilitated by identification of target antigens expressed by viruses and tumors, improvement in strategies for the isolation and genetic engineering of antigen-specific T cells with intrinsic qualities that enable their persistence in vivo, and recognition that transferring T cells into a lymphopenic environment improves the efficiency of cell transfer and treatment efficacy. Insights into the obstacles to routinely achieving an effective antitumor response either by T-cell therapy or vaccination have been derived from careful analysis of clinical trials, and further development of immune cell therapy combined with interventions that target specific regulatory or inhibitory pathways that are present in tumor microenvironments and impede effective immunity represent promising areas for future applications.
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Acronyms and Abbreviations:
ALL, acute lymphatic leukemia; BCMA, B-cell maturation antigen; CAR, chimeric antigen receptor; cDNA, complementary DNA; CDR3, complementarity determining region 3; CEA, carcinoembryonic antigen; CLL, chronic lymphatic leukemia; CMV, cytomegalovirus; CRS, cytokine release syndrome; CTL, cytotoxic T lymphocyte; DLI, donor lymphocyte infusion; E, early viral protein; EBV, Epstein-Barr virus; EGFR, epidermal growth factor receptor; ERBB2IP, erbb2 interacting protein; GD2, disialoganglioside; GVHD, graft-versus-host disease; GVL, graft-versus-leukemia; HHV-6, human herpes virus-6; HLA, human leukocyte antigen; HSCT, hematopoietic stem cell transplantation; HSV, herpes simplex virus; HSV-TK, herpes simplex virus thymidine kinase; iCasp9, inducible caspase-9; IE, immediate early viral protein; IFN-γ, interferon-γ; IL, interleukin; L1CAM, L1-cell adhesion molecule; LCL, lymphoblastoid cell line; LPD, lymphoproliferative disease; mAbs, monoclonal antibodies; mHAgs, minor histocompatibility antigens; MHC, major histocompatibility complex; PBMC, peripheral blood mononuclear cell; PD-1 receptor, programmed death-1 receptor; PML-RARα, promyelocytic leukemia–retinoic acid receptor α protein; scFV, single-chain variable fragment; SNP, single nucleotide polymorphism; TCM, central memory T cell; TCR, T-cell receptor; TE, effector T cell; TEM, effector memory T cell; Th, T helper; TIL, tumor-infiltrating lymphocyte; TREG, regulatory T cell; TSCM, T memory stem cell; WT-1, Wilms tumor antigen-1.
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ADOPTIVE CELLULAR THERAPY OF VIRAL DISEASES
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Two broad subsets of antigen-specific T cells cooperate to terminate acute viral infections and control reactivation of latent viruses. CD8+ cytotoxic T lymphocytes (CTLs) recognize viral peptides presented by major histocompatibility complex (MHC) class I molecules and lyse infected cells, and produce inflammatory cytokines. CD4+ T-helper (Th) cells recognize viral peptides presented by class II MHC molecules and produce cytokines that amplify T-cell responses and promote B-cell proliferation and antibody production. A deficiency of CD8+ and CD4+ Th cells occurs after allogeneic hematopoietic stem cell transplantation (HSCT) as a consequence of the administration of intensive chemoradiotherapy, anti–T-cell monoclonal antibodies (mAbs), and/or immunosuppressive drugs, and these patients are at risk for ...