title: Uncoupling T-cell expansion from effector differentiation in cell-based immunotherapy.
abstract: Adoptive cellular immunotherapy (ACT) is a potentially curative therapy for patients with advanced cancer. Eradication of tumor in mouse models and humans correlates with both a high dose of adoptively transferred cells and cells with a minimally differentiated phenotype that maintain replicative capacity and multipotency. We speculate that response to ACT not only requires transfer of cells with immediate cytolytic effector function to kill the bulk of fast-growing tumor but also transfer of tumor-specific cells that maintain an ability for self-renewal and the capacity to produce a continual supply of cytolytic effector progeny until all malignant cells are eliminated. Current in vitro methods to expand cells to sufficient numbers and still maintain a minimally differentiated phenotype are hindered by the biological coupling of clonal expansion and effector differentiation. Therefore, a better understanding of the physiologic mechanism that couples cell expansion and differentiation in CD8(+) T cells may improve the efficacy of ACT.
authors: Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.|Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA.|Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.
authors: Joseph G
authors: JG
authors: Crompton
authors: Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Madhusudhanan
authors: M
authors: Sukumar
authors: Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Nicholas P
authors: NP
authors: Restifo
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D006801:Humans; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive / Q000379:methods; D007376:Interleukin-2 / Q000494:pharmacology; D009369:Neoplasms / Q000276:immunology / Q000628:therapy; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism
chemical_list: D007376:Interleukin-2; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7
keywords: CD8+ T cells; T-cell based-therapy; adoptive cell transfer; adoptive cellular immunotherapy; effector differentiation; replicative senescence