title: Human melanoma immunotherapy using tumor antigen-specific T cells generated in humanized mice.
abstract: A major factor hindering the exploration of adoptive immunotherapy in preclinical settings is the limited availability of tumor-reactive human T cells. Here we developed a humanized mouse model that permits large-scale production of human T cells expressing the engineered melanoma antigen MART-1-specific TCR. Humanized mice, made by transplantation of human fetal thymic tissue and CD34+ cells virally-transduced with HLA class I-restricted melanoma antigen (MART-1)-specific TCR gene, showed efficient development of MART-1-TCR+ human T cells with predominantly CD8+ cells. Importantly, MART-1-TCR+CD8+ T cells developing in these mice were capable of mounting antigen-specific responses in vivo, as evidenced by their proliferation, phenotypic conversion and IFN-γ production following MART-1 peptide immunization. Moreover, these MART-1-TCR+CD8+ T cells mediated efficient killing of melanoma cells in an HLA/antigen-dependent manner. Adoptive transfer of in vitro expanded MART-1-TCR+CD8+ T cells induced potent antitumor responses that were further enhanced by IL-15 treatment in melanoma-bearing recipients. Finally, a short incubation of MART-1-specific T cells with rapamycin acted synergistically with IL-15, leading to significantly improved tumor-free survival in recipients with metastatic melanoma. These data demonstrate the practicality of using humanized mice to produce potentially unlimited source of tumor-specific human T cells for experimental and preclinical exploration of cancer immunotherapy. This study also suggests that pretreatment of tumor-reactive T cells with rapamycin in combination with IL-15 administration may be a novel strategy to improve the efficacy of adoptive T cell therapy.
authors.affiliation: The First Bethune Hospital and Institute of Immunology, Jilin University, Changchun, China.|Columbia Center for Translational Immunology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Columbia Center for Translational Immunology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA.
authors.forename: Jinxing
authors.initials: J
authors.lastname: Xia
authors.affiliation: The First Bethune Hospital and Institute of Immunology, Jilin University, Changchun, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Fan
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wargo
authors.affiliation: The First Bethune Hospital and Institute of Immunology, Jilin University, Changchun, China.|Columbia Center for Translational Immunology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA.
authors.forename: Yong-Guang
authors.initials: YG
authors.lastname: Yang
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D007114:Immunization; D007167:Immunotherapy; D008213:Lymphocyte Activation; D058965:MART-1 Antigen / Q000276:immunology; D008545:Melanoma / Q000276:immunology* / Q000556:secondary / Q000628:therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D015789:HLA-A2 Antigen; D058965:MART-1 Antigen; D010446:Peptide Fragments
keywords: Immune response; Immunity; Immunology and Microbiology Section; T cells; TCR; animal model; immunotherapy; melanoma
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