Human melanoma immunotherapy using tumor antigen-specific T cells generated in humanized mice

// Zheng Hu 1,2 , Jinxing Xia 2 , Wei Fan 1 , Jennifer Wargo 3 and Yong-Guang Yang 1,2 1 The First Bethune Hospital and Institute of Immunology, Jilin University, Changchun, China 2 Columbia Center for Translational Immunology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA 3 Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Correspondence to: Yong-Guang Yang, email: // Keywords : animal model, immunotherapy, melanoma, TCR, T cells, Immunology and Microbiology Section, Immune response, Immunity Received : July 15, 2015 Accepted : January 13, 2016 Published : January 27, 2016 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.