Oncotarget

Research Papers: Immunology:

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

Zheng Hu, Jinxing Xia, Wei Fan, Jennifer Wargo and Yong-Guang Yang _

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Oncotarget. 2016; 7:6448-6459. https://doi.org/10.18632/oncotarget.7044

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Abstract

Zheng Hu1,2, Jinxing Xia2, Wei Fan1, Jennifer Wargo3 and Yong-Guang Yang1,2

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.


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