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

Oncotarget. 2016 Feb 9;7(6):6448-59. doi: 10.18632/oncotarget.7044.

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.

Keywords: Immune response; Immunity; Immunology and Microbiology Section; T cells; TCR; animal model; immunotherapy; melanoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • Cells, Cultured
  • Cytotoxicity, Immunologic / immunology*
  • HLA-A2 Antigen / immunology
  • Humans
  • Immunization
  • Immunotherapy*
  • Lymphocyte Activation
  • MART-1 Antigen / immunology
  • Melanoma / immunology*
  • Melanoma / secondary
  • Melanoma / therapy*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Peptide Fragments / administration & dosage
  • Peptide Fragments / pharmacology
  • T-Lymphocytes, Cytotoxic / immunology*

Substances

  • HLA-A2 Antigen
  • MART-1 Antigen
  • Peptide Fragments