T-cell receptor gene therapy of established tumors in a murine melanoma model

John D. Abad, Claudia Wrzensinski, Willem Overwijk, Moniek A. De Witte, Annelies Jorritsma, Cary Hsu, Luca Gattinoni, Cyrille J. Cohen, Chrystal M. Paulos, Douglas C. Palmer, John B.A.G. Haanen, Ton N.M. Schumacher, Steven A. Rosenberg, Nicholas P. Restifo, Richard A. Morgan

Research output: Contribution to journalArticlepeer-review

Abstract

Adoptive cell transfer therapy using tumor-infiltrating lymphocytes for patients with metastatic melanoma has demonstrated significant objective response rates. One major limitation of these current therapies is the frequent inability to isolate tumor-reactive lymphocytes for treatment. Genetic engineering of peripheral blood lymphocytes with retroviral vectors encoding tumor antigen-specific T-cell receptors (TCRs) bypasses this restriction. To evaluate the efficacy of TCR gene therapy, a murine treatment model was developed. A retroviral vector was constructed encoding the pmel-1 TCR genes targeting the B16 melanoma antigen, gp100. Transduction of C57BL/6 lymphocytes resulted in efficient pmel-1 TCR expression. Lymphocytes transduced with this retrovirus specifically recognized gp100-pulsed target cells as measured by interferon-γ secretion assays. Upon transfer into B16 tumor-bearing mice, the genetically engineered lymphocytes significantly slowed tumor development. The effectiveness of tumor treatment was directly correlated with the number of TCR-engineered T cells administered. These results demonstrated that TCR gene therapy targeting a native tumor antigen significantly delayed the growth of established tumors. When C57BL/6 lymphocytes were added to antigen-reactive pmel-1 T cells, a reduction in the ability of pmel-1 T cell to treat B16 melanomas was seen, suggesting that untransduced cells may be deleterious to TCR gene therapy. This model may be a powerful tool for evaluating future TCR gene transfer-based strategies.

Original languageEnglish (US)
Pages (from-to)1-6
Number of pages6
JournalJournal of Immunotherapy
Volume31
Issue number1
DOIs
StatePublished - Jan 2008

Keywords

  • Gene therapy
  • Murine
  • T-cell receptor
  • gp100 tumor antigen

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology
  • Cancer Research

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