T-Cell Receptor Gene Therapy of Established Tumors in a... : Journal of Immunotherapy (original) (raw)

Basic Studies

T-Cell Receptor Gene Therapy of Established Tumors in a Murine Melanoma Model

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

*Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD

†Netherlands Cancer Institute, Amsterdam, The Netherlands

Supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

John D. Abad and Claudia Wrzensinski contributed equally to this work.

Financial Disclosure: All of the authors have declared there are no financial conflicts of interest related to this work.

Reprints: Richard A. Morgan, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, CRC, Room 3W/3-3864, 10 Center Drive, Bethesda, MD 20892 (e-mail: [email protected]).

Received for publication September 4, 2007; accepted September 19, 2007

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.