Laurence Cooper

Pediatrics - Patient Care, Pediatrics

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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; et al. (Profiled Author: Willem Overwijk)

Journal of Immunotherapy. 2008;31(1):1-6.

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. © 2008 Lippincott Williams & Wilkins, Inc.

PMID: 18157006     PMCID: PMC2235937

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