Journal
JOURNAL OF IMMUNOTHERAPY
Volume 31, Issue 1, Pages 1-6Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CJI.0b013e31815c193f
Keywords
murine; gene therapy; T-cell receptor; gp100 tumor antigen
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Funding
- Intramural NIH HHS [Z01 BC010763-01, Z99 CA999999] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [Z01BC010984, ZIABC010985, Z01SC003800, ZIABC010763, Z01BC011037] Funding Source: NIH RePORTER
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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 an tigen-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 gp 100-pulsed target cells as measured by interferon-gamma 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.
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