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Eradication of large solid tumors by gene therapy with a T cell receptor targeting a single cancer-specific point mutation

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Item Type:Article
Title:Eradication of large solid tumors by gene therapy with a T cell receptor targeting a single cancer-specific point mutation
Creators Name:Leisegang, M. and Engels, B. and Schreiber, K. and Yew, P.Y. and Kiyotani, K. and Idel, C. and Arina, A. and Duraiswamy, J. and Weichselbaum, R.R. and Uckert, W. and Nakamura, Y. and Schreiber, H.
Abstract:PURPOSE: Cancers usually contain multiple unique tumor-specific antigens produced by single amino acid substitutions (AAS) and encoded by somatic non-synonymous single nucleotide substitutions. We determined whether adoptively transferred T cells can reject large, well-established solid tumors when engineered to express a single type of T cell receptor (TCR) that is specific for a single AAS. EXPERIMENTAL DESIGN: By exome and RNA sequencing of an UV-induced tumor, we identified an AAS in p68 (mp68), a co-activator of p53. This AAS seemed to be an ideal tumor-specific neoepitope because it is encoded by a trunk mutation in the primary autochthonous cancer and binds with highest affinity to the MHC. A high-avidity mp68-specific TCR was used to genetically engineer T cells as well as to generate TCR-transgenic mice for adoptive therapy. RESULTS: When the neoepitope was expressed at high levels and by all cancer cells, their direct recognition sufficed to destroy intra-tumor vessels and eradicate large, long-established solid tumors. When the neoepitope was targeted as autochthonous antigen, T cells caused cancer regression followed by escape of antigen-negative variants. Escape could be thwarted by expressing the antigen at increased levels in all cancer cells or by combining T cell therapy with local irradiation. Therapeutic efficacies of TCR-transduced and TCR-transgenic T cells were similar. CONCLUSIONS: Gene therapy with a single TCR targeting a single AAS can eradicate large established cancer but a uniform expression and/or sufficient levels of the targeted neoepitope or additional therapy are required to overcome tumor escape.
Keywords:T Cell Receptor (TCR), Tumor-Specific Single Amino Acid Substitution (AAS), Adoptive T Cell Therapy (ATT), Tumor Heterogeneity, Tumor Escape, Animals, Mice
Source:Clinical Cancer Research
ISSN:1078-0432
Publisher:American Association for Cancer Research (U.S.A.)
Volume:22
Number:11
Page Range:2734-2743
Date:1 June 2016
Official Publication:https://doi.org/10.1158/1078-0432.CCR-15-2361
PubMed:View item in PubMed

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