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

Leisegang, Matthias and Engels, Boris and Schreiber, Karin and Yew, Poh Yin and Kiyotani, Kazuma and Idel, Christian and Arina, Ainhoa and Duraiswamy, Jaikumar and Uckert, Wolfgang and Nakamura, Yusuke and Schreiber, Hans (2015) Eradication of large solid tumors by gene therapy with a T cell receptor targeting a single cancer-specific point mutation. Eradication of large solid tumors by gene therapy with a T cell receptor targeting a single cancer-specific point mutation.

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.

Item Type: Article
Date Deposited: 22 Dec 2015 00:45
Last Modified: 22 Dec 2015 00:45
URI: https://oak.novartis.com/id/eprint/26185

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