Leisegang, Matthias, Engels, Boris, Schreiber, Karin, Yew, Poh Yin, Kiyotani, Kazuma , Idel, Christian, Arina, Ainhoa , Duraiswamy, Jaikumar, Uckert, Wolfgang , 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