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


  • M. Leisegang
  • B. Engels
  • K. Schreiber
  • P.Y. Yew
  • K. Kiyotani
  • C. Idel
  • A. Arina
  • J. Duraiswamy
  • R.R. Weichselbaum
  • W. Uckert
  • Y. Nakamura
  • H. Schreiber


  • Clinical Cancer Research


  • Clin Cancer Res 22 (11): 2734-2743


  • 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.