Targeting cancer-specific mutations by T cell receptor gene therapy

Abstract

The ease of sequencing the cancer genome, identifying all somatic mutations and grafting mutation-specific T cell receptor (TCR) genes into T cells for adoptive transfer allow, for the first time, a truly tumor-specific and effective therapy. Mutation-specific TCR gene therapy might achieve optimal efficacy with least possible toxicity. Recent clinical data confirm the long-standing evidence from experimental cancer models that antigens encoded by the tumor-specific somatic mutations are potentially the best targets for adoptive T cell therapy. Open questions are, how many somatic mutations create suitable epitopes, whether only individual-specific or also recurrent somatic mutations qualify as suitable epitopes and how neoantigen-specific TCRs are most efficiently obtained. Tumor heterogeneity needs to be considered; therefore, it will be important to identify immunogenic driver mutations that occurred early, are essential for cancer cell survival and present in all cancer cells.

Figure 1. Mutation-specific T cells

Somatic mutations in cancer may create a neoepitope that can be recognized by T cells.

Figure 2. Strategies to isolate mutation-specific TCRs

TCRs can either be isolated from T cells of cancer-bearing humans (top) or cancer-free HLA-transgenic mice (bottom). The advantage of obtaining TILs from humans is that their TCRs are truly specific for the neoepitope. In contrast, TCRs from HLA-transgenic mice are derived from a tumor-free environment. Note that epitope/TCR analysis in an experimental cancer model is not included but in our opinion is important to exclude therapeutically inefficient epitopes and/or TCRs.