Targeting cancer-specific mutations by T cell receptor gene therapy

T Blankenstein, M Leisegang, W Uckert… - Current opinion in …, 2015 - Elsevier
T Blankenstein, M Leisegang, W Uckert, H Schreiber
Current opinion in immunology, 2015Elsevier
Highlights•T cell therapy can eradicate large tumors.•Cancer-specific mutations creating
neoepitopes are potentially the best target.•Mutant epitopes can be retained in patients
despite specific T cell responses.•TCR gene therapy of cancer is feasible.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 …
Highlights
  • T cell therapy can eradicate large tumors.
  • Cancer-specific mutations creating neoepitopes are potentially the best target.
  • Mutant epitopes can be retained in patients despite specific T cell responses.
  • TCR gene therapy of cancer is feasible.
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.
Elsevier