Optimizing T‐cell receptor avidity with somatic hypermutation.

Adoptive transfer of T cells that have been genetically modified to express an antitumor T‐cell receptor (TCR) is a potent immunotherapy, but only if TCR avidity is sufficiently high. Endogenous TCRs specific to shared (self) tumor‐associated antigens (TAAs) have low affinity due to central tolerance. Therefore, for effective therapy, anti‐TAA TCRs with higher and optimal avidity must be generated. Here, we describe a new in vitro system for directed evolution of TCR avidity using somatic hypermutation (SHM), a mechanism used in nature by B cells for antibody optimization. We identified 44 point mutations to the Pmel‐1 TCR, specific for the H‐2Db‐gp10025‐33 melanoma antigen. Primary T cells transduced with TCRs containing two or three of these mutations had enhanced activity in vitro. Furthermore, the triple‐mutant TCR improved in vivo therapy of tumor‐bearing mice, which exhibited improved survival, smaller tumors and delayed or no relapse. TCR avidity maturation by SHM may be an effective strategy to improve cancer immunotherapy. What's new? Immunotherapies such as CAR‐T and adoptive T cell therapy use T cells that recognize and attack specific antigens on cancer cells. However, many of these antigens occur on both cancer and normal cells, and the T‐cell receptors (TCRs) don't bind very well. In this study, the authors used a technique called somatic hypermutation (SHM) to improve TCR binding. They then tested this approach in tumor‐bearing mice, and found that T cells carrying a mutated TCR improved survival and reduced tumor size. SHM may thus help to improve TCR binding for cancer immunotherapy. [ABSTRACT FROM AUTHOR]