High-affinity oligoclonal TCRs define effective adoptive T cell therapy targeting mutant KRAS-G12D

Significance Adoptive T cell therapy (ACT) is an experimental cancer immunotherapy with partial clinical responses (∼20%). A mechanistic understanding of T cell receptors (TCR) isolated from tumors and defining the biochemical attributes associated with tumor elimination may improve the ACT success rate. Here, we studied a successful case of ACT targeting HLA-C–restricted KRAS-G12D neoantigens. Through biochemical, structural, and cellular approaches, we define how these TCRs recognized their neoantigens. Key findings were that these TCRs were of higher affinity than most tumor-specific TCRs identified to date and these TCRs were specific for two distinct neoantigens. Whether these are general features of successful ACT remains to be seen, but this approach may serve as a basis for future rational improvement of ACT.