TCR-engineered T cells targeting a shared β-catenin mutation eradicate solid tumors in vivo

CTNNB1/ ꞵ-catenin is mutated in 3.3% of solid cancers, with several recurrent gain-of-function mutations occurring early during cancer formation. This includes the shared driver mutation CTNNB1S37F, estimated to occur in >7000 new cancer cases in 2024 in the US. However, to offer attractive immunotherapy targets, neoantigens must be presented at sufficient levels on tumor cells to be recognized by T cells. Here, we identify two neopeptides encoded by CTNNB1S37F presented on the frequent HLA-A*02:01 and HLA-A*24:02 alleles, from cell lines naturally expressing the mutation and HLA-alleles. T-cell receptors (TCRs) specifically recognizing the mutant peptides were isolated from naïve healthy donor T cells. T cells re-directed with the CTNNB1S37F TCRs efficiently killed CTNNB1S37F+ cell lines in vitro, eradicated established tumors in an in vivo melanoma mouse model naturally expressing the mutation and prevented relapses during the >100-day follow-up period. TCR T cells targeting CTNNB1S37F could form basis for promising immunotherapy in solid cancers.