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

HLA-bound peptides encoded by recurrent driver mutations are candidate targets for T cell-directed immunotherapy. Here we identify two neopeptides encoded by the CTNNB1^S37F mutation presented on the frequent HLA-A*02:01 and HLA-A*24:02 molecules in cell lines naturally expressing the mutation and HLA alleles. This mutation leads to a gain of function in β-catenin and is estimated to occur in >7,000 new cancer cases annually in the United States. T cell receptors (TCRs) that specifically recognize the mutant peptides were isolated from naive healthy donor T cells. T cells redirected with CTNNB1-S37F TCRs efficiently killed CTNNB1^S37F+ cell lines and patient-derived organoids in vitro and eradicated established tumors in a melanoma cell line mouse model and a patient-derived xenograft model of endometrial adenocarcinoma naturally expressing the mutation and the restricting HLA. We propose that TCR-T cells targeting CTNNB1-S37F can serve as a basis for solid cancer immunotherapy.