T cell receptor-engineered T cells targeting the TP53R248Q neoantigen elicit antitumor effects in human cancer models.

Malignant tumors with TP53 mutations exhibit poor therapeutic outcomes and high recurrence rates. T cell receptor-based (TCR-based) T cell therapy shows great promise for targeting intracellular cancer neoantigens. However, the immunogenic potential of TP53 hotspot mutations remains poorly characterized. Here, we identified an immunogenic neoantigen derived from the recurrent TP53R248Q mutation, presented by the prevalent HLA-A*11:01 allele. Additionally, we isolated a TP53R248Q-reactive TCR that specifically recognized the TP53R248Q mutation without any discernible cross-activity with cognate WT TP53 or other TP53 mutants at the same codon position. Functional characterization revealed that TP53R248Q TCR-T cells exhibited selective cytotoxicity against tumor cells expressing both the TP53R248Q mutation and HLA-A*11:01 in vitro. Importantly, the adoptive transfer of TP53R248Q TCR-T cells exhibited significant antitumor activity in a clinically relevant patient-derived xenograft model engrafted with TP53R248Q/HLA-A*11:01-positive human tumor tissues. Collectively, our study validates the immunogenicity of the TP53R248Q hotspot mutation and provides a TCR with high therapeutic potential for the development of T cell therapies targeting TP53R248Q/HLA-A*11:01-positive cancers.