Mutant KRAS peptide targeted CAR-T cells engineered for cancer therapy.

Despite the success of chimeric antigen receptor (CAR)-T cell therapies in hematological malignancies, clinical success against solid tumors is limited due to low therapeutic efficacy or dose-limiting toxicity. Developing therapies that trigger potent, yet manageable, immune responses capable of eliminating highly heterogeneous and immunosuppressive tumor cell populations remains a key challenge. Here, we harness multiple genetic approaches to develop a CAR-T cell therapy targeting tumors. First, we screen binders targeting oncogenic KRAS G12V mutations presented by peptide-MHC complexes. Subsequently, we incorporate these neoantigen binders into CAR-T cells (mKRAS NeoCARs) and demonstrate their efficacy in xenograft models of metastatic lung, pancreatic, and renal cell cancer. Finally, we enhance the in vivo efficacy and safety profile of mKRAS NeoCARs via inducible secretion of IL-12 and T cell receptor deletion. Together, these screening and engineering processes provide a modular platform for expanding the therapeutic index of cellular immunotherapies that target cancer.