LAUSR

Target identification for CAR T cell therapies remains challenging due to the limited repertoire of tumor-specific surface proteins. Intracellular proteins presented in the context of cell surface HLA provide a wide pool of potential antigens targetable through TCR mimic antibodies. Mass spectrometry (MS) of HLA ligands from eight hematological and non-hematological cancer cell lines identified a shared, non-immunogenic, HLA-A*02 restricted ligand (ALNEQIARL) derived from the kinetochore-associated NDC80 gene. CAR T cells directed against the ALNEQIARL:HLA-A*02 complex demonstrated high sensitivity and specificity for recognition and killing of multiple cancer types, especially those of hematological origin and were efficacious in mouse models against a human leukemia and a solid tumor. In contrast, no toxicities towards resting or activated healthy leukocytes as well as hematopoietic stem cells were observed. This demonstrates how MS can inform the design of broadly reactive therapeutic TCR mimic CAR T cell therapies that can target multiple cancer types currently not druggable by small molecules, conventional CAR T cells, T cells or antibodies.