A TCR mimic CAR T cell specific for NDC80 is broadly reactive with solid tumors and hematologic malignancies

• Published in: Blood 2022-08, Vol.140 (8), p.861-874
• Main Authors: Klatt, Martin G., Dao, Tao, Yang, Zhiyuan, Liu, Jianying, Mun, Sung Soo, Dacek, Megan M., Luo, Hanzhi, Gardner, Thomas J., Bourne, Christopher, Peraro, Leila, Aretz, Zita E.H., Korontsvit, Tanya, Lau, Michael, Kharas, Michael G., Liu, Cheng, Scheinberg, David A.
• Format: Article
• Language: English
• Subjects: Animals; Antibodies - metabolism; Cytoskeletal Proteins - metabolism; Hematologic Neoplasms - metabolism; Hematologic Neoplasms - therapy; HLA-A Antigens; Humans; Immunobiology and Immunotherapy; Immunotherapy, Adoptive - methods; Mice; Neoplasms; Receptors, Antigen, T-Cell; T-Lymphocytes
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2021012882

Target identification for chimeric antigen receptor (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 T-cell receptor mimic antibodies. Mass spectrometry (MS) of HLA ligands from 8 hematologic and nonhematologic 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 exhibited high sensitivity and specificity for recognition and killing of multiple cancer types, especially those of hematologic origin, and were efficacious in mouse models against a human leukemia and a solid tumor. In contrast, no toxicities toward resting or activated healthy leukocytes as well as hematopoietic stem cells were observed. This shows how MS can inform the design of broadly reactive therapeutic T-cell receptor 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. •HLA-A*02:ALNEQIARL derived from NDC80 is a broadly presented cancer immunotherapy target with high abundance in hematologic malignancies.•CAR T cells designed for this target exhibit high sensitivity and specificity with no relevant toxicity toward hematopoietic stem cells. [Display omitted]