12.16.21

Cross-HLA Targeting of Intracellular Oncoproteins With Peptide-Centric CARs

Yarmarkovich M, Marshall QF, Warrington JM, et al. Cross-HLA Targeting of Intracellular Oncoproteins With Peptide-Centric CARs. Nature. 2021; (doi: 10.1038/s41586-021-04061-6).

More cancer patients with solid tumors might benefit from chimeric antigen receptor (CAR) therapy if additional tumor-specific membrane proteins were identified, and researchers believe peptide-centric CARs (PC-CARs) could make that possible. They developed and describe a system for identifying tumor-specific antigens derived from non-mutated oncoproteins. While most oncogenic drivers are intracellular proteins that only target mutated peptides presented by individual human leukocyte antigen (HLA) allotypes, the team created PC-CARs that were able to recognize the unmutated peptide QYNPIRTTF found in neuroblastoma. The investigators also theorized that PC-CARs would identify QYNPIRTTF on other HLA allotypes, which was confirmed by computational modeling. Importantly, potent and targeted killing of neuroblastoma cells expressing these HLAs was observed in vitro and complete tumor regression occurred in lab mice. PC-CARs may be the key to opening up the pool of immunotherapeutic targets to include non-immunogenic intracellular oncoproteins, say investigators, who believe the techniques demonstrated in their research will inform the discovery of tumor-specific targets in neuroblastoma and other cancers with an unmet need.

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