Engineering chimeric antigen receptor neutrophils from human pluripotent stem cells for targeted cancer immunotherapy

Abstract

Neutrophils, the most abundant white blood cells in circulation, are closely related to cancer development and progression. Healthy primary neutrophils present potent cytotoxicity against various cancer cell lines through direct contact and via generation of reactive oxygen species. However, due to their short half-life and resistance to genetic modification, neutrophils have not yet been engineered with chimeric antigen receptors (CARs) to enhance their antitumor cytotoxicity for targeted immunotherapy. Here, we genetically engineered human pluripotent stem cells with synthetic CARs and differentiated them into functional neutrophils by implementing a chemically defined platform. The resulting CAR neutrophils present superior and specific cytotoxicity against tumor cells both in vitro and in vivo. Collectively, we established a robust platform for massive production of CAR neutrophils, paving the way to myeloid cell-based therapeutic strategies that would boost current cancer-treatment approaches.

Keywords: CP: Cancer; CP: Immunology; adoptive cellular therapy; cancer immunotherapy; chemically defined; chimeric antigen receptor; definitive hematopoiesis; directed differentiation; genome editing; glioblastoma; human pluripotent stem cells; neutrophils.