RT Journal Article
SR Electronic
T1 Engineering chimeric antigen receptor neutrophils from human pluripotent stem cells for targeted cancer immunotherapy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.03.02.482679
DO 10.1101/2022.03.02.482679
A1 Yun Chang
A1 Ramizah Syahirah
A1 Xuepeng Wang
A1 Gyuhyung Jin
A1 Sandra E. Torregrosa-Allen
A1 Bennett D. Elzey
A1 Sydney N Hummel
A1 Tianqi Wang
A1 Xiaojun Lian
A1 Qing Deng
A1 Hal E. Broxmeyer
A1 Xiaoping Bao
YR 2022
UL http://biorxiv.org/content/early/2022/03/04/2022.03.02.482679.abstract
AB Neutrophils, the most abundant white blood cells in the circulation, are closely related to cancer development and progression. Primary neutrophils from healthy donors present potent cytotoxicity against different human cancer cell lines through direct contact and via the generation of reactive oxygen species (ROS). However, due to their short half-life and resistance to genetic modification, neutrophils have not yet been engineered with widely used chimeric antigen receptors (CARs) to enhance their anti-tumor cytotoxicity for targeted immunotherapy. Here, we genetically engineered human pluripotent stem cells (hPSCs) with different synthetic CARs and successfully differentiated them into functional neutrophils by implementing a novel chemically-defined differentiation platform. Neutrophils expressing the chlorotoxin (CLTX)-T-CAR presented specific cytotoxicity against glioblastoma (GBM) cells both in monolayer and 3D cultures. In a GBM xenograft mouse model, systematically-administered CLTX-T-CAR neutrophils also displayed enhanced anti-tumor activity and prolonged animal survival compared with peripheral blood-neutrophils, hPSC-neutrophils and CLTX-NK-CAR natural killer (NK) cells. Collectively, we established a new platform for production of CAR-neutrophils, paving the way to myeloid cell-based therapeutic strategies that would complement and boost current cancer treatment approaches.Competing Interest StatementA patent related to this manuscript is under application (Y.C., R.S., Q.D., and X.B.).