(59e) Engineer CAR-Neutrophils from Hpscs for Targeted Cancer Immunotherapy

The major focus of our research is to engineer human pluripotent stem cells (hPSCs) for targeted cell and cancer therapies. In this talk, I will focus on our recent development of a simplified, chemically-defined platform for producing definitive hematopoietic stem and progenitor cells (HSPCs) and neutrophils for targeted cancer immunotherapy. 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 chimeric antigen receptors (CARs) to enhance their anti-tumor cytotoxicity for targeted immunotherapy. Here, we genetically engineered human pluripotent stem cells with different synthetic CARs and successfully differentiated them into functional neutrophils by implementing an innovative chemically-defined differentiation platform. The resulting CAR-neutrophils presented superior and specific cytotoxicity against tumor cells both in vitro and in vivo. Collectively, we established a new platform for the production of CAR-neutrophils, paving the way to myeloid cell-based therapeutic strategies that would complement and boost current cancer treatment approaches. By reducing the complexity of hematopoietic induction and constructing stable CAR-expressing hPSCs, our approach will offer enhanced understanding of human embryonic hematopoiesis and expedite the development of hPSC-derived off-the-shelf hematopoietic and immune cell products for therapeutic purpose.