Non-clinical efficacy, safety, and stable clinical cell processing of iPSC-derived anti-GPC3 CAR-expressing NK/ILC cells
Abstract
The use of allogeneic, pluripotent stem-cell-derived immune cells for cancer immunotherapy has been the subject of recent clinical trials. In Japan, investigator-initiated clinical trials will soon begin for ovarian cancer treatment using human leukocyte antigen (HLA)-homozygous-induced pluripotent stem cell (iPSC)-derived anti-glypican-3 (GPC3) chimeric antigen receptor (CAR)-expressing natural killer/innate lymphoid cells (NK/ILC). Using pluripotent stem cells as the source for allogeneic immune cells facilitates stringent quality control of the final product, in terms of efficacy, safety, and producibility. In this paper, we describe our methods for the stable, feeder-free production of CAR-expressing NK/ILC cells from CAR-transduced iPSCs with clinically relevant scale and materials. The average number of cells that could be differentiated from 1.8-3.6 x 106 iPSC within 7 weeks was 1.8-4.0 x 109 . These cells showed stable CD45/CD7/CAR expression, effector functions of cytotoxicity, and IFN-γ production against GPC3-expressing tumor cells. When the CAR-NK/ILC cells were injected into a GPC3-positive, ovarian-tumor-bearing, immunodeficient mouse model, we observed a significant therapeutic effect that prolonged the survival ...Continue Reading
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