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Development of Hematopoietic Stem Cell-Engineered Invariant Natural Killer T Cells for Cancer Immunotherapy


Cell-based immunotherapy has become the new-generation cancer medicine. Invariant natural killer T (iNKT) cells are potent immune cells for targeting cancer; however, healthy donor blood contains extremely low numbers of endogenous iNKT cells, making it exceedingly challenging to generate adequate iNKT cells for cell therapy. In this study, we aim to develop both autologous and allogeneic hematopoietic stem cell-engineered iNKT (HSC-iNKT) cell therapy that has potential to provide patients with therapeutic levels of iNKT cells for the treatment of cancers. Through combining hematopoietic stem cell (HSC) gene engineering and HSC differentiation, we achieved the generation of human HSC-iNKT cells at high yield and purity. The first generation of HSC-iNKT cells were generated using a bone marrow-liver-thymus (BLT) humanized mouse model, the second generation of HSC-iNKT cells were generated using an Artificial Thymic Organoid (ATO) culture system, and the third generation of HSC-iNKT cells were developed using an Ex Vivo Feeder-Free culture system. These HSC-iNKT cells closely resembled endogenous iNKT cells, effectively targeted tumor cells using multiple mechanisms in vitro and in vivo, and most attractively, exhibited high safety and low immunogenicity. These cells could be further engineered with chimeric antigen receptor (CAR) to enhance tumor targeting, or/and gene-edited to ablate surface HLA molecules and further reduce immunogenicity. Collectively, these preclinical studies demonstrated the feasibility, safety, and cancer therapy potential of HSC-iNKT cell products and laid a foundation for their future translational and clinical development.

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