Development of allogeneic HSC-engineered iNKT cells for off-the-shelf cancer immunotherapy

Cell-based immunotherapy has become the new-generation cancer medicine, and “off-the-shelf” cell products that can be manufactured at large scale and distributed readily to treat patients are necessary. Invariant natural killer T (iNKT) cells are ideal cell carriers for developing allogeneic cell therapy because they are powerful immune cells targeting cancers without graft-versus-host disease (GvHD) risk. However, healthy donor blood contains extremely low numbers of endogenous iNKT cells. Here, by combining hematopoietic stem cell (HSC) gene engineering and in vitro differentiation, we generate human allogeneic HSC-engineered iNKT (AlloHSC-iNKT) cells at high yield and purity; these cells closely resemble endogenous iNKT cells, effectively target tumor cells using multiple mechanisms, and exhibit high safety and low immunogenicity. These cells can be further engineered with chimeric antigen receptor (CAR) to enhance tumor targeting or/and gene edited to ablate surface human leukocyte antigen (HLA) molecules and further reduce immunogenicity. Collectively, these preclinical studies demonstrate the feasibility and cancer therapy potential of AlloHSC-iNKT cell products and lay a foundation for their translational and clinical development. [Display omitted] •Allogeneic HSC-iNKT cells are generated in vitro at high yield and purity•Allogeneic HSC-iNKT cells effectively target tumor cells using multiple mechanisms•Allogeneic HSC-iNKT cells exhibit high safety and low immunogenicity•A preclinical study demonstrated feasibility, safety, and cancer therapy potential Li et al. report the preclinical development of allogeneic-hematopoietic-stem-cell-engineered invariant natural killer T (HSC-iNKT) cells for off-the-shelf cancer therapy. Allogeneic HSC-iNKT cells demonstrate cancer therapy potential and a high safety profile.