Abstract
Clinical application of autologous chimeric antigen receptor (CAR)-T cells is complicated by limited targeting of cancer types, as well as the time-consuming and costly manufacturing process. We develop CD70-targeted, induced pluripotent stem cell-derived CAR-natural killer (NK) (70CAR-iNK) cells as an approach for universal immune cell therapy. Besides the CD70-targeted CAR molecule, 70CAR-iNK cells are modified with CD70 gene knockout, a high-affinity non-cleavable CD16 (hnCD16), and an interleukin (IL)-15 receptor α/IL-15 fusion protein (IL15RF). Multi-gene-edited 70CAR-iNK cells exhibit robust cytotoxicity against a wide range of tumors. In vivo xenograft models further demonstrate their potency in effectively targeting lymphoma and renal cancers. Furthermore, we find that recipient alloreactive T cells express high levels of CD70 and can be eliminated by 70CAR-iNK cells, leading to improved survival and persistence of iNK cells. With the capability of tumor targeting and the potential to eliminate alloreactive T cells, 70CAR-iNK cells are potent candidates for next-generation universal immune cell therapy.