CD70-targeted iPSC-derived CAR-NK cells display potent function against tumors and alloreactive T cells
Linqin Wang, Yiyun Wang, Xiangjun He, Zhuomao Mo, Mengyu Zhao, Xinghua Liang, Kejia Hu, Kexin Wang, Yanan Yue, Guolong Mo, Yixuan Zhou, Ruimin Hong, Linghui Zhou, Youqin Feng, Nian Chen, Lihong Shen, Xiaobin Song, Wen Zeng, Xiaofeng Jia, Yuxuan Shao, Pengfei Zhang, Mengqi Xu, Dongrui Wang, Yongxian Hu, Luhan Yang, He Huang
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.