Due to the limitations of autologous chimeric antigen receptor (CAR)-T cells, alternative sources of cellular immunotherapy, including CAR macrophages, are emerging for solid tumors. Human induced pluripotent stem cells (iPSCs) offer an unlimited source for immune cell generation. Here, we develop human iPSC-derived CAR macrophages targeting prostate stem cell antigen (PSCA) (CAR-iMacs), which express membrane-bound interleukin (IL)-15 and truncated epidermal growth factor receptor (EGFR) for immune cell activation and a suicide switch, respectively. These allogeneic CAR-iMacs exhibit strong antitumor activity against human pancreatic solid tumors in vitro and in vivo, leading to reduced tumor burden and improved survival in a pancreatic cancer mouse model. CAR-iMacs appear safe and do not exhibit signs of cytokine release syndrome or other in vivo toxicities. We optimized the cryopreservation of CAR-iMac progenitors that remain functional upon thawing, providing an off-the-shelf, allogeneic cell product that can be developed into CAR-iMacs. Overall, our preclinical data strongly support the potential clinical translation of this human iPSC-derived platform for solid tumors, including pancreatic cancer.

由于自体嵌合抗原受体 (CAR)-T 细胞的局限性，针对实体瘤的细胞免疫疗法的替代来源（包括 CAR 巨噬细胞）正在出现。人类诱导多能干细胞 (iPSC) 为免疫细胞的生成提供了无限的来源。在这里，我们开发了靶向前列腺干细胞抗原 (PSCA) 的人 iPSC 衍生的 CAR 巨噬细胞 (CAR-iMacs)，它表达膜结合白细胞介素 (IL)-15 和截短的表皮生长因子受体 (EGFR)，用于免疫细胞激活和分别是自杀开关。这些同种异体 CAR-iMac在体外和体内对人类胰腺实体瘤表现出强大的抗肿瘤活性，从而减少胰腺癌小鼠模型的肿瘤负荷并提高生存率。 CAR-iMac 看起来很安全，并且没有表现出细胞因子释放综合征或其他体内毒性的迹象。我们优化了 CAR-iMac 祖细胞的冷冻保存，使其在解冻后仍保持功能，提供了可开发为 CAR-iMac 的现成同种异体细胞产品。总体而言，我们的临床前数据有力地支持了这种人类 iPSC 衍生平台对实体瘤（包括胰腺癌）的潜在临床转化。