肿瘤细胞治疗研究
英文原题：Human anti-PSCA CAR macrophages possess potent antitumor activity against pancreatic cancer.
Human anti-PSCA CAR macrophages possess potent antitumor activity against pancreatic cancer.
我们的临床前数据有力支持这一人 iPSC 衍生平台用于实体瘤（包括胰腺癌）的潜在临床转化。
由于自体嵌合抗原受体（CAR）T 细胞存在局限，包括 CAR 巨噬细胞在内的其他细胞免疫疗法来源正在成为实体瘤治疗的研究方向。人诱导多能干细胞（iPSC）可为免疫细胞生成提供无限来源。本研究开发了靶向前列腺干细胞抗原（PSCA）的人 iPSC 来源 CAR 巨噬细胞（CAR-iMac），分别表达膜结合型白细胞介素-15（IL-15）以激活免疫细胞，以及截短型表皮生长因子受体（EGFR）作为自杀开关。这些异基因 CAR-iMac 在体外和体内均对人胰腺实体瘤表现出强效抗肿瘤活性，可降低胰腺癌小鼠模型中的肿瘤负荷并延长生存。CAR-iMac 看起来安全，未见细胞因子释放综合征或其他体内毒性迹象。研究还优化了 CAR-iMac 前体细胞的冷冻保存，使其解冻后仍保持功能，从而获得可进一步制备 CAR-iMac 的现货型异基因细胞产品。总体而言，临床前数据有力支持将这一人 iPSC 来源平台转化至实体瘤临床研究，包括胰腺癌。
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.
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