人源抗 PSCA CAR 巨噬细胞对胰腺癌具有强大的抗肿瘤活性。
Human anti-PSCA CAR macrophages possess potent antitumor activity against pancreatic cancer.
机构信息
Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA.
Department of Computational and Quantitative Medicine, City of Hope National Medical Center, Los Angeles, CA 91010, USA.
出版信息
Cell Stem Cell. 2024 Jun 6;31(6):803-817.e6. doi: 10.1016/j.stem.2024.03.018. Epub 2024 Apr 24.
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,包括 CAR 巨噬细胞在内的替代性细胞免疫疗法正在涌现,用于治疗实体瘤。人诱导多能干细胞 (iPSC) 为免疫细胞的产生提供了无限的来源。在这里,我们开发了针对前列腺干细胞抗原 (PSCA) 的人 iPSC 衍生的 CAR 巨噬细胞 (CAR-iMacs),其表达膜结合白细胞介素 (IL)-15 和截断的表皮生长因子受体 (EGFR),分别用于免疫细胞激活和自杀开关。这些同种异体 CAR-iMacs 在体外和体内对人胰腺实体瘤表现出强烈的抗肿瘤活性,导致肿瘤负担减少和胰腺癌小鼠模型的生存率提高。CAR-iMacs 似乎是安全的,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 前体细胞的冷冻保存,解冻后仍保持功能,提供了即用型的同种异体细胞产品,可以进一步开发成 CAR-iMacs。总的来说,我们的临床前数据强烈支持将这种源自人 iPSC 的平台用于实体瘤(包括胰腺癌)的临床转化。
相似文献
Cell Stem Cell. 2024-6-6
引用本文的文献
Clin Cancer Res. 2025-8-4
Cancer Cell Int. 2025-7-28
MedComm (2020). 2025-7-25
Cancer Immunol Immunother. 2025-7-24
Front Immunol. 2025-6-12
Vaccines (Basel). 2025-6-19
本文引用的文献
Nat Immunol. 2024-1
Stem Cell Reports. 2023-2-14
Int J Mol Sci. 2022-11-10
Nat Immunol. 2022-8
J Transl Med. 2022-5-23