Human anti-PSCA CAR macrophages possess potent antitumor activity against pancreatic cancer

IF 19.8 1区 医学 Q1 CELL & TISSUE ENGINEERING Cell stem cell Pub Date : 2024-04-24 DOI:10.1016/j.stem.2024.03.018
Zahir Shah, Lei Tian, Zhixin Li, Lewei Jin, Jianying Zhang, Zhenlong Li, Tasha Barr, Hejun Tang, Mingye Feng, Michael A. Caligiuri, Jianhua Yu
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Abstract

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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人类抗胰腺癌 CAR 巨噬细胞对胰腺癌具有强大的抗肿瘤活性
由于自体嵌合抗原受体(CAR)-T 细胞的局限性,包括 CAR 巨噬细胞在内的细胞免疫疗法替代来源正在出现,用于实体瘤的治疗。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,我们开发了针对前列腺干细胞抗原(PSCA)的人iPSC衍生CAR巨噬细胞(CAR-iMacs),它们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),分别用于激活免疫细胞和自杀开关。这些异体 CAR-iMacs 在体外和体内对人类胰腺实体瘤表现出很强的抗肿瘤活性,在胰腺癌小鼠模型中减轻了肿瘤负担,提高了生存率。CAR-iMacs 看起来很安全,没有细胞因子释放综合征或其他体内毒性症状。我们优化了 CAR-iMac 祖细胞的冷冻保存,使其在解冻后仍能保持功能,从而提供了一种现成的异体细胞产品,可以开发成 CAR-iMacs。总之,我们的临床前数据有力地支持了这一人类 iPSC 衍生平台用于实体瘤(包括胰腺癌)的潜在临床转化。
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来源期刊
Cell stem cell
Cell stem cell 生物-细胞生物学
CiteScore
37.10
自引率
2.50%
发文量
151
审稿时长
42 days
期刊介绍: Cell Stem Cell is a comprehensive journal covering the entire spectrum of stem cell biology. It encompasses various topics, including embryonic stem cells, pluripotency, germline stem cells, tissue-specific stem cells, differentiation, epigenetics, genomics, cancer stem cells, stem cell niches, disease models, nuclear transfer technology, bioengineering, drug discovery, in vivo imaging, therapeutic applications, regenerative medicine, clinical insights, research policies, ethical considerations, and technical innovations. The journal welcomes studies from any model system providing insights into stem cell biology, with a focus on human stem cells. It publishes research reports of significant importance, along with review and analysis articles covering diverse aspects of stem cell research.
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