CD70-targeted iPSC-derived CAR-NK cells display potent function against tumors and alloreactive T cells.

IF 11.7 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2025-01-21 Epub Date: 2025-01-09 DOI:10.1016/j.xcrm.2024.101889

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, Wenxiu Zeng, Xiaofeng Jia, Yuxuan Shao, Peng Zhang, Mengqi Xu, Dongrui Wang, Yongxian Hu, Luhan Yang, He Huang

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引用次数: 0

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.

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cd70靶向ipsc衍生的CAR-NK细胞显示出对抗肿瘤和同种异体反应性T细胞的强大功能。

自体嵌合抗原受体(CAR)-T细胞的临床应用由于靶向癌症类型有限以及制造过程耗时和昂贵而变得复杂。我们开发了靶向cd70的诱导多能干细胞衍生的car -自然杀伤（NK）（70CAR-iNK）细胞作为通用免疫细胞治疗的方法。除了CD70靶向CAR分子外，70CAR-iNK细胞还通过敲除CD70基因、高亲和力不可切割CD16 （hnCD16）和白细胞介素(IL)-15受体α/IL-15融合蛋白（IL15RF）进行修饰。多基因编辑的70CAR-iNK细胞对多种肿瘤表现出强大的细胞毒性。体内异种移植模型进一步证明了其有效靶向淋巴瘤和肾癌的效力。此外，我们发现受体同种异体反应性T细胞表达高水平的CD70，可以被70CAR-iNK细胞消除，从而提高iNK细胞的存活率和持久性。70CAR-iNK细胞具有肿瘤靶向能力和消除同种异体反应性T细胞的潜力，是下一代通用免疫细胞治疗的有力候选者。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.