Multimodal targeting of metastatic renal cell carcinoma via CD70-directed allogeneic CAR-NKT cells.

IF 10.6 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2025-09-16 Epub Date: 2025-08-29 DOI:10.1016/j.xcrm.2025.102321

Yan-Ruide Li, Junhui Hu, Zhe Li, Enbo Zhu, Yuning Chen, Tyler Halladay, Xinyuan Shen, Ying Fang, Yichen Zhu, Zibai Lyu, Yanxin Tian, Jie Huang, Annabel S Zhao, Nathan Y Ma, Catherine Zhang, Yongpeng Xie, Hanwei Zhang, Tzung Hsiai, Arnold I Chin, Lily Wu, Lili Yang

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引用次数: 0

Abstract

Renal cell carcinoma (RCC) represents about 90% of kidney cancers, with 30%-40% of patients developing metastatic disease despite current treatments. Conventional chimeric antigen receptor (CAR)-T therapy targeting CD70 shows promise but faces challenges due to its autologous, personalized nature. Here, we develop allogeneic CD70-directed CAR-engineered invariant natural killer T (^AlloCAR70-NKT) cells from hematopoietic stem and progenitor cells using a clinically guided culture method. These cells expand robustly with high purity and no fratricide risk. ^AlloCAR70-NKT cells exhibit potent cytotoxicity against primary and metastatic RCC via CAR- and natural killer (NK) receptor-mediated mechanisms and selectively target the immunosuppressive tumor microenvironment (TME) through T cell receptor (TCR) recognition. Additionally, they eliminate CD70⁺ host alloreactive T cells, promoting therapeutic persistence. Taken together, our findings support the therapeutic potential of ^AlloCAR70-NKT cells as a next-generation, off-the-shelf immunotherapy with dual tumor- and TME-targeting functionality and the added capacity to eliminate alloreactive T cells, which offers a compelling strategy for treating metastatic RCC.

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通过cd70导向的异体CAR-NKT细胞多模式靶向转移性肾细胞癌。

肾细胞癌（RCC）约占肾癌的90%，尽管目前治疗，仍有30%-40%的患者发展为转移性疾病。传统的靶向CD70的嵌合抗原受体(CAR)-T疗法显示出希望，但由于其自身的、个性化的性质，面临着挑战。在这里，我们使用临床引导培养方法从造血干细胞和祖细胞中培养出同种异体cd70定向car工程的不变性自然杀伤T细胞（AlloCAR70-NKT）。这些细胞生长健壮，纯度高，没有杀兄弟的危险。AlloCAR70-NKT细胞通过CAR-和自然杀伤（NK）受体介导的机制对原发性和转移性RCC表现出强大的细胞毒性，并通过T细胞受体（TCR）识别选择性靶向免疫抑制肿瘤微环境（TME）。此外，它们消除CD70+宿主同种异体反应性T细胞，促进治疗的持久性。综上所述，我们的研究结果支持AlloCAR70-NKT细胞作为下一代现成的免疫疗法的治疗潜力，具有双重肿瘤和tme靶向功能，以及消除同种异体反应性T细胞的额外能力，这为治疗转移性RCC提供了一个令人信服的策略。

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.