Validation of CCL20-driven CAR-γδ T secreting PD-1 blockade with enhanced trafficking into solid tumor

IF 4.1 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2025-08-28 DOI:10.1016/j.isci.2025.113463

Dengji Zhang , Yuan Tang , Wei Sun , Yunkun Guan , Yipeng Cheng , Yuqi Zhu , Xiaying Zhao , Xinyi Yang , Huanzhang Zhu

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Abstract

The primary challenges of CAR-T cells for solid tumor treatment involve the efficient delivery and infiltration of CAR-T cells into the tumor site, as well as overcoming the immunosuppressive tumor microenvironment. Combining chemokine-guided trafficking and delivery with the clearance of immunosuppressive barriers represents a promising strategy. An EGFR-targeted CAR-γδ T, CAR-E276 that co-expresses CCR6 and secretes PD1 blockade was in vivo validated using a non-small cell lung cancer (NSCLC) CDX model. The results from CAR-E276 indicated that integrating chemokines, checkpoint blockades, and γδ T cell properties into CAR-T cells facilitated their efficient trafficking into tumor tissues, ensured prolonged persistence, and achieved robust tumor-killing effects without inducing GvHD. Notably, CAR-E276 also exhibited potential for off-the-shelf and allogeneic applications. These findings are expected to offer valuable insights and drive the development of CAR-T therapies targeting solid tumors.

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ccl20驱动的CAR-γδ T分泌PD-1阻断增强实体瘤运输的验证

CAR-T细胞用于实体肿瘤治疗的主要挑战包括将CAR-T细胞有效地递送和浸润到肿瘤部位，以及克服免疫抑制的肿瘤微环境。将趋化因子引导的贩运和递送与清除免疫抑制屏障相结合是一种很有前途的策略。使用非小细胞肺癌（NSCLC） CDX模型在体内验证了一种共同表达CCR6并分泌PD1阻断物的egfr靶向CAR-γδ T CAR- e276。CAR-E276的研究结果表明，将趋化因子、检查点阻断物和γδ T细胞特性整合到CAR-T细胞中，可以促进CAR-T细胞有效地运输到肿瘤组织中，确保持久存在，并在不诱导GvHD的情况下实现强大的肿瘤杀伤效果。值得注意的是，CAR-E276也表现出了现成和同种异体应用的潜力。这些发现有望提供有价值的见解，并推动针对实体肿瘤的CAR-T疗法的发展。

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

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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