The high efficacy of claudin18.2-targeted CAR-T cell therapy in advanced pancreatic cancer with a strategy to ensure the safety of patients.

IF 12.1 1区医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Molecular Therapy Pub Date : 2025-01-09 DOI:10.1016/j.ymthe.2025.01.012

Guocheng Zhong, Xiaomin Zhang, Ruocong Zhao, Zheng Guo, Chenguang Wang, Chuan Yu, Dongzhe Liu, Ke Hu, Yujie Gao, Bochen Zhao, Xianhao Liu, Xuanren Shi, Lei Chen, Yisheng Li, Li Yu

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引用次数: 0

Abstract

Pancreatic cancer (PC) is one of the most lethal digestive system tumors. Claudin18.2 is highly expressed in PC tissue and could serve as a suitable target for CAR-T therapy. In the present study, we reported the utilization of tEGFR-expressing claudin18.2-targeted CAR-T cells to treat 3 patients with advanced PC. Intriguingly, all 3 patients achieved disease remission after CAR-T cell infusion, with 1 complete remission (CR) and 2 partial remissions (PR). However, gastric mucosal injury was observed, which was recognized as on-target off-tumor toxicity (OTOT) and may be due to the expression of claudin18.2 on normal gastric tissues. To control the severe OTOT in patient 3, cyclophosphamide and cetuximab were administered to deplete CAR-T cells, and they successfully controlled OTOT. Single cell transcriptome and TCR sequencing revealed the objective alterations of CAR-T cell clones after cetuximab treatment. Collectively, the present study showed the robust anti-tumor activity of claudin18.2-targeted CAR-T cells against PC, and reported the feasibility of antibody-dependent safety switch strategy to control the OTOT caused by CAR-T cells in patients. Our study may pave the way for the development of a novel strategy to treat patients with advanced PC in the future.

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claudin18.2靶向CAR-T细胞治疗晚期胰腺癌的高疗效，并确保患者的安全性。

胰腺癌是最致命的消化系统肿瘤之一。Claudin18.2在PC组织中高表达，可以作为CAR-T治疗的合适靶点。在本研究中，我们报道了利用表达claud18.2的tegfr靶向CAR-T细胞治疗3例晚期PC患者。有趣的是，所有3例患者在CAR-T细胞输注后均获得疾病缓解，其中1例完全缓解（CR）， 2例部分缓解（PR）。然而，观察到胃粘膜损伤，这被认为是靶外肿瘤毒性（on-target off-tumor toxicity， OTOT），可能是由于claudin18.2在正常胃组织中的表达。为了控制患者3的严重OTOT，使用环磷酰胺和西妥昔单抗来消耗CAR-T细胞，成功地控制了OTOT。单细胞转录组和TCR测序揭示了西妥昔单抗治疗后CAR-T细胞克隆的客观变化。综上所述，本研究显示了claudin18.2靶向CAR-T细胞对PC具有强大的抗肿瘤活性，并报道了抗体依赖安全开关策略控制CAR-T细胞在患者体内引起的OTOT的可行性。我们的研究可能为未来发展一种治疗晚期PC患者的新策略铺平道路。

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

Molecular Therapy 医学-生物工程与应用微生物

CiteScore

19.20

自引率

3.20%

发文量

357

审稿时长

3 months

期刊介绍： Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.