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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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.