MSLN and CLDN18.2 dual-target CAR-T therapy: Enhancing cancer treatment with improved efficacy and safety.

作者：Shasha Yang, Kaichun Wu, Jiantao Wang, Xuefeng Kong, Zhongjun Shi, Huajing Wang, Xiaowen He · 发表于：Journal of Clinical Oncology · 年份：2025 · DOI：10.1200/jco.2025.43.16_suppl.e16381 · 被引用次数：2 · 研究领域：CAR-T cell therapy research、Biosimilars and Bioanalytical Methods

e16381 Background: While CAR-T cell therapy has been highly successful in treating hematologic malignancies, its application to solid tumors remains challenging due to the unique complexities of these cancers. MSLN and CLDN18.2, which show limited expression in normal tissues but are over-expressed in several tumor tissues, represent promising targets for CAR-T therapy. However, targeting CLDN18.2 carries the risk of gastrointestinal toxicity due to off-target effects on normal tissues. Notably, MSLN and CLDN18.2 are not co-expressed in healthy tissues but are frequently overexpressed together in malignancies such as gastric and pancreatic cancers，both notoriously difficult to treat and associated with poor prognoses. Methods: Given that CLDN18.2-BBζcaused gastrorrhagia toxicity in our preclinical mouse models, we developed OriC613 utilizing an "AND" logic gate design to enhance safety while maintaining anti-tumor efficacy.. OriC613 incorporates an anti-CLDN18.2 scFv with high binding strength and an anti-MSLN V H H with moderate binding affinity, ensuring full activation exclusively in tumor cells co-expressing both MSLN and CLDN18.2. Results: In both in vitro and in vivo models, OriC613 shows more potent cytotoxicity against MSLN & CLDN18.2 double-positive cells than MSLN-CD3ζ, and the secretion of IFN-γ and IL-2 is positively correlated with the expression levels of MSLN and CLDN18.2. Notably, OriC613 exhibited no cytotoxic effect on cells expressing CLDN18.2 alone, ei...