OriC613: A novel therapeutic strategy for gastric and pancreatic cancers utilizing dual-targeting CAR-T cells against MSLN and CLDN18.2 with a favorable safety profile and potent efficacy

Background: CAR-T cell therapy has demonstrated significant efficacy in hematologic malignancies; however, its application to solid tumors remains limited by on-target, off-tumor toxicity. Mesothelin(MSLN) and claudin 18.2(CLDN18.2) are tumor-associated antigens overexpressed in several solid tumors with minimal co-expression in normal tissues, which presents a therapeutic opportunity for a dual-targeting strategy to enhance tumor selectivity. Methods: To address gastric toxicity observed with CLDN18.2-directed CAR-T cells in preclinical models, we developed OriC613, a dual-antigen targeting CAR-T based on AND-logic gate. The construct incorporates a high-affinity anti-CLDN18.2 scFv and a moderate-affinity anti-MSLN V H H, engineered to achieve full T-cell activation only upon engagement of both antigens. Results: OriC613 demonstrated a favorable safety profile characterized by the absence of cytotoxic activity against CLDN18.2-positive normal gastric models. It exhibited enhanced cytotoxic potency against dual-positive tumor compared to conventional MSLN-targeted CAR-T. In pancreatic cancer re-challenge models, it promoted continued T-cell expansion and maintained cytokine production capacity. OriC613 mediated significant tumor regression in high-burden gastric in-vivo model, demonstrating robust antitumor activity while maintaining the safety profile. It also supported sustained T-cell persistence with detectable engraftment in bone marrow and spleen. Conclusions: OriC613 demonstrates potent antitumor activity and reduced toxicity profile by leveraging co-expression of MSLN and CLDN18.2. These preclinical findings support further clinical development of this dual-targeting CAR-T approach in patients with gastric or pancreatic adenocarcinoma.