CELL INTELLIGENCE · 肿瘤细胞治疗研究

Pancreatic ductal adenocarcinoma (PDAC) and lung adenocarcinoma (LUAD) remain lethal malignancies with limited therapeutic options, highlighting an urgent need for more effective treatments. Integrin v 6 (ITGB6) is a receptor preferentially expressed in specific types of tumors, such as PDAC and LUAD, and represents a promising yet largely untapped target for cellular immunotherapy. We aimed to develop and preclinically validate a novel chimeric antigen receptor T-cell (CAR-T) therapy targeting ITGB6 for these aggressive solid tumors. A third-generation anti-ITGB6 CAR was designed and constructed, incorporating both CD28 and TLR2 co-stimulatory domains. TLR2 signaling enhances T-cell expansion, cytokine production, and infiltration into solid tumor. The potency and specificity of anti-ITGB6 CAR-T cells were assessed against a panel of ITGB6-positive PDAC and LUAD cell lines, patient-derived organoids (PDOs), orthotopic models, and patient-derived xenograft (PDX) models. Anti-ITGB6 CAR-T cells demonstrated potent cytotoxicity against ITGB6-positive PDAC and LUAD models in vitro, effectively targeting both cell lines and PDOs. In murine xenograft models, a single dose of anti-ITGB6 CAR-T cells induced significant tumor suppression and prolonged survival, with no evidence of on-target/off-tumor toxicity was observed. Our findings provide compelling preclinical proof-of-concept for anti-ITGB6 CAR-T therapy as a potent and safe investigational strategy against ITGB6-positive solid tumors, supporting its clinical translation for patients with PDAC and LUAD.