Cell子刊：敲除这两个基因，提高CAR-T细胞治疗实体瘤的效果

Core Viewpoint - The study highlights the urgent need for advancements in treatment for late-stage pancreatic ductal adenocarcinoma (PDAC), where the median survival is less than one year [3]. Group 1: Clinical Trial Findings - A phase 1 clinical trial evaluated the safety and efficacy of anti-MSLN CAR-T cell therapy in patients with advanced PDAC, showing good tolerance but limited effectiveness [4][12]. - The trial involved three groups of patients receiving CAR-T cells via different administration routes: intravenous, intraperitoneal, and hepatic artery, with overall good tolerance and no severe treatment-related adverse events [8]. - The median overall survival for patients was 6.7 weeks, and the median progression-free survival was 3.9 weeks [8]. Group 2: Mechanisms of Resistance - Single-cell genomics revealed that infused CAR-T cells expressed exhaustion markers, including transcription factors ID3 and SOX4, indicating functional impairment [9]. - In mouse models, knocking out ID3 or SOX4 individually enhanced efficacy, but dual knockout of both genes led to longer progression-free survival, suggesting a potential pathway for designing more effective CAR-T cells for PDAC [9][12]. Group 3: Implications for Future Research - The findings suggest that while anti-MSLN CAR-T cell therapy is well-tolerated, further research is needed to overcome the limitations in efficacy observed in PDAC patients [12]. - The study provides insights into the mechanisms of resistance and potential strategies for improving CAR-T cell therapy in treating PDAC [9][12].