Cell & Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District, Camperdown 2050, Australia.
Faculty of Medicine and Health, The University of Sydney, Camperdown 2050, Australia.
Pharmacol Res. 2022 Aug;182:106329. doi: 10.1016/j.phrs.2022.106329. Epub 2022 Jun 27.
Cellular therapies utilizing T cells expressing chimeric antigen receptors (CARs) have garnered significant interest due to their clinical success in hematological malignancies. Unfortunately, this success has not been replicated in solid tumors, with only a small fraction of patients achieving complete responses. A number of obstacles to effective CAR-T cell therapy in solid tumors have been identified including tumor antigen heterogeneity, poor T cell fitness and persistence, inefficient trafficking and inability to penetrate into the tumor, immune-related adverse events due to on-target/off-tumor toxicity, and the immunosuppressive tumor microenvironment. Many preclinical studies have focused on improvements to CAR design to try to overcome some of these hurdles. However, a growing body of work has also focused on the use of local and/or regional delivery of CAR-T cells as a means to overcome poor T cell trafficking and inefficient T cell penetration into tumors. Most trials that incorporate locoregional delivery of CAR-T cells have targeted tumors of the central nervous system - repurposing an Ommaya/Rickham reservoir for repeated delivery of cells directly to the tumor cavity or ventricles. Hepatic artery infusion is another technique used for locoregional delivery to hepatic tumors. Locoregional delivery theoretically permits increased numbers of CAR-T cells within the tumor while reducing the risk of immune-related systemic toxicity. Studies to date have been almost exclusively phase I. The growing body of evidence indicates that locoregional delivery of CAR-T cells is both safe and feasible. This review focuses specifically on the use of locoregional delivery of CAR-T cells in clinical trials.
利用嵌合抗原受体 (CAR) 表达 T 细胞的细胞疗法因其在血液恶性肿瘤中的临床成功而引起了极大的关注。不幸的是，这种成功并未在实体瘤中得到复制，只有一小部分患者获得完全缓解。已经确定了许多有效的 CAR-T 细胞疗法在实体瘤中面临的障碍，包括肿瘤抗原异质性、T 细胞适应性和持久性差、低效的转移和无法穿透肿瘤、由于脱靶/肿瘤毒性引起的免疫相关不良事件，以及免疫抑制性肿瘤微环境。许多临床前研究都集中在改进 CAR 设计上，以试图克服其中的一些障碍。然而，越来越多的工作也集中在局部和/或区域性递送 CAR-T 细胞作为克服 T 细胞转移不良和 T 细胞向肿瘤渗透效率低下的手段。大多数纳入局部递送 CAR-T 细胞的试验都针对中枢神经系统的肿瘤——重新利用 Ommaya/Rickham 储液器将细胞直接递送到肿瘤腔或脑室，以进行重复递送。肝动脉输注是另一种用于局部递送肝脏肿瘤的技术。局部递送理论上允许在肿瘤内递送更多数量的 CAR-T 细胞，同时降低免疫相关全身毒性的风险。迄今为止，研究几乎都是 I 期。越来越多的证据表明，局部递送 CAR-T 细胞既安全又可行。本综述专门关注 CAR-T 细胞在临床试验中的局部递送。
