Locoregional delivery of CAR-T cells in the clinic

Cellular therapies utilizing T cells expressing chimeric antigen receptors (CARs) have garnered significant in-terest 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 hetero-geneity, 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 micro -environment. 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 ven-tricles. Hepatic artery infusion is another technique used for locoregional delivery to hepatic tumors. Locore-gional 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 spe-cifically on the use of locoregional delivery of CAR-T cells in clinical trials.