CAR-T Therapy in GBM: Current Challenges and Avenues for Improvement

Simple Summary Clinical trials in glioblastoma (GBM) using CAR-T cells have not yielded tangible results. However, clinical and immunological observations from the trials have provided key insights into ways to limit toxicities and extend the antitumor efficacy of CAR-T cells. Incorporating recent notable strides in CAR-T engineering strategies could further boost CAR-T cytotoxicity against glioblastoma, increase persistence of CAR-T cells in vivo, and reduce off-target and on-target off-tumor effects. Here, we review the challenges highlighted by past clinical trials of CAR-T cells in GBM and review recently developed strategies that have the potential to overcome them. Completed clinical trials of CAR-T cells in glioblastoma (GBM) have revealed key challenges that limit their efficacy. These include incomplete antigen coverage, downregulation of target antigen in response to therapy, exposure to immunosuppressive cells and cytokines in the tumor microenvironment and exhaustion of CAR-T cells. To overcome these challenges, CAR-T cells have been modified to maximize effector function and resist immunosuppression in the tumor while limiting toxicities to the host. Adoption of these novel CAR-T strategies in GBM can overcome the "cold tumor" phenotype of GBM and trigger an inflammatory cascade that maximizes tumor clearance and minimizes CAR-T dysfunction. To achieve this, understanding and harnessing the antigenic, metabolic and immunological composition of GBM is crucial. Here we review the findings from completed clinical trials of CAR-T cells in GBM as well as novel strategies that could improve CAR-T survival and function in the tumor.