Chimeric Antigen Receptor T Cells for Glioblastoma: Current Concepts, Challenges, and Future Perspectives.

Glioblastoma is the most common malignant primary brain tumor and is associated with a poor prognosis even after multimodal therapy. Chimeric antigen receptor (CAR) T cells have emerged as a promising therapeutic avenue in glioblastoma. CARs incorporate antigen-recognition moieties that endow autologous T cells with specificity against antigens expressed on glioblastoma (e.g., interleukin [IL]-13Rα2, epidermal growth factor receptor variant III [EGFRvIII], and human epidermal growth factor receptor 2 [HER2]). Compelling antitumor effects of such therapy have been shown in murine glioblastoma models. In humans, 5 phase I/II studies on IL-13Rα2-, EGFRvIII-, and HER2-directed CAR T cells for the treatment of glioblastoma have been published suggesting an acceptable safety profile. However, antitumor effects fell short of expectations in these initial clinical studies. Tumor heterogeneity, antigen loss, and the immunosuppressive tumor microenvironment are among the most important factors to limit the efficacy of CAR T-cell therapy in glioblastoma. Novel target antigens, modification of CAR T-cell design, the combination of CAR T-cell therapy with other therapeutic approaches, but also the use of CAR natural killer cells or CAR macrophages may optimize antitumor effects. Numerous clinical trials studying such approaches are ongoing, as well as several preclinical studies. With an increasing understanding of immune-escape mechanisms of glioblastoma and novel manufacturing techniques for CARs, CAR T cells may provide clinically relevant activity in glioblastoma. This review focuses on the use of CAR T cells in glioblastoma, but also introduces the basic structure, mechanisms of action, and relevant side effects of CAR T cells.