Combination Therapies of CAR-T Cells for Glioblastoma: Current Advances, Challenges, and Future Perspectives

Glioblastoma multiforme (GBM) is one of the most aggressive malignant brain tumours among adults. Since many conventional therapies have demonstrated limited advancement, an emerging immunotherapy called Chimeric Antigen Receptor T-cell therapy (CAR-T therapy) is gradually becoming the hope for transforming GBM treatment. However, due to intrinsic limitations, such as the immunosuppressive tumour microenvironment (TME), heterogeneity of tumour cells, antigen escape, and the blood-brain barrier (BBB), CAR-T monotherapy has also shown unexpected preclinical results. To enhance drug efficacy and overcome related challenges, many researchers have combined CAR-T therapy with other therapeutic approaches. As a result, this review focuses on the mechanisms and strengths of four distinct combination treatments with CAR-T therapy in GBM, including chemotherapy, radiotherapy, immune checkpoint inhibitor (ICI) therapy, and oncolytic virus (OV) therapy. This review concludes that these combination therapies could improve the proliferation, persistence, and infiltration of CAR-T cells, achieving higher efficacy. Nevertheless, the radical problems, like the TME and heterogeneity, remain unsolved. In summary, this review aims to provide a general idea about CAR-T combination therapies from the mechanisms, strengths, and limitations. Future research can focus on developing more late-stage clinical trials or modifying the structures of CAR-T cells.