Revolutionizing Glioblastoma Immunotherapy Conquering Transport and Biological Challenges, Innovating Combinatorial Approaches for Unprecedented Treatment Success

Abstract: Glioblastomas are the most common primary brain cancer and present many challenges in treatment, with the current standard-of-care treatments yielding a median survival rate of less than 15 months. While immunotherapy against cancer has been very effective in some cancers, its application in glioblastoma has been limited so far. The following review touches upon some of the critical challenges associated with successful immunotherapy in glioblastoma, covering transport-related obstacles presented by the blood-brain barrier, biological complexity within the central nervous system, and the interplay between glioblastoma and immune cells. Ongoing clinical trials testing the efficacy of different immunotherapeutic strategies, including immune checkpoint blockade, vaccination, and adoptive cell transfer, are discussed. These strategies are inherently challenged by the low immunogenicity of glioblastoma, the unique immuneprotective mechanisms of the immune system within the CNS, and the predominant features of the immune-suppressive tumor microenvironment. Current therapeutic modalities reviewed include surgical resection, radiation therapy, and temozolomide-based chemotherapy, with discussions on new forms of approaches to enhance immune activation: vaccines, oncolytic viruses, and adoptive cell therapies such as CAR T cells and NK cells. The perpetual problem of resistance to immunotherapy underlines the need for combination strategies and precise testing within advanced in-vitro and animal tumor models, considering the large variability in glioblastomas.