Fig. 2.

Charts show mechanisms of brain tumor immunotherapy. Various immunotherapeutic strategies have been developed to overcome tumor immune evasion and to reprogram dysregulated immune microenvironment as means of improving clinical outcomes. Checkpoint pathways (top left) play critical role in maintaining immune homeostasis by inhibiting cytotoxic T-cell efficacy, facilitating tumor immune evasion. This recognition led to development of monoclonal antibodies targeting these receptors. Disrupting checkpoint signaling unlocks cytotoxic T cell–mediated tumor cell killing, reduces numbers of regulatory T cells, and promotes proinflammatory cytokines within tumor bed. Use of immune checkpoint blockade has markedly improved overall survival in several solid tumors, including metastatic melanoma, leading to great interest in its use in glioblastoma. PD-L1 = programmed cell death ligand 1. Chimeric antigen receptor (CAR) T cells (top right) have gained wide use in therapy for various hemopoietic-based lymphomas and are emerging as potential therapeutic avenue in glioblastoma. CAR T cells are genetically modified to express CAR. This incorporates antigen-recognition moieties that endow autologous T cells with specificity against glioblastoma antigens, such as epidermal growth factor receptor variant III. Major area of therapeutic cancer research is construction of oncolytic viruses (bottom left) that not only target cancer cells but also retain their ability to infect, usurping host replication machinery and releasing newly made progeny to infect other transformed cells after lysing and killing host cell. One approach is to deliver therapeutic genes, such as inactivating mutation in thymidine kinase gene, via viral vector. Second approach is direct induction of tumor cell cytotoxicity. Both approaches subsequently present tumor antigen and potentiate adaptive immune response. In vaccine-based immunotherapies (bottom right), tumor-associated antigens are used to train immune system to target tumor cells through various immune mechanisms in effort to induce cytotoxic tumor effects. Tumor antigens are presented to antigen-presenting immune cells, such as dendritic cells, ex vivo. These administered cells then induce potent adaptive immune stimulus against tumor.