Immunomodulation mediated by anti-angiogenic therapy improves viral vaccination against GL261 glioma tumors.

Abstract

Abstract Glioblastoma multiforme (GBM) is a lethal cancer of the central nervous system with a median survival rate of 15 months with treatment. Thus, there is a critical need to develop novel therapies for GBM. Immunotherapy is emerging as a promising therapeutic strategy. However, current standard-of-care therapies for GBM, in particular anti-angiogenic therapies that block vascular endothelial growth factor (VEGF), may have undefined consequences on the efficacy of immunotherapy. While this treatment is primarily prescribed to reduce tumor vascularization, multiple immune cell types also express VEGF receptors, including the most potent antigen‑presenting cell, the dendritic cell (DC). Therefore, we assessed the role of anti-VEGF therapy in combination with a novel tumor antigen-specific picornaviral vaccination in the GL261 syngeneic murine model of glioma. We hypothesized that treatment of GL261 glioma-bearing mice with anti‑VEGF therapy will act synergistically with anti-tumor picornaviral vaccination by enhancing DC maturation. We found that VEGF blockade results in a more mature DC phenotype in the brain and tumor-draining lymph node, as demonstrated by an increase in the expression of the co‑stimulatory molecules B7-1 and B7-2. Furthermore, we observed an increase in brain infiltrating, tumor antigen-specific CD8 T cells. This change in immune response directly correlates with a significant reduction in tumor burden, as measured by bioluminescence imaging, and a significantly improved survival rate of mice receiving both anti-VEGF therapy and viral vaccination compared to either treatment alone. Thus, anti-angiogenic therapy can be used in conjunction with and enhance immunotherapy for GBM.