OVERCOMING LOCAL AND PERIPHERAL IMMUNE SUPPRESSION IN GLIOMA TO FACILITATE EFFEC

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The long-term translational goal of this project is to overcome mechanisms of immunoresistance that diminish efficacy of immunotherapy for glioma patients, particularly glloblastoma (GBM). In the previous cycle we completed a Phase I clinical trial and a Phase II clinical trial for recurrent GBM patients immunized with an experimental vaccine, after surgical resection. These trials demonstrated that autologous glioma-derived heat shock protein peptide complex-96 (HSPPC-96) vaccine Is safe, evokes a CD4+ and CD8+ tumor specific T-cell response and Increases survival of recurrent GBM patients as compared to historical controls. In the previous SPORE cycle we also identified proteins that contribute to glioma immunoresistance, including B7-Homologue 1 (B7-H1) that is expressed on the glioma ceil surface, induces CD8+ T- cell apoptosis and Is positively regulated by PI(3)K. Our observations explain how the PI(3)K/B7-H1 pathway can directly inhibit T-cell killing of tumor. In the next cycle of this project we plan to test the hypothesis that Immunosuppressive tumor effects of PI(3)K/B7-H1 pathway activation can also be mediated indirectly, through expansion of the regulatory T cell (Treg) pool (Aim 1) and through expression of B7-H1 protein on tumor infiltrating macrophages (Aim 2) in patients with low grade astrocytoma (LGA), anaplastic astrocytoma (/^A), and GBM. To determine the clinical impact of PI(3)K/B7-H1 pathway activation on response to glioma immunotherapy we will initiate a randomized trial comparing the standard of care (intravenous bevacizumab) to HSPPG-96 combined with bevacizumab in recurrent GBM patients (Aim 3).