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).

Public Health Relevance

Active immunotherapy for GBM patients offers the hope of specificity without toxicity, however peripheral immune responses have not always correlated with clinical success. In the present proposal we will use novel approaches to reverse the immunoresistance in an effort to optimize immunotherapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
San Francisco
United States
Zip Code
Amirian, E Susan; Scheurer, Michael E; Zhou, Renke et al. (2016) History of chickenpox in glioma risk: a report from the glioma international case-control study (GICC). Cancer Med 5:1352-8
Amirian, E Susan; Armstrong, Georgina N; Zhou, Renke et al. (2016) The Glioma International Case-Control Study: A Report From the Genetic Epidemiology of Glioma International Consortium. Am J Epidemiol 183:85-91
Koestler, Devin C; Jones, Meaghan J; Usset, Joseph et al. (2016) Improving cell mixture deconvolution by identifying optimal DNA methylation libraries (IDOL). BMC Bioinformatics 17:120
Walsh, Kyle M; Ohgaki, Hiroko; Wrensch, Margaret R (2016) Epidemiology. Handb Clin Neurol 134:3-18
Phillips, Joanna J; Gong, Henry; Chen, Katharine et al. (2016) Activating NRF1-BRAF and ATG7-RAF1 fusions in anaplastic pleomorphic xanthoastrocytoma without BRAF p.V600E mutation. Acta Neuropathol 132:757-760
Ladomersky, Erik; Zhai, Lijie; Gritsina, Galina et al. (2016) Advanced age negatively impacts survival in an experimental brain tumor model. Neurosci Lett 630:203-8
Dasgupta, Tina; Olow, Aleksandra K; Yang, Xiaodong et al. (2016) Survival advantage combining a BRAF inhibitor and radiation in BRAF V600E-mutant glioma. J Neurooncol 126:385-93
Duleh, Steve; Wang, Xianhong; Komirenko, Allison et al. (2016) Activation of the Keap1/Nrf2 stress response pathway in autophagic vacuolar myopathies. Acta Neuropathol Commun 4:115
Amirian, E Susan; Zhou, Renke; Wrensch, Margaret R et al. (2016) Approaching a Scientific Consensus on the Association between Allergies and Glioma Risk: A Report from the Glioma International Case-Control Study. Cancer Epidemiol Biomarkers Prev 25:282-90
Ojha, Juhi; Codd, Veryan; Nelson, Christopher P et al. (2016) Genetic Variation Associated with Longer Telomere Length Increases Risk of Chronic Lymphocytic Leukemia. Cancer Epidemiol Biomarkers Prev 25:1043-9

Showing the most recent 10 out of 293 publications