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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA097257-12
Application #
8760341
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
12
Fiscal Year
2014
Total Cost
$325,621
Indirect Cost
$118,937
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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