The long-term goal of this project is to optimize immunotherapy for patients with malignant glioma. Several trials have shown the feasibility, safety, and anecdotal efficacy of glioma vaccines. However the general applicability of effective glioma immunotherapy has yet to be clearly documented. Vaccine therapies designed to provoke a cellular immune response may depend upon both tumor specific CD8+ T-cells and cytokine-stimulated natural killer (NK) cells. Tumor-specific cytotolytic CD8+ T-cells (CTLs) can undergo anergy or apoptosis in response to proteins expressed by gliomas, while NK cells may be rendered ineffective by proteins that confer resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated killing. B7-Homologue 1 (B7-H1), also known as programmed death ligand 1 (PD-L1), is a recently discovered cell surface protein that inhibits anti-tumor immunity by inducing T-cell apoptosis, impairing cytokine production, and diminishing the cytotoxicity of activated T-cells. FADD-containing inhibitor of caspase-8 cleavage short protein (FLIPS) may confer resistance to TRAIL-mediated NK cell killing. We believe that tumor specific proteins such as B7-H1 and FLIPS can limit the efficacy of glioma immunotherapy. In our preliminary results, we show that B7-H1 and FLIPS are positively regulated by the PI(3)K/Akt/mTOR pathway, and that glioma cells with this pathway activated are immunoresistant. In addition we show that an autologous patient-specific vaccine containing glioma-derived heat shock protein peptide complex-96 (HSPPC-96) appears to be safe, while evoking a tumor specific T-cell response and an increase in circulating NK cells. To translate our experimental findings into the clinic, we will test the hypothesis that activation of the PI(3)K/Akt/mTOR pathway in glioma suppresses innate (NK cell) and adaptive (T-cell) anti-glioma immune responses. In order to test our hypothesis in a clinically relevant in vitro system, aims #1 and #2 utilize glioma cells directly from glioblastoma multiforme (GBM) patients and passaged as xenografts, prior to culturing to assess the impact of PI(3)K/Akt/mTOR pathway on resistance to NK and T cell killing.
In aim #3 we will study gliomas taken directly from patients to assess the relationship between PI(3)K/Akt/mTOR pathway activation and T-cell infiltration, and in aim #4 we will test our hypothesis within the context of an ongoing HSPPC-96 phase l/ll vaccine trial for glioma patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
3P50CA097257-10S1
Application #
8540603
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
Project End
Budget Start
2011-05-01
Budget End
2013-04-30
Support Year
10
Fiscal Year
2012
Total Cost
$59,989
Indirect Cost
$21,441
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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