The long-term goal of this project is to optimize immunotherapy for patients with malignant glioma. Severaltrials have shown the feasibility, safety, and anecdotal efficacy of glioma vaccines. However the generalapplicability of effective glioma immunotherapy has yet to be clearly documented. Vaccine therapiesdesigned to provoke a cellular immune response may depend upon both tumor specific CD8+ T-cells andcytokine-stimulated natural killer (NK) cells. Tumor-specific cytotolytic CD8+ T-cells (CTLs) can undergoanergy or apoptosis in response to proteins expressed by gliomas, while NK cells may be renderedineffective 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 arecently 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 inhibitorof caspase-8 cleavage short protein (FLIPS) may confer resistance to TRAIL-mediated NK cell killing. Webelieve that tumor specific proteins such as B7-H1 and FLIPS can limit the efficacy of gliomaimmunotherapy. In our preliminary results, we show that B7-H1 and FLIPS are positively regulated by thePI(3)K/Akt/mTOR pathway, and that glioma cells with this pathway activated are immunoresistant. Inaddition we show that an autologous patient-specific vaccine containing glioma-derived heat shock proteinpeptide complex-96 (HSPPC-96) appears to be safe, while evoking a tumor specific T-cell response and anincrease in circulating NK cells. To translate our experimental findings into the clinic, we will test thehypothesis that activation of the PI(3)K/Akt/mTOR pathway in glioma suppresses innate (NK cell) andadaptive (T-cell) anti-glioma immune responses. In order to test our hypothesis in a clinically relevant in vitrosystem, aims #1 and #2 utilize glioma cells directly from glioblastoma multiforme (GBM) patients andpassaged as xenografts, prior to culturing to assess the impact of PI(3)K/Akt/mTOR pathway on resistanceto NK and T cell killing.
In aim #3 we will study gliomas taken directly from patients to assess therelationship between PI(3)K/Akt/mTOR pathway activation and T-cell infiltration, and in aim #4 we will testour hypothesis within the context of an ongoing HSPPC-96 phase l/ll vaccine trial for glioma patients.
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