PI3-Kinase activation and immunoresistance in glioma

University Of California, San Francisco, San Francisco CA

Investigators

Linked publications & trials

Abstract

[unreadable] DESCRIPTION (provided by applicant): The long-term goal of this project is to optimize immunotherapy for patients with malignant glioma. The short-term goal is to provide an optimal training environment for the applicant to pursue a research plan within the realm of glioma immunology. 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 depend upon tumor specific CD8+ T-cells. Tumor-specific cytolytic CD8+ T-cells (CTLs) can undergo anergy or apoptosis in response to proteins expressed by gliomas. 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. When expressedgulated by the PI(3)K pathway. Gliomas with activation of this pathway are resistant to tumor-specific T-cell killing. In addition we show that an autologous patient-specific vaccine containing glioma-derived heat shock protein peptide complex-96 (HSPPC-96) is safe, while evoking a tumor specific T-cell response. Our Phase l/ll investigator initiated clinical trial evaluating HSPPC-96 in recurrent glioma patients provides a unique training opportunity to study PI(3)K pathway activation and clinical response to immunotherapy. Our data suggest that in the absence of attempts to inhibit the PI(3)K pathway, glioma patients will be poor candidates for autologous HSPPC-96 or any immunotherapy dependent upon activated T-cells. To further validate our preliminary results, we will test the hypothesis that activation of the PI(3)K pathway in glioma suppresses adaptive (T-cell) anti-glioma immune responses. Glioma specimens from patients will be analyzed for T-cell infiltrates and activation ofpression of B7-H1, and reduction of B7-H1 protein levels with siRNA . [unreadable] [unreadable] [unreadable] [unreadable][unreadable][unreadable] be evaluated to determine if activation of the PI(3)K correlates with a poor clinical response to immunotherapy. In addition a series of mechanistic experiments will be pursued. Using primary glioma cultures established directly from operative specimens we will test the effect of PI(3)K pathway inhibition on T-cell mediated killing, as well as over-ex[unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable]