Research & Training: Brain Tumor SPORE
Project 5
Heat Shock Protein Vaccine Development: Glioma Immunoresistance and PI(3)K/Akt/mTOR Pathway Activation
Principal Investigator - Andrew Parsa, MD, PhD
Clinical Co-Principal Investigator - Russell O. Pieper, PhD
Several clinical trials have shown the feasibility, safety, and anecdotal efficacy of glioma vaccines, although an effective clinical glioma immunotherapy regimen has yet to be developed. The goal of this project is to develop effective vaccine therapy for the treatment of glioma.
Vaccine therapies designed to provoke a cellular immune response depend on activation of both CD8-positive, tumor-specific T-cells and natural killer cells. The investigators in this project have found that two proteins, B7-homologue 1 (B7-H1) and FLIPs, are overexpressed by glioma cells and interfere with the therapeutic immune response by inducing CD8-positive T cell apoptosis and by blocking NK cells activation. Furthermore, both B7-H1 and FLIPs appear to be positively regulated by the same PI(3)K/Akt/mTOR pathway that contributes to the formation and maintenance of gliomas. This project therefore will test the hypothesis that activation of the PI(3)K/Akt/mTOR pathway in human glioma suppresses the T- and NK-cell-mediated anti-glioma immune response, and that modulation of this pathway may improve vaccine efficacy. This hypothesis will be tested within the context of an ongoing phase I/II clinical trial of a newly developed heat shock protein vaccine (HSPPC-96). If successful, this work may lead to the implementation of the first effective vaccine for the treatment of human brain tumors.
