Malignant glioma is a fatal neurological disease for which recent medical advances have only offered modest improvements in survival. PI(3)K pathway activation mediated by PTEN loss represents an important molecular feature of glioma progression. Multiple agents that target the PI(3)K pathway are under development. To date, these agents have been limited by systemic toxicity and demonstrated marginal efficacy. Convection enhanced delivery utilizing liposomal encapsulation represents a local delivery method with the potential to circumvent these limitations by delivering higher concentrations to the CNS while minimizing systemic toxicity. Hypothesis driven combination therapy with pathway specific inhibitors and other therapeutic modalities provides an avenue for the rational improvement of glioma therapy. Immunotherapy provides a tumor specific means of targeting glioma cells regardless of location in the CNS. Our recently published work has demonstrated a link between B7-H1 mediated tumor immunoresistance and PI(3)K pathway activation. The goal of our proposed study is to demonstrate that local delivery of PI(3)K inhibitors is more effective than systemic delivery and that a combined approach of PI(3)K inhibition and immunotherapy leads to improved therapeutic outcomes in the treatment of malignant glioma. Accordingly, we have developed the following specific aims: 1) To define the kinetics and magnitude of CNS and systemic toxicity of PI(3)K pathway inhibition 2) To analyze the molecular and therapeutic impact of PI(3)K pathway inhibition 3) To measure efficacy of combination therapy using adoptively transferred tumor specific T-cells after PI(3)K pathway inhibition. Our proposed project will evaluate the toxicity and efficacy of the mTOR inhibitor, CCI-779, after systemic delivery or local delivery by CED with and without liposomal encapsulation in a xenograft glioma rodent model. Combination therapy utilizing CED of inhibitor liposomes and the adoptive transfer of tumor specific CTLs into a rodent xenograft model will be assayed for therapeutic response. The proposed research project will directly contribute to public health by comparing response to systemic versus locally delivered inhibitors of a molecular pathway key to malignant glioma. The project will further explore the impact of inhibition of this pathway on resistance of glioma cells to attack by the immune system. Demonstration of improved outcomes with combination therapy will support the development of human clinical trials using specific pathway inhibition to improve response to immunotherapy. ? ? ?
| Waldron, James S; Yang, Isaac; Han, Seunggu et al. (2010) Implications for immunotherapy of tumor-mediated T-cell apoptosis associated with loss of the tumor suppressor PTEN in glioblastoma. J Clin Neurosci 17:1543-7 |
