The broad, long-term objectives of our research are: i) to develop and optimize dendritic cell-based immunotherapy approaches for the treatment of brain tumors; and ii) to gain a better understanding of the mechanisms of immune responses generated by dendritic cell-based strategies targeting central nervous system (CMS) neoplasms. Toward these goals, we have previously investigated strategies of pulsing dendritic cells (DC) with autologous tumor peptides and tumor lysates for therapy of malignant gliomas, which we have developed from pre-clinical studies to completion of Phase I clinical trials and initiation of multi-center Phase II trials. Using patient samples from our previous and ongoing clinical trials, we recently made the observation that many malignant gliomas express melanoma-associated antigens (MAA). We hypothesize that the shared expression of MAA on gliomas and melanomas may stem from the common neuroectodermal origin of melanocytes and astrocytes. In recent pre-clinical studies in our laboratory, we have shown that both human and murine gliomas express MAA that can be specifically recognized and targeted by the cellular immune system, and that DCs loaded with MAA peptides can protect against intracerebral glioma challenge in a murine model. This work is important because it identifies a set of endogenous tumor-associated antigens (TAA) on gliomas that have well-characterized cytotoxic T-lymphocyte (CTL) epitopes and defined HLA restriction. In this current grant proposal, we wish to expand upon these observations made from our previous clinical trials and pre-clinical data. The specific research proposed in this application is intended to test the hypothesis that melanoma-associated antigens (MAA) expressed on malignant gliomas can be immunotherapeutically targeted to induce effective anti-tumor clinical and immune responses against CNS tumors. In order to accomplish this, the specific aims of this proposal are: (1) to evaluate the efficacy and immunologic mechanisms of using a toll-like receptor 7 agonist (imiquimod) to enhance the anti-tumor effects of MAA peptide-pulsed DC vaccination in pre-clinical in vivo models; and (2) to evaluate the clinical and immune responses induced by MAA peptide-pulsed DC vaccination in HLA-A2.1 patients with human glioblastoma in a Phase l/ll clinical trial. If the clinical and immune responses seen in our proposed clinical trial (Aim 2) are not sufficiently robust, we have designed a simultaneous set of hypothesis-driven pre-clinical studies (Aim 1) to delve into the mechanisms by which toll-like receptor agonists can potentially augment our DC vaccine approach. Thus, this is a truly bi-directional translational project that is directly related to our long-term objectives stated above and to the mission of promoting public health. ? ? ?
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