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. To do this, we propose three specific aims designed to understand, both in pre-clinical animal models as well as in clinical patient samples, the mechanisms of anti-tumor immunity critical for CMS tumor eradication. Immunotherapy for glioma has traditionally lagged behind other peripheral tumors where defined CTL targets are known. In our recent pre-clinical studies we have shown that both human and murine gliomas express melanoma-associated antigens (MAA)that can be recognized by the cellular immune system. We believe that the shared expression of MAA on gliomas and melanomas stems from their common neuroectodermal origin. Our discovery was important because it identified a set of endogenous tumor-associated antigens (TAA) on gliomas that have well characterized cytotoxic T lymphocyte (CTL) epitopes. Using our T cell receptor transgenic mouse model, in vivo imaging methodologies, and Toll-like receptor (TLR) agonists, we have designed a systematic set of studies to not only test the therapeutic value of targeting MAA on CMS tumors, but provide a model to test the basic immunological requirements for generating anti-tumor immunity to defined, endogenous MAA located in the CNS. Our central hypothesis is that CNS gliomas express MAA, which can be targeted by immunotherapies that enhance T cell and DC activation and trafficking. Thus, this is a mechanistic and translational project that is directly related to our long-term objectives stated above and to the mission of promoting public health.
