Gliomas are the most common primary neoplasm of the central nervous system and the most common solid tumor in children. However, despite three decades of active clinical investigation, the prognosis for patients with high-grade gliomas, the most common type, remains dismal, with median survival of less than a year. Immunotherapy is particularly appealing for the treatment of glioma due to the potential specificity of the immune response to eradicate deeply infiltrating tumor without damaging surrounding brain. Dendritic cells (DC) are the most potent presenters of antigen to na?ve T lymphocytes and most current clinical studies have focused on DC-based paradigms. Unfortunately, while DC immunotherapy for brain tumors has been successful in preclinical prevention models, efficacy against existing tumor has been modest in preclinical and clinical studies. It has recently been shown that DC and na?ve lymphocytes both express a chemokine receptor, which is responsible for co-migration of these cells to the lymph node in response to this chemokine. DC genetically modified to secrete this chemokine facilitate extra-nodal priming by presenting antigen at the site of vaccination even in the absence of lymph nodes. If this approach could be successfully applied to gliomas, it could potentially surmount immunologic privilege within the brain, thus overcoming current problems in immunotherapy of malignant brain neoplasms. However the efficacy of this approach has not yet been assessed for immunologically privileged sites such as the brain. Our hypothesis is that chemokine transduced DC will induce traffic of effector lymphocytes and antigen presenting cells to the brain and induce a therapeutic, tumor-specific immune response. We will test this hypothesis by pursuing five specific aims focused on evaluating the potential of chemokine transduced DC to induce immune priming within the brain as well as efficacy in preclinical prevention and treatment models of glioma, alone or in combination with various cytokines. The results will be significant because they will provide insight into immunoregulation within the brain, as well as methods to surmount immunological privilege in the context of malignant brain neoplasms. It will also provide the candidate with intensive research training in research methodology and immunotherapy as part of his goal to develop into an independent investigator to develop translational therapies for the treatment of intracranial malignancies. ? ? ?
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