Despite aggressive surgical resections, high-dose radiation therapy, and toxic chemotherapy, the vast majority of patients with malignant brain tumors survive less than one year making conventional therapy for malignant brain tumors the most expensive therapy per quality-adjusted life-year saved currently provided. Moreover, the failure of these treatment modalities to be tumor-specific at the molecular level, results in inevitable damage to surrounding normal brain that incapacitates patients treated with these traditional modalities. The inherent specificity of immunologic recognition offers the prospect of targeting malignant cells more precisely. Several studies have documented the exceptional ability of dendritic cells (DCs) to activate the immune system and produce encouraging human antitumor responses. The epidermal growth factor mutation, EGFRvIII, found on the majority of malignant gliomas, represents a tumor-specific target for such an approach. Our preclinical results demonstrate that DCs loaded with a KLH conjugate of an EGFRvIII peptide induce potent humoral and cell-mediated immune responses. Although anti-EGFRvIII, DC-based immunotherapy will allow antigen-specific immune responses to be clearly monitored and potentially optimized, we believe that human antitumor responses will likely be enhanced and the spectrum and utility of this paradigm expanded by targeting additional antigens. However, existing techniques for identifying potential targets are labor intensive, do not systematically assess the entire neoplastic genome, and do not assess the potential risk of autoimmunity posed by targeting these antigens. Serial analysis of gene expression (SAGE) is a contemporary approach to gene expression analysis that allows rapid identification of genes that are over-expressed in neoplastic cells. SAGE databased mining and rapid expression screening has allowed our group to identify a large number of genes uniquely expressed in malignant gliomas that may function as specific tumor antigens. To select those with immunologic relevance and those that are unlikely to induce autoimmune reactivity, we have developed a unique system based on the loading of autologous DCs with genes or gene fragments. Using this technique, we have demonstrated that DCs loaded with tumor-specific RNAs can specifically activate autologous T cells without activating autoreactive T cells. The hypothesis to be tested in this project is that malignant gliomas can be selectively targeted for therapeutic immunotherapy without the induction of autoimmunity using DCs loaded with the tumor-specific EGFRvIII and other additional genes found by SAGE to be uniquely expressed by malignant gliomas.
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