The identification of antigens associated with tumor destruction is a major goal of cancer immunology. Vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony stimulating factor (GM-CSF) generates potent, specific, and long-lasting anti-tumor immunity in murine models through improved tumor antigen presentation by dendritic cells and macrophages. Two phase I clinical trials evaluating this immunization strategy in patients with disseminated melanoma revealed the consistent induction in distant metastases of dense T and B cell infiltrates that effectuated substantial tumor necrosis and fibrosis. The ATP6S1 subunit of the vacuolar-ATPase complex, the putative opioid growth factor receptor OGFR, and the melanoma inhibitor of apoptosis protein (ML-IAP) were identified as target antigens for antibodies or T cells in some long-term responding patients. In a pilot study of previously vaccinated patients, the subsequent administration of a humanized blocking antibody against cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) stimulated additional tumor destruction with lymphocyte and granulocyte infiltrates, albeit with the development of T cell reactivity to normal melanocytes. These findings motivated larger clinical trials testing autologous, GM-CSF secreting melanoma cell vaccines followed by CTLA-4 antibody blockade. The analysis of clinical samples obtained from these studies should help elucidate the mechanisms and targets of immune-mediated tumor destruction.
The specific aims of this proposal are to: 1. Identify antigens eliciting humoral responses associated with immune-mediated tumor destruction 2. Determine whether CD4+ and CD8+ T cell responses are coordinately stimulated against these antigens 3. Determine whether altered expression or mutation contributes to the immunogenicity of these antigens 4. Determine whether vaccination with the murine homologs of these antigens can stimulate protective immunity against challenge with murine melanoma cells.
