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The long term goal of our research is to improve the generation of tumor-specific immunity in tumor-bearing individuals and to generate vaccines that prophylactically protect high-risk individuals from developing tumors. Our studies are particularly focused on metastatic cancer because of the lack of efficacious therapies against metastases. Over the past approximately 10 years, we have demonstrated that the immune system can be harnessed to control tumor cell growth and that both CD4+ and CD8+T lymphocytes are required, with CD4+ T cells playing a key role. Our strategy, therefore, has focused on facilitating T cell responses to tumors, and particularly on generating tumor-specific CD4+ T lymphocytes. Using gene transfer techniques we have developed cell-based tumor vaccines consisting of tumor cells as the vaccine "base," and including MHC class II and selected antigen presentation and signaling molecules. We have hypothesized that the vaccines are efficacious because they directly present endogenously synthesized, MHC class II-restricted tumor peptides directly to CD4+ T cells. In vivo experiments with tumor-bearing mice (sarcoma, mammary carcinoma, and melanoma) demonstrate that the vaccines are effective therapeutic agents for the treatment of mice with established solid, primary tumor or metastatic disease. In a prophylactic setting, vaccination of tumor-free mice results in potent, long-term immune protection.

We are also exploring the mechanism(s) by which the vaccines activate the immune response. In vivo experiments using bone marrow chimeras and genetically marked tumor cells demonstrate that the vaccine cells directly present endogenously synthesized tumor peptides to CD4+ T lymphocytes. Although the vaccines act as antigen presenting cells for tumor-encoded peptides, the mechanism of uptake of peptide by MHC class II molecules is unclear. Inhibition studies using drugs that selectively block intracellular trafficking pathways, however, suggest that the endogenously synthesized tumor antigens are processed, loaded onto MHC class II molecules, and carried to the cell surface via an unconventional pathway.

We are also interested in identifying the effector mechanisms that directly mediate tumor regression, as well as the genes, cells, and factors that contribute to activation of the effector mechanisms. Studies with IL-12, NK-deficient, and interferon-gamma knockout mice suggest that in addition to T cells, angiogenesis and NK-related mechanisms may be involved. We anticipate that a thorough understanding of the mechanisms underlying tumor regression following vaccination will enable us to develop more efficacious cancer vaccines.