Major accomplishments include: (a) The demonstration that external beam irradiation of tumor can upregulate Fas and other molecules to render tumor cells more susceptible to T-cell-mediated killing, and the first demonstration of the mechanism of such synergy employing a vaccine and external beam irradiation of tumor to enhance anti-tumor responses. These findings have now been translated to clinical studies. (b) The demonstration that multi-modal therapy (vaccine, external beam irradiation of tumor, and control of regulatory T cells) can be used to further enhance antigen-specific T-cell responses, antigen cascade, and anti-tumor activity. (c) The demonstration that certain chemotherapeutic agents, alone and in synergy with radiation, can alter the phenotype of human tumor cells rendering them more susceptible to antigen-specific T-cell-mediated lysis. (d) The demonstration for the first time of the mechanism by which anti-CTLA-4 monoclonal antibody (MAb) acts to enhance vaccine efficacy: by enhancing the avidity of antigen-specific T cells. These studies have led to clinical trials and have important implications in the analyses of immune responses in those trials. (e) The development of a vaccine model for human familial adenomatous polyposis (FAP) in which intestinal tumors of MIN (multiple intestinal neoplasia) mice express carcinoembryonic antigen (CEA) as a self-antigen, and the demonstration that CEA-TRICOM (TRIad of COstimulatory Molecules) vaccines can reduce tumor burden of these spontaneously arising intestinal tumors, and the demonstration that vaccine plus COX-2 inhibitor (Celebrex) can eliminate spontaneously arising colon tumors expressing CEA. These studies have led to discussions with the NCI Cancer Prevention Program for potential clinical trials for human FAP.
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