Most tumor antigens (Ag) are also expressed by normal tissues and therefore induce immunological tolerance in the tumor-bearing host. Yet, these self proteins are major targets available for active specific immunotherapies. These therapies need to be developed in animal models that mimic the conditions in cancer patients. The human gastrointestinal carcinoma-associatedAg GA733 (EpCAM) has been a suitable target for passive and active immunotherapy of these tumors in cancer patients. Mice expressing the homologue of the human Ag, murine epithelial glycoprotein (mEGP), on normal and tumor tissues provide a relevant animal model of active specific immunotherapy against the GA733 Ag. Our major goal is to define vaccines that significantly and reproducibly inhibit growth of established mouse colon carcinoma cells in this tumor model system. Our major hypothesis is that mimics of mEGP, by virtue of being similar, but not identical to mEGP will effectively immunize mice and induce regression of established, mEGP-positive colon carcinomas. Specifically we will: 1) Test the hypothesis that mEGP mimics induce protective immunity against established, subcutaneous tumors and visceral metastasis. This involves: a) Generation and selection of mEGP mimics (anti-idiotypic antibodies [Ab2], Ab2 fragments, peptides or minigenes derived from the VH and VL regions of Ab2, peptides derived from synthetic libraries and mimicking the epitope recognized by anti-mEGP monoclonal antibody, and peptides and minigenes of mEGP CTL epitopes);and b) Evaluation of vaccines for their capacity to inhibit subcutaneous and visceral, metastatic growth of CT26-mEGP colon carcinoma cells in the therapeutic setting in mice. 2) Determine the mechanism of tumor growth inhibition by mEGP mimics. This involves: a) Evaluation of humoral immune responses (cytotoxic antibodies) and cellular immune responses (proliferative, cytotoxic and delayed-type hypersensitive lymphocytes in mice with regressing tumors after immunization with mEGP mimics;b) Determination of the direct role in tumor growth inhibition of antibodies, CD8+ or CD4+ T lymphocytes, memory lymphocytes, and epitope spreading. The proposed studies provide the basis for vaccinations of colorectal cancer patients against the GA733 Ag.
