RECOMBINANT VACCINES FOR ACTIVE SPECIFIC IMMUNOTHERAPY OF HUMAN CARCINOMA

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Certain tumor associated antigens (TAAs) represent potential targets for active specific immunotherapy. Human carcinoembryonic antigen (CEA) is a 180 Kd glycoprotein which is overexpressed in human colorectal, gastric, pancreatic, breast and non-small cell carcinomas. CEA is an oncofetal protein and is considered to be weakly immunogenic in humans. Humoral or cell mediated responses to CEA have not been well documented in normal or cancer patients. The copresentation of CEA with a strong immunogen such as vaccinia virus would represent a logical approach to inducing anti-CEA responses for tumor immunotherapy. We have constructed and characterized a recombinant vaccinia virus expressing human CEA and have used it as an immunogen to study its effect on tumor growth in mice bearing CEA- expressing tumors. Rodent tumors do not express CEA. In order to develop a model system for active anti-CEA therapies, we have transduced a mouse colon adenocarcinoma cell line, MC-38, with human CEA. These tumors grow in syngeneic C57BL/6 mice and will eventually kill the animal. We have used this tumor model to evaluate the efficacy of our recombinant vaccine to prevent tumor growth in mice and its ability to elicit cell mediated and humoral anti-CEA immune responses. Animals immunized with the recombinant vaccine were resistant to challenge with the syngeneic tumor cells expressing CEA. Moreover, when mice having a palpable CEA tumor burden were immunized with the recombinant vaccine tumor growth was greatly reduced or eliminated. The recombinant vaccine immunized animals developed anti-CEA antibody titers and demonstrated a strong DTH response to CEA-expressing tumor cells. T cells isolated from immunized mice responded specifically to soluble CEA and could also mediate lysis of the CEA-expressing tumor cell line. No toxicity was observed in these animals. Immunogenicity and safety of this recombinant vaccine was tested in non human primates. Animals immunized with the recombinant vaccine developed strong anti-CEA antibody responses and specific DTH responses. PBLs from immunized monkeys were found to proliferate in response to CEA stimulation. Blood counts and differentials and hepatic and renal chemistries remained normal in all animals throughout the study and for up to 1 year following the primary immunization.