DESIGN OF LIVE RECOMBINANT VACCINES FOR ACTIVE SPECIFIC IMMUNOTHERAPY

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Ongoing studies involve the construction and preclinical evaluation of the safety and immunogenicity of recombinant pox viruses expressing human tumor associated antigens. These include carcinoembryonic antigen (CEA), prostate specific antigen (PSA), and the human breast cancer antigen, MUC1. We demonstrated that CEA could be used as a target for active specific immunotherapy. Immunization of mice with a recombinant vaccinia virus expressing CEA (rV-CEA) was able to elicit antitumor activity. Recombinant vaccinia viruses expressing PSA and MUC1 were also found to be safe vaccines and to elicit the appropriate anti-tumor responses. Rhesus monkeys immunized with rV-PSA were able to elicit PSA- specific humoral as well as cell-mediated immune responses. Various costimulatory signals delivered through T-cell surface molecules are required for the activation of naive T-cells by antigen-bearing target cells. The expression of the B7 gene family as well as other costimulatory molecules, such as CD70, LFA3 and ICAM-1, have been shown to be an important component for the induction and maintenance of antitumor responses in experimental models. We have constructed and evaluated the ability of recombinant vaccinia viruses expressing B7-1, B7-2, CD70, LFA3 and ICAM-1 to deliver costimulatory molecules at the site of antigen presentation and enhance cell mediated anti-tumor responses. Tumor cells infected with rV-B7-1 and B7-2 and ICAM-1 resulted in no tumor growth in the animals, while tumor cells infected with wild type vaccinia virus led to tumor growth and the death of the host. These studies demonstrated the utility and ease of using recombinant vaccinia viruses to deliver costimulatory molecules to tumor cells for potential gene therapy and recombinant approaches to cancer immunotherapy. We have also demonstrated the utility of admixing these recombinant costimulatory vaccinia viruses with rV-CEA and rV-MUC1 to enhance tumor associated antigen-specific T-cell responses and antitumor immunity in murine tumor models. Improvement of T-cell immunogenicity and specificity of tumor associated antigen vaccines has been accomplished by constructing recombinant vaccinia viruses containing minimal determinants of an immunodominant epitope of tumor associated antigens. Second generation vaccines expressing tumor associated antigens are being developed using nonreplicating pox viruses such as avipox, fowl pox and MVA (Modified Vaccinia Ankara).