Recently, different tumor associated antigens (TAAs) which are capable of being recognized by tumor infiltrating lymphocytes have been identified. The success of cancer therapies may depend on the induction of effective cellular immune responses against TAAs. A very promising approach to treat tumors involves the use of recombinant viral vectors expressing the desired TAAs, since most viruses are able to elicit strong and long-lasting immune responses against their expressed antigens. Earlier it was shown that transfectant influenza virus vectors could induce powerful cellular immune responses against the expressed antigens in mice, especially when they were administered in combination with recombinant vaccinia viruses expressing the same antigen. In this application, the antitumor immune responses elicited by transfectant influenza viruses expressing a model TAA will be analyzed in mice. Novel protocols of immunization, including the use of two different viral vectors to induce powerful antitumor cellular immune responses, will be studied. In addition, experiments focused on improving the safety of the transfectant influenza viruses have also been designed. The influence of cis-acting RNA sequences in the regulation of influenza virus gene expression, in viral pathogenicity, and immunogenicity will be determined. Stably attenuated transfectant influenza viruses expressing a model murine TAA will be engineered and their antitumor properties will be characterized. Finally, influenza virus vectors expressing human tumor associated antigens from melanoma tumors will be constructed for possible future use in humans. The ability of cells which have been infected with these viruses to be recognized by tumor infiltrating lymphocytes will be analyzed. The proposed research may advance the field of cancer therapy towards possible novel ways to treat human tumors and prolong survival of cancer patients.
| Garcia-Sastre, A (2001) Inhibition of interferon-mediated antiviral responses by influenza A viruses and other negative-strand RNA viruses. Virology 279:375-84 |
