The ectopic expression of tumor antigens in animals models has been shown in induce tumor-specific immunity and is an approach that may prove useful for human cancer treatment. We propose to study adenovirus-mediated expression of tumor antigens for inducing anti-tumor immunity in order to better understand the nature of this process and explore its potential for human use. Adenoviruses can be oncogenic in animals but they can also induce a strong immune response that is protective against tumors that express adenoviral antigens. This suggests that under the right conditions, ectopic antigens expressed by the virus could generate a potent cellular immune response that can destroy cells expressing those antigens. During infection, adenovirus vectors can achieve high levels of antigen expression and the host anti-viral response may play an """"""""adjuvant"""""""" role in stimulating an immune response tot he antigen by recruiting needed immune effector cells or by inducing production of immunostimulatory cytokines in the local environment. Much knowledge has been accumulated relating to the biology of adenoviral infections in the last 20 years. We will use that knowledge to systematically develop a vector to generate strong antitumor immunity. Specifically, we propose to: 1) Optimize several basic variables relating to dose, route and scheduling using a adenoviral vector that expresses either the human papilloma virus 16 E7 protein or the rat HER-2/neu protein. The vaccines will be tested against a challenge of increasing numbers of tumor cells that express the same proteins. The tumor models have been developed as part of Projects 1 and 2. The vaccine will also be tested in a therapeutic mode to see if it can cause regression of established tumors. If the vaccine is not maximally protective, we will determine if variation of the virus that affect viral replication and immunogenicity will improve the response against ectopic antigens. 2) Develop combinations of the virus that can deliver additional genes that can influence the immune response including B7.1 GM-CSF, IL-2 and IFNgamma. 3) Perform immunological studies to understand the mechanisms of adenovirally induced anti-tumor response. 4) Use that information to design better vaccine strategies that may combine components of all of the projects within this program.
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