Several different vaccine strategies have been evaluated and combined in an attempt to amplify T-cell responses toward induction of anti-tumor immunity. The model tumor antigen used in many of these studies was carcinoembryonic antigen (CEA). While initial T-cell activation studies were conducted in conventional mice and then tested, results from the clinical trials suggested immune and clinical responses less dramatic than in the murine models. One strategy to improve the clinical outcome has been the use of recombinant viral vectors encoding CEA modified dendritic cells. Based upon several lines of observation, this strategy appears to be capable of further improvement when using a heterologous prime-boost vaccination strategy, using alternative means of introducing the tumor antigen. Therefore, we propose pre-clinical and clinical studies of combined vaccine strategy studies, in this instance capitalizing upon the known efficacy of fowlpox CEA virus based constructs, but now combining this expertise with use of adenovirus based vectors also encoding CEA. Exciting data from the HIV vaccine literature suggest that heterologous prime-boost vaccine strategies have significantly benefited from the utilization of first generation Ad based vectors, showing dramatically improved evidence of inducing immune critical T-cell responses in human subjects. Uniquely, our group has previously constructed several new generations of Ad vector that will allow us to investigate and optimize the use of Ad vectors as vaccines for a variety of antigens. Once the most optimized Ad encoding CEA is delineated, we will determine the efficacy of the vector alone, or in heterologous prime-boost vaccine strategies utilizing rigorous animal models. A key innovation will be our ability to synergize with the other projects and cores in this program project, for example we will evaluate the anti-tumor efficacy of heterologous prime-boost strategies utilizing the optimal Ad-CEA vector vaccine, combined with either the aforementioned fowlpox-CEA vector vaccine, or an alphavirus based CEA vector vaccine (the latter being developed in Project #2 of this overall proposal). These studies are intended to demonstrate that the use of heterologous prime-boost regimens (via the use of two different recombinant vectors) can further amplify T-cell responses toward tumor associated antigens such as CEA. Finally, we will initiate pre-clinical studies and a pilot project of active immunotherapy using the most optimized adenovirus+CEA vector based vaccine, a prelude to a combined pox/Ad or alphavirus/Ad heterologous prime-boost clinical trial.
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