Various vaccine strategies have been evaluated and combined in an attempt to amplify T-cell responses to induce or enhance anti-tumor immunity. One model tumor antigen, carcinoembryonic antigen (CEA), has been shown to be an effective tumor rejection antigen in preclinical animal studies. When tested in clinical trials, immunological and clinical responses to many vaccine strategies targeting CEA were less dramatic than observed in murine models, although one promising strategy recently evaluated in clinical trials has been recombinant fowlpox-modified dendritic cells (DC). In addition, enhanced immune responses appear to result when priming of immune responses with one particular vector is combined with boosting immune responses with a heterologous vector encoding the same target antigen. Therefore, we propose to construct and evaluate an alphavirus replicon particle vaccine expressing CEA, termed CEA-VRP, for potential use in combination vaccine strategies. In preliminary studies, we have inserted the CEA gene into a replicon vector and have shown that 1) CEA-VRP expresses CEA to high levels, 2) the CEA expression product is appropriately modified and transported within infected cells, 3) CEA VRP efficiently infect human DC in vitro (up to 70%), 4) apoptosis in VRP-infected DC is induced slowly suggesting DC migration and function would be adequately maintained, and 5) mice immunized with CEA-VRP rapidly develop anti-CEA antibody and T cell responses. The proposed preclinical studies in CEA-transgenic mice will evaluate the immune and anti-tumor responses induced by CEA-VRP, alone or in heterologous prime-boost protocols with a fowlpox vector expressing CEA, by either direct vector inoculation or by immunization with DC infected with the recombinant vector(s). We will then manufacture a CEA-VRP production lot to GMP standards, submit an IND, and perform a phase I clinical study in which patients with CEA over-expressing malignancies will receive active immunotherapy with CEA-VRP modified DC. This phase 1 study is designed to establish the safety and immunogenicity of this approach and enable future clinical trials with this novel vector in heterologous prime and boost vaccine strategies.
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