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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Subcommittee G - Education (NCI)
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Duke University
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Aldhamen, Y A; Seregin, S S; Kousa, Y A et al. (2013) Improved cytotoxic T-lymphocyte immune responses to a tumor antigen by vaccines co-expressing the SLAM-associated adaptor EAT-2. Cancer Gene Ther 20:564-75
Morse, Michael A; Niedzwiecki, Donna; Marshall, John L et al. (2013) A randomized phase II study of immunization with dendritic cells modified with poxvectors encoding CEA and MUC1 compared with the same poxvectors plus GM-CSF for resected metastatic colorectal cancer. Ann Surg 258:879-86
Osada, Takuya; Morse, Michael A; Hobeika, Amy et al. (2012) Novel recombinant alphaviral and adenoviral vectors for cancer immunotherapy. Semin Oncol 39:305-10
Seregin, Sergey S; Aldhamen, Yasser A; Rastall, David P W et al. (2012) Adenovirus-based vaccination against Clostridium difficile toxin A allows for rapid humoral immunity and complete protection from toxin A lethal challenge in mice. Vaccine 30:1492-501
Ren, Xiu-Rong; Wei, Junping; Lei, Gangjun et al. (2012) Polyclonal HER2-specific antibodies induced by vaccination mediate receptor internalization and degradation in tumor cells. Breast Cancer Res 14:R89
Seregin, Sergey S; Amalfitano, Andrea (2011) Gene therapy for lysosomal storage diseases: progress, challenges and future prospects. Curr Pharm Des 17:2558-74
Hartman, Zachary C; Wei, Junping; Glass, Oliver K et al. (2011) Increasing vaccine potency through exosome antigen targeting. Vaccine 29:9361-7
Schuldt, Nathaniel J; Aldhamen, Yasser A; Appledorn, Daniel M et al. (2011) Vaccine platforms combining circumsporozoite protein and potent immune modulators, rEA or EAT-2, paradoxically result in opposing immune responses. PLoS One 6:e24147
Seregin, Sergey S; Aldhamen, Yasser A; Appledorn, Daniel M et al. (2011) TRIF is a critical negative regulator of TLR agonist mediated activation of dendritic cells in vivo. PLoS One 6:e22064
Osada, Takuya; Chen, Minyong; Yang, Xiao Yi et al. (2011) Antihelminth compound niclosamide downregulates Wnt signaling and elicits antitumor responses in tumors with activating APC mutations. Cancer Res 71:4172-82

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