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Therapy of Established Tumors in a Novel Murine Model Transgenic for Human Carcinoembryonic Antigen and HLA-A2 with a Combination of Anti-idiotype Vaccine and CTL Peptides of Carcinoembryonic Antigen

¹ Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio; ² University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and ³ H. Lee Moffitt Cancer Center, University of South Florida, Tampa, Florida

Requests for reprints: Malaya Bhattacharya-Chatterjee, The Vontz Center for Molecular Studies, University of Cincinnati, 3125 Eden Avenue, Cincinnati, OH 45267-0509. Phone: 513-558-0425; Fax: 513-558-1096; E-mail: malaya.chatterjee{at}uc.edu.

Induction of potent and sustained antitumor immunity depends on the efficient activation of CD8⁺ and CD4⁺ T cells. Immunization using dendritic cells loaded with tumor antigens constitute a powerful platform for stimulating cellular immunity. Our previous studies suggested that vaccination with an anti-idiotype antibody 3H1, which mimics a specific epitope of carcinoembryonic antigen (CEA), has the potential to break immune tolerance to CEA and induce anti-CEA antibody as well as CEA-specific CD4⁺ T-helper responses in colon cancer patients as well as in mice transgenic for human CEA. Here, we have combined the anti-idiotype 3H1 with the CTL peptides of CEA to augment both T-helper and CTL responses in a clinically relevant mouse model, which is transgenic for both CEA and HLA-A2. We have evaluated the potential of two different HLA-A2–restricted epitopes of CEA pulsed into dendritic cells in a therapeutic setting. The overall immune responses and survival were enhanced in groups of mice immunized with agonist peptide for CEA₆₉₁ (YMIGMLVGV)–pulsed dendritic cells or CAP1-6D (YLSGADLNL, agonist peptide for CAP-1)–pulsed dendritic cells. Mice immunized with peptide-pulsed dendritic cells along with 3H1-pulsed dendritic cells resulted in significant increase in survival compared with mice immunized with peptide-pulsed dendritic cells alone (P < 0.02). IFN- ELISPOT and ⁵¹Cr-release assays showed that HLA-A2–restricted, CEA-specific CTL responses were augmented by combined dendritic cell vaccinations. The combined vaccination strategy resulted in increased antigen-specific proliferation of splenocytes and secretion of Th1 cytokines by CD4⁺ T cells that correlated with increased survival. These results suggest the potential use of this vaccination strategy for future clinical applications. [Cancer Res 2007;67(6):2881–92]

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