CpG oligonucleotides enhance the tumor antigen-specific immune response of an anti-idiotype antibody-based vaccine strategy in CEA transgenic mice |
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Authors: | Asim Saha Rathindra Nath Baral Sunil K Chatterjee Kartik Mohanty Smarajit Pal Kenneth A Foon F James Primus Arthur M Krieg George J Weiner Malaya Bhattacharya-Chatterjee |
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Institution: | (1) Department of Internal Medicine and the Barrett Cancer Center, University of Cincinnati, Cincinnati, OH, USA;(2) Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA;(3) Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA;(4) Coley Pharmaceutical Group, Wellesley, MA, USA;(5) Department of Internal Medicine, University of Iowa, Iowa City, IA, USA;(6) The Vontz Center for Molecular Studies, University of Cincinnati, Room 1316, 3125 Eden Avenue, Cincinnati, OH 45267-0509, USA |
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Abstract: | A murine monoclonal anti-idiotype (Id) antibody, 3H1 has been developed and characterized previously. Anti-Id 3H1 mimics a specific epitope of carcinoembryonic antigen (CEA) and can be used as a surrogate antigen for CEA. 3H1 induced anti-CEA immunity in different species of animals as well as humans and showed promise as a potential vaccine candidate in phase I/II clinical trials for colon cancer patients. One area of interest to us has been the development of new immune adjuvants that may augment the potency of 3H1 as a tumor vaccine. Oligodeoxynucleotides containing unmethylated CpG motifs (CpG ODN) are potent immunostimulatory agents capable of enhancing the Ag-specific Th1 response when used as immune adjuvants. In this study, we have evaluated the efficacy of 3H1 as a tumor vaccine when admixed with a select CpG ODN 1826 in transgenic mice that express human CEA. The vaccine potential of 3H1 was also assessed in the presence of another widely used adjuvant, QS-21. 3H1 coupled to keyhole limpet hemocyanin (KLH) and mixed with Freund’s adjuvant (FA) was used as a gold standard in this system. 3H1 vaccination with different adjuvants induced both humoral and cellular anti-3H1, as well as anti-CEA immunity in CEA transgenic mice. The immune sera could lyse CEA-transfected murine colon carcinoma cells, C15 effectively in an antibody-dependent cellular cytotoxicity assay. The anti-CEA antibody responses were somewhat comparable in each adjuvant-treated group of mice, whereas cellular immune responses were significantly greater when CpG was used as an adjuvant. Splenocytes obtained from 3H1–CpG-immunized mice showed an increased proliferative CD4+ Th1-type T-cell response when stimulated in vitro with 3H1 or CEA and secreted elevated levels of Th1 cytokines (IL-2, IFN-γ). This vaccine also induced MHC class I antigen-restricted CD8+ T-cell responses. In a solid tumor model, C15 tumor growth was significantly inhibited by 3H1 vaccinations. In 3H1–CpG-vaccinated mice, the duration of survival was, however, longer compared to the 3H1–QS21-vaccinated mice. These findings suggest that 3H1-CpG vaccinations can break peripheral tolerance to CEA and induce protective antitumor immunity in this murine model transgenic for human CEA. |
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Keywords: | Anti-idiotype antibody Cancer vaccine Carcinoembryonic antigen Transgenic mice CpG ODN Immunotherapy |
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