CpG oligonucleotides enhance the tumor antigen-specific immune response of an anti-idiotype antibody-based vaccine strategy in CEA transgenic mice

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

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)515-527
Number of pages13
JournalCancer Immunology, Immunotherapy
Volume55
Issue number5
DOIs
StatePublished - May 1 2006

Bibliographical note

Funding Information:
We would like to thank Dr. Jeffrey Schlom (NIH) for providing the MC-38 cell lines. We also thank Mary B. Palascak and Peter Ciraolo for flow cytometry and Audrey Morrison for typing the manuscript. This work was supported in part by NIH grants RO1 CA86025, RO1 CA91878, and RO1 CA104804.

Keywords

  • Anti-idiotype antibody
  • Cancer vaccine
  • Carcinoembryonic antigen
  • CpG ODN
  • Immunotherapy
  • Transgenic mice

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