This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zeytin, H. E. Articles by Greiner, J. W. Search for Related Content PubMed PubMed Citation Articles by Zeytin, H. E. Articles by Greiner, J. W.

Combination of a Poxvirus-Based Vaccine with a Cyclooxygenase-2 Inhibitor (Celecoxib) Elicits Antitumor Immunity and Long-Term Survival in CEA.Tg/MIN Mice

¹ Laboratories of Tumor Immunology and Biology, and ² Biosystems and Cancer, Center for Cancer Research, and ³ Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, NIH, Bethesda, Maryland

The present study was designed to determine whether: (a) chronic administration of dietary celecoxib (Celebrex), a potent nonsteroidal anti-inflammatory drug, which targets the cyclooxygenase-2 (COX-2) enzyme, negatively impacts host immunity; and (b) celecoxib can be coupled with a poxvirus-based vaccine to impact tumor burden in a murine tumor model of spontaneous adenomatous polyposis coli. Naive mice fed the celecoxib-supplemented diets developed eosinophilia with lowered plasma prostaglandin E₂ levels and reduced COX-2 mRNA expression levels in their splenic T cells. Responses of splenic T, B, and natural killer cells to broad-based and antigen-specific stimuli were, for the most part, unchanged in those mice as well as COX-2 knockout mice; exceptions included: (a) reduced IFN- production by concanavalin A- or antigen-stimulated T cells; and (b) heightened lipopolysaccharide response of naive B cells from mice fed a diet supplemented with 1000 ppm of celecoxib. When transgenic mice that express the human carcinoembryonic antigen (CEA) gene (CEA transgenic) were bred with mice bearing a mutation in the Apc⁸⁵⁰ gene (multiple intestinal neoplasia mice), the progeny (CEA transgenic/multiple intestinal neoplasia) spontaneously develop multiple intestinal neoplasms that overexpress CEA and COX-2. Beginning at 30 days of age, the administration of a diversified prime/boost recombinant CEA-poxvirus-based vaccine regimen or celecoxib (1000 ppm)-supplemented diet reduced the number of intestinal neoplasms by 54% and 65%, respectively. Combining the CEA-based vaccine with the celecoxib-supplemented diet reduced tumor burden by 95% and significantly improved overall long-term survival. Both tumor reduction and improved overall survival were achieved without any evidence of autoimmunity directed at CEA-expressing or other normal tissues. Celecoxib is prescribed for the treatment of familial adenomatous polyposis in humans, and the CEA-based vaccines have been well tolerated and capable of eliciting anti-CEA host immune responses in early clinical studies. The results suggest that the administration of a recombinant poxvirus-based vaccine is compatible with celecoxib, and this combined chemoimmuno-based approach might lead to an additive therapeutic antitumor benefit not only in patients diagnosed with familial adenomatous polyposis but, perhaps, in other preventive settings in which COX-2 overexpression is associated with progression from premalignancy to neoplasia.

This article has been cited by other articles:

				J. Schlom, J. L. Gulley, and P. M. Arlen Paradigm Shifts in Cancer Vaccine Therapy Experimental Biology and Medicine, May 1, 2008; 233(5): 522 - 534. [Abstract] [Full Text] [PDF]

				C. J. Rogers, D. Berrigan, D. A. Zaharoff, K. W. Hance, A. C. Patel, S. N. Perkins, J. Schlom, J. W. Greiner, and S. D. Hursting Energy Restriction and Exercise Differentially Enhance Components of Systemic and Mucosal Immunity in Mice J. Nutr., January 1, 2008; 138(1): 115 - 122. [Abstract] [Full Text] [PDF]

				C Bauer, F Bauernfeind, A Sterzik, M Orban, M Schnurr, H A Lehr, S Endres, A Eigler, and M Dauer Dendritic cell-based vaccination combined with gemcitabine increases survival in a murine pancreatic carcinoma model Gut, September 1, 2007; 56(9): 1275 - 1282. [Abstract] [Full Text] [PDF]

				J. Schlom, P. M. Arlen, and J. L. Gulley Cancer Vaccines: Moving Beyond Current Paradigms Clin. Cancer Res., July 1, 2007; 13(13): 3776 - 3782. [Abstract] [Full Text] [PDF]

				A. R. Haas, J. Sun, A. Vachani, A. F. Wallace, M. Silverberg, V. Kapoor, and S. M. Albelda Cycloxygenase-2 Inhibition Augments the Efficacy of a Cancer Vaccine Clin. Cancer Res., January 1, 2006; 12(1): 214 - 222. [Abstract] [Full Text] [PDF]

				D. A. Laheru, D. M. Pardoll, and E. M. Jaffee Genes to vaccines for immunotherapy: how the molecular biology revolution has influenced cancer immunology Mol. Cancer Ther., November 1, 2005; 4(11): 1645 - 1652. [Abstract] [Full Text] [PDF]

				C. Schwegler, A. Dorn-Beineke, S. Nittka, C. Stocking, and M. Neumaier Monoclonal Anti-idiotype Antibody 6G6.C4 Fused to GM-CSF Is Capable of Breaking Tolerance to Carcinoembryonic Antigen (CEA) in CEA-Transgenic Mice Cancer Res., March 1, 2005; 65(5): 1925 - 1933. [Abstract] [Full Text] [PDF]

				A. C. Patel, N. P. Nunez, S. N. Perkins, J. C. Barrett, and S. D. Hursting Effects of Energy Balance on Cancer in Genetically Altered Mice J. Nutr., December 1, 2004; 134(12): 3394S - 3398S. [Abstract] [Full Text] [PDF]