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 E(2) 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-gamma 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 Apc(Delta850) 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.