Studies are ongoing to better define the role of exogenous cytokines in vaccine design and development. For these and other ongoing studies, several transgenic (Tg) mouse strains have been developed for vaccine therapy tumor models. These include Tg mice that express either CEA or MUC-1 as self-antigens at sites similar to those expressed in humans, and two Tg mouse strains that develop spontaneous tumors. Double Tg mouse strains have recently been developed in which spontaneous tumors arise that express either CEA or MUC-1 as self-antigen and in tumor tissue. Preclinical and clinical studies have now demonstrated the role of GM-CSF in vaccine therapy by recruitment of dendritic cells. Recombinant avipox viruses have now been developed that express GM-CSF as a transgene. When administered as a single injection, these vectors have recently been shown to enhance both the percentage and absolute number of APC (including dendritic cells) in the regional lymph nodes that drain the injection site. Both the magnitude and duration of this response was shown to be far greater than that achieved with the administration of four daily injections of recombinant GM-CSF protein. Recent studies have shown that the co-administration of recombinant avipox virus expressing CEA with recombinant avipox virus expressing GM-CSF significantly enhanced CEA-specific immunity, with an accompanying immunotherapeutic response in tumor-bearing CEA Tg mice. Studies are ongoing to use the new transgenic tumor models to better define novel vaccine strategies. Studies were 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. 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.
| Yang, Sixun; Tsang, Kwong-Yok; Schlom, Jeffrey (2005) Induction of higher-avidity human CTLs by vector-mediated enhanced costimulation of antigen-presenting cells. Clin Cancer Res 11:5603-15 |
| Reali, E; Canter, D; Zeytin, H et al. (2005) Comparative studies of Avipox-GM-CSF versus recombinant GM-CSF protein as immune adjuvants with different vaccine platforms. Vaccine 23:2909-21 |
| Hodge, James W; Chakraborty, Mala; Kudo-Saito, Chie et al. (2005) Multiple costimulatory modalities enhance CTL avidity. J Immunol 174:5994-6004 |
| Zeytin, Hasan E; Patel, Arti C; Rogers, Connie J et al. (2004) Combination of a poxvirus-based vaccine with a cyclooxygenase-2 inhibitor (celecoxib) elicits antitumor immunity and long-term survival in CEA.Tg/MIN mice. Cancer Res 64:3668-78 |
| Palena, Claudia; Arlen, Philip; Zeytin, Hasan et al. (2003) Enhanced expression of lymphotactin by CD8+ T cells is selectively induced by enhancer agonist peptides of tumor-associated antigens. Cytokine 24:128-42 |
