Improvements in the use of traditional breast cancer therapies have improved the overall survival of women with early stage disease. Remarkable advances in research have created a unique opportunity for developing active vaccination strategies that engage the bodys own immune system in the fight against breast cancer. Human Epidermal Growth Factor Receptor 2 (HER-2/neu) is a breast tumor antigen (Ag) commonly overexpressed in 30% of breast cancer cases. HER-2/neu-targeted DNA-based and fiber-modified dendritic cell (DC)-based vaccines are both analyzed as potent elements in eliciting HER-2/neu specific antitumor immune responses. A HER-2/neu-expressing DNA plasmid (pcDNA/neu) coadministered with the appropriate adjuvant vector was the first study looking at improving vaccine efficacy and enhancing immune responses. Various protection and prevention studies, using FVB/N (wild-type) and FVB/neuN [transgenic (Tg)] mice and Tg1-1 tumor cells, derived from a spontaneous tumor from Tg mice, are used to help narrow down the large panel of adjuvant vectors. Results showed the adjuvant vector pcDNA/TNF-α, when coadministered with pcDNA/neu, induced more efficient protective tumor-specific immunity and significantly delayed breast cancer development in Tg mice.<p>Another study utilized an<i>in vivo</i> murine tumor model expressing the rat neu Ag to compare the immunization efficacy between DC transduced with replication-deficient fiber-modified adenovirus (AdV) containing neu (AdV(RGD)neu), to form DC(RGD)neu, and non-modified DCneu. DC(RGD)neu displayed an upregulation of immunologically important molecules and inflammatory cytokine expression through FACS Analysis, and more importantly increased expression of neu, when compared to DCneu. DC(RGD)neu stimulated a higher percentage of HER-2/neu-specific CD8+ T cells, a stronger neu-specific CTL response, and induced a much stronger Th1- and Th2-type immune response than DCneu. Furthermore, vaccination with DC(RGD)neu induced enhanced protective tumor-specific immunity compared to DCneu in wild-type and Tg mice.<p>Overall the construction of recombinant vectors containing two transgenes (HER-2/neu and TNF-α), can not overcome the induction of HER-2/neu-directed immune tolerance. The fiber-modified (RGD) DCneu vaccine induced enhanced anti-HER-2/neu immunity compared to non-modified DCneu in the prevention of breast cancers.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:SSU.etd-03262007-161505 |
| Date | 27 March 2007 |
| Creators | Sas, Sheena Emm |
| Contributors | Xiang, Jim, Tabel, Henry, Saxena, Anurag, Sami, Amer, Qureshi, Mabood, Krahn, John |
| Publisher | University of Saskatchewan |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://library.usask.ca/theses/available/etd-03262007-161505/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Saskatchewan or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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