Abstract
The success of vaccines in the prevention of infections has resulted in immune targeting approaches being explored for the prevention and/or treatment of a variety of non-infectious diseases such as Alzheimer's disease, atherosclerosis, and even nicotine addiction. Vaccines developed for the treatment cancer have been in therapeutic human clinical trials for several years and are, at last, showing some success in randomized Phase III studies giving hope to their ultimate use in cancer prevention. To be effective, vaccines must arm the immune system to target and destroy the disease causing agent. In infections, the pathogen has been defined. In cancer, particularly breast cancer, the etiologic agent is generally unknown. Although the specific cause of a breast cancer may be multifactorial, there are a limited number of genetic alterations that will induce initiation and maintenance of the malignancy. If immunogenic, these proteins involved in breast cancer initiation could serve as vaccine candidates.
Recent evidence indicates that Type I immunity, associated with the production of IFN-gamma (g), is needed for cancer eradication. Type I immunity enhances cross priming at the site of cancer initiation by activating local antigen presenting cells (APC) to more efficiently present immunogenic proteins or tumor antigens to T cells. Cross priming is the primary method by which immunity is generated against cancer as tumor cells do not express the recognition molecules needed for immune activation. IFN-g is primarily secreted by CD4+ T-helper 1 cells (Th1). Vaccine strategies designed to elicit tumor antigen specific Th1 immunity have the potential to generate epitope spreading (a broadening of immunity to additional antigens), concurrently stimulate antigen specific cytotoxic (CTL) CD8+ T cells, and establish immunologic memory. Immunologic memory will ensure that the destructive immune response will deploy when the antigen is expressed in the future.
Development of vaccines for breast cancer prevention must focus both on the antigen used in vaccination as well as the method of immunization to ensure the appropriate immune response is generated. One approach is to target immunogenic proteins expressed in ductal carcinoma in situ or high risk hyperproliferative breast lesions. We developed a multi-antigen polyepitope vaccine targeting immunogenic proteins associated with pre-invasive breast cancer or hyperproliferative lesions and assessed whether we could prevent the development of breast cancer in middle aged TgMMTV-neu mice. The multi-antigen vaccine inhibited tumor growth in 50-80% of mice and was superior to individual antigen immunizations in protecting mice against breast cancer (p<0.05). Designed to elicit antigen specific CD4+ Th1 vaccine induced tumor protection was mediated by CD4+ T-cells. Studies were performed in mature mice and vaccine failure appeared to be secondary to subclinical disease present at the time of immunization. We combined antiproliferative agents with immunization to increase vaccine efficacy. Bexarotene, an RXR agonist, administered in combination with vaccination significantly enhanced disease free survival and was 50% more effective in inhibiting tumor development than vaccine alone. Combination chemo-immunoprophylaxis, may be an effective approach to breast cancer prevention even when administered in the presence of subclinical disease.
Citation Format: Mary L. (Nora) Disis. Vaccines to prevent breast cancer. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr CN01-01.
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