Abstract
Abstract To be effective, vaccines must arm the immune system to target and destroy disease causing agents. In infection, the pathogen has been defined. In cancer, the etiologic agent is generally unknown. Although the specific cause of a cancer may be multifactorial, there are a limited number of genetic alterations that will induce initiation and maintenance of the malignancy. Proteins expressed during the malignant transformation would be excellent targets for a preventative vaccine could they be identified. We have shown overexpression of cancer associated proteins is a potential mechanism by which they become immunogenic. Arming the immune system to eliminate cells that had up regulated proteins related to cancer initiation could protect against the development of invasive malignancy. 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. Our group has been evaluating a variety of methods to identify antigens associated with high risk or pre-invasive lesions in a variety of cancers. Effective strategies which have yielded numerous candidates include genomic screening of lesions as well as mining the pre-diagnostic antibody repertoire of transgenic animals whose tumors have been shown to have significant genetic similarity to human invasive cancers. Moreover, we have developed a strategy to construct selective Th1-inducing vaccines which requires the elimination of Th2 inducing epitopes that are found in abundance in the natural sequences of self-proteins. Transgenic animals developing cancer provide a stringent model for testing and immune evaluation of multi-antigen vaccines for cancer prevention. Animals are genetically engineered to develop cancer, so prevention in this setting is a challenge. Experiments have shown superior clinical efficacy of multi-antigen vaccines for cancer prevention in transgenic models of breast cancer and intestinal adenomas compared to single antigen approaches. Citation Format: Mary L. (Nora) Disis, Juan Pablo Marquez, Sasha E. Stanton. Multi-antigen vaccines for cancer prevention. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr CN04-01.
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