Abstract SY24-03: Vaccines for the prevention of cancer

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Abstract Active immunization against infectious disease pathogens has been one of the most successful primary disease prevention modalities to impact human health. In developed countries, common childhood infections such as polio and diphtheria have been nearly eradicated due to standardized childhood vaccination regimens. Stimulating an effective immune response via antigen-targeted immunization will result in the development of immunologic memory allowing neutralizing antibodies or cytotoxic T cells to become mobilized when exposed to the pathogen at a later date. The development of effective vaccines against viruses that are associated with cancer initiation, such hepatitis B/hepatoma and human papilloma virus/cervical cancer, have resulted in a decrease in the incidence of these malignancies. For the majority of common human cancers, however, there are few infectious pathogens identified as direct etiologic agents instrumental in the induction of malignancy. Tumor-associated proteins that can serve as immunologic targets for active immunization have been identified. The majority of identified tumor antigens are not mutated, but rather, are self proteins. Over the last decade a variety of vaccination strategies have been developed to allow the generation of immunity to these cancer-related proteins and vaccines targeting such antigens have been used for the treatment of a wide variety of human malignancy. Although the clinical success of cancer vaccines has been variable, several observations can be made: (1) functional tumor-specific T cell and antibody immunity can be generated after vaccination in patients with cancer targeting such ubiquitous antigens as hTERT, HER-2/neu, and EGFR, (2) in clinical trials that have enrolled hundreds of patients, immunization against nonmutated self tumor antigens has not resulted in excessive toxicity. Indeed, in most reported studies of vaccination with antigen and standard adjuvants, toxicity is limited to grade 1 and 2 events, and (3) vaccines are most likely to be clinically effective when administered in a minimal disease state. The safety profile of cancer vaccines in the therapeutic setting has allowed the exploration of multiantigen immunization for cancer prevention. Mice that have been genetically engineered to develop specific malignancies offer a model to evaluate cancer prevention approaches, in particular active immunization. Investigations have shown that such murine models often have similar genetic alterations and histology as the human malignancy being modeled. Moreover, the antigenic repertoire in mice is similar to that observed in humans as well. We have developed a multiantigen polyepitope vaccine targeting immunogenic proteins associated with oncogenesis and assessed whether we could prevent the development of breast cancer in middle-aged TgMMTV-neu mice. The multiantigen 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). Studies demonstrated that vaccine induced tumor protection was mediated by T cells and even vaccinated mice that were unprotected by immunization and eventually developed tumors demonstrated evidence of high levels of type I immunity, evidence of T cells with potent antitumor activity, and tumor trafficking CD8+ T cells. To determine the cause of vaccine failure, we evaluated the mammary tissue of 18 week old animals at the time of immunization which revealed a significant incidence of subclinical breast tumors, both premalignant and malignant. The addition of bexarotene, a retinoid X receptor (RXR) agonist, to multiantigen vaccination significantly increased the proportion of protected animals and was superior to both bexarotene and vaccine alone in inhibiting the development of breast cancer (p<0.01). There was no evidence of autoimmune toxicity in immunized mice. These data suggest breast cancer vaccines targeting biologically relevant proteins may be an effective approach to the prevention of breast cancer even when administered in the presence of subclinical disease if combined with an antiproliferative agent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY24-03. doi:10.1158/1538-7445.AM2011-SY24-03