Working Towards the Development of Vaccines for the Treatment and Prevention of Early Breast Cancer

Robert   E.   Roses; Min      Xu; Shuwen      Xu; Ursula      Koldovsky; Gilsoo      Son; Gary   K.   Koski; Brian   J.   Czerniecki

Abstract

Recent studies of immune responses to pathogens have identified pathogen-associated molecular patterns (PAMPs) recognized by the innate immune system through specialized receptors called toll-like receptors (TLRs). Signaling through these receptors initiates robust immune responses. By exploiting TLR signaling pathways, immunity to tumor- associated antigens may be generated. Many tumor-associated antigens are involved in the regulation of tumor phenotype or carcinogenesis. Immune targeting of these antigens may either alter the tumor phenotype, yielding a more treatable tumor, or eradicate early tumor stem cells preventing tumor formation. The oncoprotein HER-2/neu, which is overexpressed in a significant number of pre-malignant breast lesions of ductal carcinoma in situ (DCIS), may provide such a target. Immune responses directed against HER-2/neu may eliminate the disease, make tumors more amenable to antiestrogen therapy, or prevent escape of hormone-resistant tumor phenotypes. Effective breast cancer prevention in preclinical studies utilizing HER-2/neu transgenic murine models has stimulated interest in, and optimism regarding, protective breast cancer vaccines in humans. Induction of anti-HER-2/neu T cell (CD4+ and CD8+) and B cell responses has been demonstrated in an ongoing clinical study targeting HER-2/neu using a TLR agonist stimulated dendritic cell (DC) vaccine. Moreover, these vaccinations lead to reductions in both HER-2/neu expression and extent of DCIS. HER-2/neu expression and aromatase activity have recently been linked through the intermediary cyclooxygenase 2 (COX2). This convergence between growth factor and hormone mediated pathways reinforces the notion that a significant number of breast cancers may be prevented through effective immune targeting of HER-2/neu. As progress is made in the development of vaccines for breast cancer prevention, the contributions of immune-mediated effector and inhibitory mechanisms to the pathogenesis of HER-2/neu over-expressing breast cancers will need to be better understood.

Keywords: EGFR family, ductal carcinoma in situ, Trastuzumab, Tumor Antigen, Regulatory T Cells

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