Cancer Vaccines Targeting HER2/neu for Early Breast Cancer

Abstract

Recent studies of immune responses to pathogens have identified pathogen-associated molecular patterns 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 HER2/neu, which is often overexpressed in ductal carcinoma in situ (DCIS), may provide such a target. Immune responses directed against HER2/neu may eliminate the disease, make tumors more amenable to anti-estrogen therapy, or prevent escape of hormone-resistant tumor phenotypes. Effective breast cancer prevention in preclinical studies utilizing murine HER2/neu transgenic models has stimulated interest in, and optimism regarding, protective breast cancer vaccines in humans. Induction of anti-HER2/neu T cell (CD4+ and CD8+) and B cell responses has been demonstrated in an ongoing clinical study targeting HER2/neu using a TLR agonist-primed dendritic cell vaccine Moreover, these vaccinations lead to reductions in both HER2/neu expression and extent of DCIS HER2/neu expression and aromatase activity have recently been linked through the intermediary cyclooxygenase 2 (COX-2) This convergence between growth factor and hormone mediated pathways provides additional support for the notion that a significant number of breast cancers may be prevented through effective immune targeting of HER2/neu. As progress is made towards the development of vaccines for breast cancer prevention, the contributions of immune-mediated effecter and inhibitory mechanisms to the pathogenesis of HER2/neu overexpressing breast cancer will need to be better understood.