Immune-based approaches to breast cancer susceptibility and treatment

Breast cancer is one of the leading causes of cancer deaths for women in the United States. Women who inherit a mutated form of the BRCA2 gene have a very high probability of developing breast cancer. Very little is known to date about the protein product of this gene or its normal biological function. We have developed immunological reagents against the BRCA2 protein in order to study some of these questions. Using these reagents, we have shown that this protein is expressed at high levels in several epithelial tissues, suggesting a potential role for BRCA2 in processes of cellular differentiation. Further elucidation of the role BRCA2 plays in normal breast biology may help us to understand why tumorigenesis occurs in hereditary cases, as well as non-inherited breast cancer.;Prevention of metastatic breast cancer is limited to early detection and surgical resection of a localized tumor. Treatment for advanced stages of breast cancer is often unsuccessful due to micrometastasis of the tumor prior to therapy. Thus, new methods to treat and prevent metastatic breast cancer are sorely needed. Immunotherapy, which utilizes the specificity of the immune system to target the destruction of tumor cells, is a very promising form of therapy. Immunotherapeutic approaches are much more specific for cancer cells, and therefore less toxic than conventional therapeutic approaches. In addition, once we have developed a better understanding of how to manipulate the immune system, immunotherapy will potentially be a much more effective approach to cancer treatment, and the use of immune-based "cancer vaccines" may even be used preventatively.;EGFRvIII, a variant form of the epidermal growth factor receptor, is found in a large percentage of breast tumors and thus may be a viable target for immunotherapy. I have developed a bispecific antibody against both EGFRvIII and the CD3-epsilon T-cell activation antigen to redirect the cytotoxic response of T-cells with a broad range of specificities against breast cancer cells that express EGFRvIII. In addition, I have developed an EGFRvIII-transducing adenovirus which will be useful in active immunotherapeutic protocols targeting the EGFRvIII tumor antigen.