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DNA Vaccines Against Breast Cancer: Synergy Through Targeting Both Tumor Cells and Tumor Stroma
HER2/neu is amplified and over expressed in many human tumors of epithelial origin, especially in adenocarcinomas of the breast and ovary. In breast cancers, HER2/neu amplification correlates with aggressive disease and is often a predictor of poor prognosis. We and others have shown that vaccination against HER2/neu generates a partially protective, predominantly antibody-mediated response. In order to improve upon this anti-tumor immunity, we sought to target, together with the HER2/neu tumor antigen, the tumor vasculature. Growth of solid tumors and their ability to metastasize requires, in fact, the presence of an independent blood supply. However, normal cells present in surrounding stroma are also critical. Therefore, antigens expressed in neovasculature and/or stromal tissues are attractive targets for immunotherapy. Tumor endothelial markers (TEMs) are a recently discovered family of endothelial markers associated with tumor specific angiogenesis. TEM8 was originally identified in human colorectal tumor, and its expression was reported to be restricted to tumor vasculature. Among all TEMs, TEM8 appears to be one of the most promising since its mRNA is not detected in wound-healing and corpus luteum tissue. We propose to combine HER2/neu and TEM8 vaccines in a mouse model of breast cancer. Our preliminary data already indicate that combining those two vaccines is significantly more effective in preventing growth of mammary tumors than either of the two therapies alone. Our main goal is to understand the mechanism of this synergy and to determine which of the immune system components play a major role in this anti-tumor immunity. We will determine whether TEM8 immunity is dependent on effector T cells by depleting immunized animals of CD8 or CD4 T cells. Furthermore, we will also characterize and quantify tumor infiltrating lymphocytes, monocytes and macrophages. An important extension of this proposal will be to generate an optimized TEM8-based vaccine. Specific mutations will be inserted in the TEM8 vaccine, in order to produce high-avidity peptides for MHC-I molecules. Our ultimate goal is to develop a clinical-grade vaccine against breast cancer: therefore we will elucidate the expression pattern of TEM8 protein in normal human breast and cancer tissue. All the information gained from these studies will directly impact the design of a more effective therapy for HER2/neu positive breast cancer and will be relevant to our efforts to translate the novel TEM8 vaccine into clinical trials.
HER2/neu is a membrane receptor belonging to the epidermal growth factor receptor family. It plays an important role in regulating cell growth and differentiation. During oncogenic transformation the number of gene copies per cell is increased, leading to a 10- to 100-fold increase in the number of HER2 receptors and to uncontrolled cell growth. The HER2/neu proto-oncogene is overexpressed in 25%-30% of human breast cancers and this overexpression is associated with a more aggressive form of the disease. Herceptin is an approved monoclonal antibody for the treatment of HER2/neu+ metastatic breast cancer. Clinical trials have shown that Herceptin administered either in combination with chemotherapy or alone may noticeably reduce tumor size and increase median time to disease progression. Those are the reasons why HER2/neu is considered a very attractive target for breast cancer immunotherapy. In our laboratory a DNA vaccine against HER2/neu has been tested and showed both a specific antibody response and partial protection in a mouse model of breast cancer. In order to improve the efficacy of our HER2/neu DNA vaccine we sought to target at the same time the tumor blood supply. All solid tumors require formation of new blood vessels to grow and metastasize. Therefore, treatments that inhibit tumor neovasculature can kill cancer cells and shrink tumors. In this proposal, we will target a molecularly defined marker, called TEM8 (Tumor Endothelial Marker 8) which is expressed in tumor vasculature and stroma, and combine TEM8 DNA with our established HER2/neu vaccine. Our preliminary data already indicate that combining those two strategies is significantly more effective in preventing growth of mammary tumors than either of the two therapies alone. The main goal of this proposal will be to understand the mechanism behind the observed synergy. Furthermore we will design and test a new generation of DNA-based vaccines. In this approach, we use computers to design vaccines that contain specific mutations selected to increase their effectiveness. Preliminary studies in our laboratory showed that this approach improves a number of our standard vaccines and increases tumor rejection. In addition, since our ultimate goal is the generation of a therapy that can be used to treat breast cancer patients, we also want to study the expression of TEM8 protein in normal human breast and cancer tissue. The results obtained will be relevant for the design of an effective therapy against breast cancer and will be important to translate the novel TEM8 vaccine into clinical trials.