) Traditional therapies, including surgery, radiation, and chemotherapy, have played a significant role in the treatment of breast cancer. However, it is unlikely that these modalities alone can be further optimized to cure the 44,000 women/year who currently fail these modalities. Immunotherapy is another modality that has recently shown promise for the treatment of breast cancer. In particular, the herceptin antibody that is specific for the HER-2/neu protein results in cancer regression in patients who are resistant to the other treatment modalities. Vaccines, a form of immunotherapy, have the advantage over other treatments in that they are specific, can amplify the response to meet the burden of existing cancer, and can induce immune memory for the cancer if it recurs. A few vaccines have already resulted in cancer remissions for patients with small disease burdens. However, it is unlikely that immunotherapy alone will cure a significant number of patients with advanced solid tumors. In this proposal, we will test the hypothesis that combining chemotherapy with vaccination can enhance the potency of HER-2/neu targeted vaccines. We will use HER-2/neu transgenic mice that naturally overexpress the HER-2/neu protein and spontaneously develop mammary tumors. We have characterized these mice and found that they demonstrate HER-2/neu specific peripheral tolerance similar to what is observed in patients with breast cancer. Using this clinically relevant model, we have generated preliminary data demonstrating synergistic interactions between certain chemotherapeutic agents and a HER-2/neu specific vaccine that induces immunity potent enough to overcome peripheral tolerance. Studies are proposed to: 1) Screen additional forms of the different treatment modalities for enhanced synergistic effects against our transplantable neu expressing tumor; 2) Dissect the mechanisms by which synergistic interactions occur for the purpose of identifying chemotherapy combinations that may enhance immunity through different mechanisms; 3) Test combinations of chemotherapy with vaccine for the treatment of transplantable tumors; 4) Test active vaccine/chemotherapy combinations for the eradication of spontaneously arising tumors; 5) Compare the most potent vaccine/chemotherapy combinations with vaccines and immune modulators identified to be potent in the other projects of this program. The final goal of this proposal is to use information gained from these studies to design a clinical study for the treatment of patients with metastatic breast cancer. The success of these studies may define a new and novel role for traditional chemotherapy.
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