Multimodality Therapy for Metastatic Breast Cancer

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DESCRIPTION (provided by applicant): Breast cancer is the most common malignancy in women in the Untied States and the number two cause of death from cancer in this group. While there has been significant improvement in the diagnosis of breast cancer, and as a result treatment of early stage disease, metastatic breast cancer cannot be cured by current therapies. The most optimistic new therapy for the treatment of metastatic breast cancer is the combination of chemotherapy with the biological response modifier trastuzumab. This approach has increased the survival time after the diagnosis of metastatic breast cancer but has not resulted in a significant increase in the complete response rate for patients. Our group has pioneered the use of dendritic cell vaccines using epitopes from the protein HER-2/neu in the treatment of women with metastatic breast cancer. While HER-2/neu is overexpressed in only 25% of tumors from patients, tumors that overexpress HER-2/neu have a poorer prognosis, thus these tumors are more commonly found in patients with metastatic disease. Our initial vaccine trial demonstrated that peptide-pulsed DCs can be generated successfully in patients-with metastatic breast cancer and that infusion of these cells did not result in greater than grade II toxicity in any patient treated. However, treatment with the vaccine alone induced clinical responses only in patients with minimal disease and this response did not persist after completion of therapy. Thus, vaccine therapy alone was not sufficient for induction of clinical responses in patients with bulk tumor. In the current clinical trial, we have attempted to remedy many of the problems associated with our initial vaccine therapy. Using animals that are transgenic for HER-2/neu and as a consequence tolerant to tumors expressing this protein, we have found that a multi-epitope DC vaccine given with trastuzumab and vinorelbine resulted in complete regression of all tumors in A2Kb x Neu transgenic mice. This was a markedly improved response compared to the use of vinorelbine, anti-Neu mAb or DC vaccination alone. As a result of these data, we have generated a phase II clinical trial in which women with metastatic breast cancer receive vinorelbine weekly for two treatments combined with trastuzumab and a DC vaccine using two epitopes from HER-2/neu that induced the most robust CD8+ T cell response in A2Kb x Neu mice. We will evaluate the toxicity and efficacy of this treatment in women with metastatic breast cancer who express HLA-A0201. Finally, we will assess the ability of this strategy to induce antigen-specific T cells in the blood after vaccination. The long-term goals of this work are to evaluate safe and effective therapies that induce a complete remission for the treatment of women with metastatic breast cancer.