DNA vaccines for metastatic breast cancer at old age

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DESCRIPTION(provided by applicant): Breast cancer is the second leading cancer in the United States with 193,700 new cases diagnosed in 2001. Elderly women have much higher breast cancer incidence and mortality rates than young women. Since demographic trends indicate that over the next decades the number of elderly women will increase substantially, strategies for breast cancer prevention and therapy need to be optimized to older patients. Current treatment for breast cancer involves surgical resection or radiation followed by adjuvant treatment or chemotherapy. Cancer vaccines are less toxic than chemotherapy or radiation and could, therefore, be especially useful for elderly patients, who are generally more subject to frailty. However, research is needed to establish whether age-specific tumor immunological variables permit optimal use of cancer vaccines for prevention and therapy of breast cancer in elderly women. A major challenge in this respect is the prevention or therapy of metastases; thus far, metastatic breast cancer is not amenable to therapy. Enhancement of specific helper and cytotoxic T lymphocyte (CTL) responses to breast tumors through vaccination could potentially lead to specific elimination of micro-metastases and/or residual tumor cells. To investigate the efficacy of breast cancer vaccination in elderly patients, it is proposed to use an immunecompetent mouse model for breast cancer metastasis in which tumor development and progression can be studied at different ages. The model is based on the injection of a syngeneic mouse mammary tumor cell line into immune competent mice, which then give rise to metastatic breast cancer without immunological rejection. We demonstrated that injection of such cells readily induce metastases in young and old mice, expressing the mouse homologs of the human MAGE-A and MAGE-B tumor-specific antigens. A DNA vaccine, based on a gene construct encoding one of these antigens, was made and demonstrated to greatly reduce the number of metastases in preventive immunizations. The long-term objective of this proposal is to further optimize this and other vaccines in mice of different ages for preventive and therapeutic applications in human elderly breast cancer patients. The specific aims of this proposal are (1) Improvement of DNA delivery systems and protein expression in vivo; (2) Development and testing of multiantigen DNA vaccines; and (3) Testing tumor-immunological parameters in young and old mice.