DNA vaccines for metastatic breast cancer at old age

描述（由申请人提供）：乳腺癌是美国第二大癌症，2001年有193,700例新诊断病例。老年妇女的乳腺癌发病率和死亡率比年轻妇女高得多。由于人口趋势表明，今后几十年老年妇女的人数将大幅增加，因此需要针对老年患者优化乳腺癌预防和治疗战略。目前对乳腺癌的治疗包括手术切除或放疗后的辅助治疗或化疗。癌症疫苗的毒性比化疗或放疗小，因此对通常更容易虚弱的老年患者特别有用。然而，需要进行研究，以确定年龄特异性肿瘤免疫变量是否允许最佳地使用癌症疫苗来预防和治疗老年妇女的乳腺癌。这方面的一个主要挑战是预防或治疗转移；到目前为止，转移性乳腺癌不适合治疗。通过疫苗接种增强特异性辅助性和细胞毒性T淋巴细胞（CTL）对乳腺肿瘤的反应可能导致特异性消除微转移和/或残留肿瘤细胞。为了研究乳腺癌疫苗接种对老年患者的疗效，我们建议建立一种免疫功能小鼠乳腺癌转移模型，在该模型中可以研究不同年龄的肿瘤发生和进展。该模型的基础是将一种同源小鼠乳腺肿瘤细胞系注射到免疫能力强的小鼠体内，然后产生转移性乳腺癌，而不会产生免疫排斥反应。我们证明，注射这些细胞很容易在年轻和年老小鼠中诱导转移，表达人类MAGE-A和MAGE-B肿瘤特异性抗原的小鼠同源物。一种基于编码其中一种抗原的基因结构的DNA疫苗被制成，并证明在预防性免疫接种中可以大大减少转移的数量。本提案的长期目标是进一步优化该疫苗和其他疫苗在不同年龄的小鼠中的预防和治疗应用于人类老年乳腺癌患者。该提案的具体目标是：(1)改善DNA传递系统和蛋白质在体内的表达；(2)多抗原DNA疫苗的研制和试验；(3)测定青年和老年小鼠的肿瘤免疫参数。

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.