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年诊断出193，700例新病例。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，在未来几十年中，老年妇女的数量将大幅增加，因此需要针对老年患者优化乳腺癌预防和治疗策略。目前乳腺癌的治疗包括手术切除或放射治疗，然后进行辅助治疗或化疗。癌症疫苗比化疗或放疗毒性小，因此对老年患者特别有用，因为他们通常更容易虚弱。然而，需要研究来确定年龄特异性肿瘤免疫学变量是否允许最佳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转移的预防或治疗;迄今为止，转移性乳腺癌不适合治疗。通过疫苗接种增强对乳腺肿瘤的特异性辅助和细胞毒性T淋巴细胞（CTL）应答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在老年患者中的有效性，建议使用乳腺癌转移的免疫耐受小鼠模型，其中可以在不同年龄研究肿瘤的发生和进展。该模型是基于将同基因小鼠乳腺肿瘤细胞系注射到免疫活性小鼠中，然后在没有免疫排斥的情况下产生转移性乳腺癌。我们证明，注射这种细胞容易诱导转移的年轻和年老的小鼠，表达人类MAGE-A和MAGE-B肿瘤特异性抗原的小鼠同源物。基于编码这些抗原之一的基因构建体的DNA疫苗被制备并证明在预防性免疫中大大减少了转移的数量。该提案的长期目标是进一步优化这种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递送系统和体内蛋白表达;（2）开发和测试多抗原DNA疫苗;（3）测试年轻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.