DNA vaccines for metastatic breast cancer at old age

用于治疗老年转移性乳腺癌的 DNA 疫苗

• 批准号: 7094077
• 负责人: CLAUDIA GRAVEKAMP
• 金额: $ 26.8万
• 依托单位: CALIFORNIA PACIFIC MED CTR RES INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7094077
• 关键词: T lymphocyte; aging; breast neoplasms; cancer prevention; complementary DNA; enzyme linked immunosorbent assay; flow cytometry; immune response; immunocytochemistry; laboratory mouse; metastasis; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; tumor antigens; vector vaccine

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.

描述（由申请人提供）：乳腺癌是2001年诊断出的193,700例新病例的第二个主要癌症。老年妇女的乳腺癌发病率和死亡率比年轻女性高得多。由于人口趋势表明，在接下来的几十年中，老年妇女的数量将大大增加，因此需要对老年患者进行优化的乳腺癌预防和治疗策略。当前对乳腺癌的治疗涉及手术切除或辐射，然后进行辅助治疗或化学疗法。癌症疫苗的毒性比化学疗法或放射线较小，因此，对于通常更容易受到脆弱的老年患者而言，可能特别有用。但是，需要进行研究来确定年龄特异性的肿瘤免疫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。在这方面，主要的挑战是预防或治疗转移。到目前为止，转移性乳腺癌不接受治疗。通过疫苗接种对乳腺肿瘤的特定辅助和细胞毒性T淋巴细胞（CTL）的增强可能导致特异性消除微型 - 近代酶和/或残留的肿瘤细胞。为了研究乳腺癌疫苗接种在老年患者中的疗效，建议使用免疫能力的小鼠模型进行乳腺癌转移，其中可以在不同年龄研究肿瘤的发育和进展。该模型基于将合成小鼠乳腺肿瘤细胞系注射到免疫胜任的小鼠中，然后导致转移性乳腺癌而不会免疫排斥。我们证明，这种细胞的注射很容易诱导年轻小鼠和老鼠的转移，表达了人Mage-A和Mage-B肿瘤特异性抗原的小鼠同源物。制作并证明了基于编码这些抗原之一的基因构建体的DNA疫苗，可大大减少预防免疫中的转移次数。该提案的长期目标是进一步优化不同年龄小鼠的这种和其他疫苗，以在人类老年乳腺癌患者中进行预防和治疗应用。该提案的具体目的是（1）改善DNA递送系统和体内蛋白质表达； （2）多蛋白DNA疫苗的开发和测试； （3）测试年轻小鼠和老鼠的肿瘤免疫学参数。