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: 8122602
• 负责人: CLAUDIA GRAVEKAMP
• 金额: $ 4.98万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 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 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8122602
• 关键词: Adjuvant; Age; Antigen Receptors; Antigens; Attenuated; Breast Cancer Prevention; Breast Cancer Treatment; CMV promoter; Cancer Patient; Cancer Vaccines; Cells; Clinical Trials; Complementary DNA; Cytotoxic T-Lymphocytes; DNA; DNA Vaccines; DNA delivery; Development; Diagnosis; Elderly; Elderly woman; Excision; Generations; Genes; Granulocyte-Macrophage Colony-Stimulating Factor; Homologous Gene; Human; Immune; Immunization; Incidence; Injection of therapeutic agent; Interleukin-7; Lead; Listeria monocytogenes; Malignant Neoplasms; Mammary Neoplasms; Metastatic Neoplasm to the Breast; Modeling; Mus; Neoplasm Metastasis; Operative Surgical Procedures; Peptides; Plasmids; Prevention; Prevention therapy; Preventive; Primary Neoplasm; Process; Radiation; Research; Residual Tumors; System; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Transcript; Tumor Antigens; Tumor Cell Line; United States; Vaccination; Vaccines; Woman; base; chemotherapy; frailty; improved; in vivo; malignant breast neoplasm; mortality; mouse model; neoplastic cell; older patient; protein expression; response; trend; tumor; uptake; 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（申请人提供）：乳腺癌是美国第二大癌症，2001年新诊断出193,700例乳腺癌。老年女性的乳腺癌发病率和死亡率远高于年轻女性。由于人口趋势表明，未来几十年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疗，然后进行辅助治疗或化疗。癌症疫苗的毒性低于化疗或放疗，因此对于通常更容易虚弱的老年患者特别有用。然而，还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，转移性乳腺癌尚不适合治疗。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) 反应可能会导致微转移和/或残留肿瘤细胞的特异性消除。为了研究老年患者乳腺癌疫苗接种的效果，建议使用免疫健全的乳腺癌转移小鼠模型，在该模型中可以研究不同年龄的肿瘤发生和进展。该模型基于将同基因小鼠乳腺肿瘤细胞系注射到具有免疫能力的小鼠体内，然后小鼠产生转移性乳腺癌，而不会产生免疫排斥。我们证明，注射此类细胞很容易在年轻和年老的小鼠中诱导转移，表达人类 MAGE-A 和 MAGE-B 肿瘤特异性抗原的小鼠同源物。一种基于编码这些抗原之一的基因构建体的 DNA 疫苗被制造出来，并被证明可以大大减少预防性免疫中的转移数量。该提案的长期目标是在不同年龄的小鼠中进一步优化该疫苗和其他疫苗，以用于人类老年乳腺癌患者的预防和治疗应用。该提案的具体目标是（1）改进DNA传递系统和体内蛋白质表达； （2）多抗原DNA疫苗的研制和试验； (3)测试年轻和年老小鼠的肿瘤免疫学参数。

项目成果

Impact of aging on cancer immunity and immunotherapy.

衰老对癌症免疫力和免疫治疗的影响。

• DOI: 10.1007/s00262-009-0743-2
• 发表时间: 2009
• 期刊: Cancer immunology, immunotherapy : CII
• 作者: Pawelec,Graham;Lustgarten,Joseph;Ruby,Carl;Gravekamp,Claudia
• 通讯作者: Gravekamp,Claudia

Cancer vaccination at older age.

老年时接种癌症疫苗。

• DOI: 10.1159/000343596
• 发表时间: 2013
• 期刊: Interdisciplinary topics in gerontology
• 作者: Gravekamp,Claudia

Mage-b vaccine delivered by recombinant Listeria monocytogenes is highly effective against breast cancer metastases.

• DOI: 10.1038/sj.bjc.6604526
• 发表时间: 2008-09-02
• 期刊: BRITISH JOURNAL OF CANCER
• 影响因子: 8.8
• 作者: Kim, S. H.;Castro, F.;Gonzalez, D.;Maciag, P. C.;Paterson, Y.;Gravekamp, C.
• 通讯作者: Gravekamp, C.

Curcumin improves the therapeutic efficacy of Listeria(at)-Mage-b vaccine in correlation with improved T-cell responses in blood of a triple-negative breast cancer model 4T1.

• DOI: 10.1002/cam4.94
• 发表时间: 2013-08
• 期刊: CANCER MEDICINE
• 影响因子: 4
• 作者: Singh, Manisha;Ramos, Ilyssa;Asafu-Adjei, Denise;Quispe-Tintaya, Wilber;Chandra, Dinesh;Jahangir, Arthee;Zang, Xingxing;Aggarwal, Bharat B.;Gravekamp, Claudia
• 通讯作者: Gravekamp, Claudia

High efficacy of a Listeria-based vaccine against metastatic breast cancer reveals a dual mode of action.

• DOI: 10.1158/0008-5472.can-08-4855
• 发表时间: 2009-07-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Kim SH;Castro F;Paterson Y;Gravekamp C
• 通讯作者: Gravekamp C