Fra-1: A new target for a genomic breast cancer vaccine

Fra-1：基因组乳腺癌疫苗的新靶点

• 批准号: 7574393
• 负责人: RALPH A. REISFELD
• 金额: $ 32.66万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7574393
• 关键词: Achievement; Adjuvant; Adverse effects; Animals; Antigen Presentation Pathway; Apoptosis; Attenuated; Back; Biological; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Treatment; Breast Carcinoma; CD8B1 gene; Cells; Chemotaxis; Clinical Data; DNA Vaccines; Data; Effector Cell; Environment; Enzyme-Linked Immunosorbent Assay; Epitopes; Evaluation; Event; Flow Cytometry; Generations; Genomics; Growth; Immune; Immune response; Immunization; Inbred BALB C Mice; Interleukin-12; Lead; Life; Longevity; Lung; Lymphoid; Lymphoid Tissue; Mammary Neoplasms; Mediating; Memory; Metastatic Neoplasm to the Lung; Modeling; Molecular; Mus; Neoplasm Metastasis; Oncologist; Oral; Organ; Pathway interactions; Phosphorylation; Process; Public Health; Recurrence; Research Design; Residual Neoplasm; Role; Salmonella typhimurium; Secondary to; Signal Transduction; Signal Transduction Pathway; Structure of aggregated lymphoid follicle of small intestine; T memory cell; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Therapeutic; Tissues; Toxic effect; Translational Research; Treatment Protocols; Vaccinated; Vaccination; Vaccines; Western Blotting; base; bench to bedside; breast cancer vaccine; cell killing; cell mediated immune response; chemokine; cytokine; design; expression vector; fos-related antigen 1; improved; in vivo; insight; interleukin-23; killings; macrophage; malignant breast neoplasm; meetings; neoplastic cell; novel; novel vaccines; pre-clinical; prevent; prophylactic; protein expression; research clinical testing; response; transcription factor; tumor; tumor growth; vaccine efficacy; vector

The overall objective is to establish the paradigm that co-expression of T-helper 1 molecular adjuvants by oral DNA vaccines targeting transcription factor Fos-related antigen 1 (Fra-1) can sufficiently prime and boost T cell-mediated immune responses in spontaneous metastatic breast cancer models to test the following hypotheses: 1) that established spontaneous pulmonary metastases can be {completely} eradicated to significantly prolong the life span of BALB/c mice; 2) that the recurrence of such metastases can be (fully) prevented in a minimal residual disease setting; 3) that prophylactic vaccination can induce an effective memory T cell response leading to long-lived protection against breast tumor growth and metastasis. The specific aims designed to test these hypotheses and to delineate as well as optimize immunological mechanisms {and signal transduction pathways} governing the mode of action of these vaccines are as follows: First, achieve optimal processing and presentation of Fra-1 by DCs and macrophages for effective priming of the immune response with expression vectors encoding Fra-1 and chemokine CCL16 followed by boosting with vectors encoding Fra-1 and secretory IL-23, all targeted to secondary lymphoid organs with attenuated Salmonella typhimurium serving as the vaccine carrier. Second, critically evaluate the efficacy of this strategy {in boosting dormant memory T cells in nonlymphoid tissues in the local tumor environment and assess their ability to kill metastatic tumor cells.} Third, {identify specific Fra-1 T cell epitopes with minigene vaccines with emphasis on the involvement of specific immunological mechanisms and signal transduction pathways underlying the prime/boost strategy to optimize DNA vaccine efficacy through the induction of a long lived memory T cell response.} Achievement of this proposal's objectives will lead to novel DNA vaccines based on rational immunological principles that may ultimately contribute to the improved treatment of breast cancer. Relevance to public health is in the proposal's deliberate translational research design resulting in preliminary data which convinced a well known oncologist to offer an early clinical evaluation of a humanized version of this breast cancer vaccine, particularly if warranted by additional compelling pre-clinical data. This allows for this vaccine to go full circle in evaluation from bench to bedside and back for further improvement.

总的目标是建立T-helper 1分子佐剂通过 针对转录因子Fos相关抗原1(Fra-1)的口服DNA疫苗可以充分启动和 在自发转移性乳腺癌模型中增强T细胞介导的免疫反应以测试 以下假设：1)已确诊的自发性肺转移瘤可能是 根除以显著延长BALB/c小鼠的寿命；2)这种转移的复发 可以在最小残留疾病的情况下(完全)预防；3)预防性疫苗接种可以诱导 有效的记忆T细胞反应导致对乳腺肿瘤生长和 转移。旨在测试这些假设并描述和优化这些假设的具体目标 支配这些细胞作用方式的免疫机制和信号转导途径 疫苗如下：第一，实现DC对Fra-1的最佳加工和呈递 巨噬细胞用编码Fra-1和Fra-1的表达载体有效地启动免疫反应 趋化因子CCL16之后用编码Fra-1和分泌型IL-23的载体加强免疫，均以 以减毒鼠伤寒沙门氏菌为疫苗载体的次级淋巴器官。第二, 严格评估这种策略的有效性{在增强非淋巴组织中的休眠记忆T细胞方面 局部肿瘤环境，并评估它们杀死转移的肿瘤细胞的能力。}第三，{识别特定的 FRA-1 T细胞表位与微基因疫苗结合，强调特异性免疫学参与 优化DNA疫苗的启动/增强策略的机制和信号转导途径 通过诱导长寿记忆T细胞反应的有效性。)这项建议的实现 目标将导致基于合理免疫学原理的新型DNA疫苗，最终可能 为改进乳腺癌的治疗做出贡献。 与公共健康相关的是该提案经过深思熟虑的翻译研究设计，导致 初步数据说服了一位知名肿瘤学家提供了人性化的早期临床评估 这种乳腺癌疫苗的版本，特别是如果有更多令人信服的临床前数据的保证。这 允许这种疫苗在评估中循环进行，从工作台到床边，再到背部，以便进一步改进。

项目成果

Oral DNA vaccines target the tumor vasculature and microenvironment and suppress tumor growth and metastasis.

口服 DNA 疫苗针对肿瘤脉管系统和微环境，抑制肿瘤生长和转移。

• DOI: 10.1111/j.1600-065x.2008.00613.x
• 发表时间: 2008
• 期刊: Immunological reviews
• 影响因子: 8.7
• 作者: Xiang,Rong;Luo,Yunping;Niethammer,AndreasG;Reisfeld,RalphA
• 通讯作者: Reisfeld,RalphA

Downregulation of transcription factor SOX2 in cancer stem cells suppresses growth and metastasis of lung cancer.

• DOI: 10.1038/bjc.2011.94
• 发表时间: 2011-04-26
• 期刊: BRITISH JOURNAL OF CANCER
• 影响因子: 8.8
• 作者: Xiang, R.;Liao, D.;Cheng, T.;Zhou, H.;Shi, Q.;Chuang, T. S.;Markowitz, D.;Reisfeld, R. A.;Luo, Y.
• 通讯作者: Luo, Y.