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: 7212238
• 负责人: RALPH A. REISFELD
• 金额: $ 32.04万
• 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 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7212238
• 关键词: Fra; new; target; genomic; breast

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：总体目标是建立一个范式，即通过口服 DNA 疫苗共表达 T 辅助细胞 1 分子佐剂，靶向转录因子 Fos 相关抗原 1 (Fra-1)，可以在自发性转移性乳腺癌模型中充分启动和增强 T 细胞介导的免疫反应，以测试以下假设：1) 已建立的自发性肺转移可以是 {完全}根除，显着延长BALB/c小鼠的寿命； 2) 在微小残留病环境中可以（完全）预防此类转移的复发； 3) 预防性疫苗接种可以诱导有效的记忆 T 细胞反应，从而对乳腺肿瘤生长和转移产生长期保护。旨在测试这些假设并描述和优化控制这些疫苗作用模式的免疫机制{和信号转导途径}的具体目标如下：首先，实现 DC 和巨噬细胞对 Fra-1 的最佳加工和呈递，以便用编码 Fra-1 和趋化因子 CCL16 的表达载体有效引发免疫反应，然后用载体加强免疫反应 编码 Fra-1 和分泌型 IL-23，均以减毒鼠伤寒沙门氏菌作为疫苗载体，靶向二级淋巴器官。其次，严格评估该策略的功效{在局部肿瘤环境中的非淋巴组织中增强休眠记忆T细胞，并评估其杀死转移性肿瘤细胞的能力。}第三，{用小基因疫苗识别特定的Fra-1 T细胞表位，重点是参与初免/加强策略的特定免疫机制和信号转导途径，以优化DNA疫苗 通过诱导长期记忆 T 细胞反应来发挥功效。}该提案目标的实现将带来基于合理免疫学原理的新型 DNA 疫苗，最终可能有助于改善乳腺癌的治疗。与公共卫生的相关性在于该提案经过深思熟虑的转化研究设计，产生的初步数据说服了一位知名肿瘤学家对这种乳腺癌疫苗的人源化版本进行早期临床评估，特别是如果有其他令人信服的临床前数据保证的话。这使得该疫苗能够从实验室到临床进行完整的评估，然后再返回以进一步改进。