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疫苗靶向TNA剂量的TNA分子辅助剂，靶向转录因子FOS相关抗原1（FRA-1）可以充分质量素数，并可以在自发性转移性癌症模型中促进T细胞介导的免疫反应，以实现抗衡性抗性的脉冲孔，以下是脉搏脉冲孔。1） {完全}消除以显着延长BALB/C小鼠的寿命； 2）在最小的残留疾病环境中，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，从而导致长期保护乳腺肿瘤生长和转移。旨在检验这些假设并描绘并优化免疫学机制（和信号转导途径）的具体目的，控制这些疫苗的作用方式如下：首先，首先，通过DCS和巨噬细胞对表达ver的有效启动启动的DCS和巨噬细胞来实现FRA-1的最佳处理和表现，并与fra的有效启动，并与fra的有效启动进行启动，并进行vereok的启动。编码FRA-1和分泌的IL-23，所有针对次级淋巴机构，鼠伤寒沙门氏菌用作疫苗载体。其次，批判性地评估该策略的功效（在局部肿瘤环境中促进非淋巴组织中休眠的记忆T细胞中，并评估其杀死转移性肿瘤细胞的能力。}第三，{{确定特定的FRA-1 T细胞表位，并在特定的免疫机制中涉及特定的免疫机制，并强调了启动的小型疫苗，并构成了繁制的繁殖率，该效率是繁制的。通过诱导长期寿命的记忆T细胞反应的功效。}该提案的目标实现将基于理性免疫学原理，最终有助于改善乳腺癌治疗的新型DNA疫苗。与公共卫生相关的是该提案的故意翻译研究设计，导致了初步数据，该数据说服了众所周知的肿瘤学家对这种乳腺癌疫苗的人性化版本进行早期临床评估，特别是如果由其他引人注目的临床前数据保证。这使得该疫苗可以在从长凳到床边的评估中进行全圈，从而进一步改进。