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

描述（由申请人提供）：总体目标是建立一个范例，即通过靶向转录因子fos相关抗原1 （Fra-1）的口服DNA疫苗共同表达T-辅助性1分子佐剂，可以充分启动和促进自发性转移性乳腺癌模型中T细胞介导的免疫反应，以测试以下假设：1)可以完全根除已建立的自发性肺转移瘤，显著延长BALB/c小鼠的寿命；2)这种转移的复发可以在最小的残留疾病环境中（完全）预防；3)预防性接种可诱导有效的记忆T细胞反应，从而长期保护乳腺肿瘤的生长和转移。为检验这些假设并描述和优化控制这些疫苗作用方式的免疫机制{和信号转导途径}，其具体目标如下：首先，通过dc和巨噬细胞对Fra-1进行最佳加工和呈递，以编码Fra-1和趋化因子CCL16的表达载体有效启动免疫应答，然后用编码Fra-1和分泌性IL-23的载体增强，以减毒鼠伤寒沙门菌为疫苗载体，靶向二级淋巴器官。其次，批判性地评估该策略在促进局部肿瘤环境中非淋巴组织中休眠记忆T细胞的功效，并评估其杀死转移性肿瘤细胞的能力。第三，用迷你基因疫苗鉴定特异性的fr -1 T细胞表位，重点是参与特异性免疫机制和信号转导途径，这些途径是通过诱导长期记忆T细胞反应来优化DNA疫苗功效的先导/增强策略的基础。实现这一提议的目标将导致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。与公共卫生相关的是该提案经过深思熟虑的转化研究设计，产生了初步数据，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，特别是在有额外令人信服的临床前数据支持的情况下。这使得该疫苗在从实验台到床边再回到进一步改进的评估过程中走了一个完整的循环。

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.