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

描述（由申请人提供）：总体目标是建立通过靶向转录因子Fos相关抗原1（Fra-1）的口服DNA疫苗共表达T辅助细胞1分子佐剂可以在自发转移性乳腺癌模型中充分引发和加强T细胞介导的免疫应答的范例，以测试以下假设：1）建立的自发性肺转移可以被{完全}根除以显著延长BALB/c小鼠的寿命; 2）在最小残留疾病环境中可以（完全）预防这种转移的复发; 3）预防性疫苗接种可以诱导有效的记忆T细胞应答，导致针对乳腺肿瘤生长和转移的长期保护。旨在检验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}的具体目的如下：第一、通过DC和巨噬细胞实现Fra-1的最佳加工和呈递，以用编码Fra-1和趋化因子CCL 16的表达载体有效引发免疫应答，然后用编码Fra-1和CCL 16的载体加强免疫应答。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次级淋巴器官。第二，严格评估这种策略的有效性{在局部肿瘤环境中促进非淋巴组织中的休眠记忆T细胞，并评估其杀死转移性肿瘤细胞的能力}。第三，{鉴定具有小基因疫苗的特异性Fra-1 T细胞表位，重点在于参与引发/加强策略的特异性免疫机制和信号转导途径，以通过诱导长寿命记忆T细胞应答来优化DNA疫苗功效}。该提案目标的实现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。与公共卫生的相关性在于该提案的深思熟虑的转化研究设计，其产生的初步数据说服了一位知名的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价，特别是如果有额外的令人信服的临床前数据支持的话。这使得该疫苗能够从实验室到床边进行完整的评估，并进行进一步的改进。

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.