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

总的目标是建立这样的范例，即辅助性T细胞1分子佐剂的共表达， 以转录因子Fos相关抗原1（Fra-1）为靶点的口服DNA疫苗， 在自发转移性乳腺癌模型中加强T细胞介导的免疫应答，以测试 以下假设：1）确定的自发性肺转移可以{完全} 根除，以显着延长BALB/c小鼠的寿命; 2）这种转移的复发 可以（完全）预防微小残留病; 3）预防性疫苗接种可以诱导 有效的记忆性T细胞应答，导致对乳腺肿瘤生长的长期保护， 转移旨在测试这些假设的具体目标，并描绘和优化 控制这些作用方式的免疫机制{和信号传导途径} 疫苗如下：首先，通过DC实现Fra-1的最佳加工和呈递， 巨噬细胞，用于用编码Fra-1的表达载体有效引发免疫应答， 趋化因子CCL 16，然后用编码Fra-1和分泌型IL-23的载体加强，所有这些都靶向 次级淋巴器官，减毒鼠伤寒沙门氏菌作为疫苗载体。第二、 批判性地评估这种策略的功效{在增强非淋巴组织中的休眠记忆T细胞， 局部肿瘤环境，并评估其杀死转移性肿瘤细胞的能力。第三，确定具体的 Fra-1 T细胞表位与小基因疫苗，重点是参与特异性免疫 优化DNA疫苗初免/加强免疫策略的机制和信号转导途径 通过诱导长寿命记忆T细胞应答的功效。实现这一建议的 这些目标将导致基于合理免疫学原理的新型DNA疫苗， 有助于改善乳腺癌的治疗。 与公共卫生的相关性体现在该提案经过深思熟虑的转化研究设计中， 初步数据说服了一位著名的肿瘤学家提供了人源化的 这种乳腺癌疫苗的版本，特别是如果有额外的令人信服的临床前数据。这 允许这种疫苗从实验室到床边进行完整的评估，然后再进行进一步的改进。

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.