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

描述(由申请人提供)：总体目标是建立这样的范式，即针对转录因子Fos相关抗原1(Fra-1)的口服DNA疫苗共表达T-helper 1分子佐剂可以充分激发和增强自发转移性乳腺癌模型中的T细胞介导的免疫反应，以检验以下假设：1)可以完全根除已建立的自发性肺转移，以显著延长BALB/c小鼠的寿命；2)在最小的残留疾病环境下，可以(完全)防止此类转移的复发；3)预防性免疫可诱导有效的记忆T细胞应答，对乳腺肿瘤的生长和转移具有长期的保护作用。为了验证这些假说，描述和优化支配这些疫苗作用模式的免疫学机制和信号转导通路，设计的具体目标如下：首先，通过编码Fra-1和趋化因子CCL16的表达载体实现DC和巨噬细胞对Fra-1的最佳处理和呈递，以有效地启动免疫应答，然后用编码Fra-1和分泌IL-23的载体增强免疫，所有这些都针对次级淋巴器官，以减毒沙门氏菌为疫苗载体。其次，严格评估这一策略的有效性(在增强局部肿瘤环境中非淋巴组织中的休眠记忆T细胞方面，并评估它们杀死转移肿瘤细胞的能力)。第三，{用微型基因疫苗识别特定的Fra-1 T细胞表位，重点是参与PRIME/Boost策略的特定免疫学机制和信号转导途径，通过诱导长寿记忆T细胞反应来优化DNA疫苗的效力。}实现这一建议的目标将导致基于合理免疫学原理的新型DNA疫苗，最终可能有助于改进乳腺癌的治疗。与公共卫生相关的是该提案经过深思熟虑的转译研究设计，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性化版本进行早期临床评估，特别是如果有更多令人信服的临床前数据的保证。这使得这种疫苗在评估过程中可以循环进行，从工作台到床边，再到后台，以便进一步改进。

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.