Vaccinating against IGFBP-2 to prevent ovarian cancer relapse

我们发现胰岛素样生长因子结合蛋白2(IGFBP-2)是一种卵巢癌抗原。 IGFBP-2正在成为卵巢癌侵袭和转移的潜在重要调节因子 潜力。IGFBP-2在卵巢癌中过度表达，其过度表达水平与 侵袭性疾病。免疫根除过表达IGFBP-2的肿瘤细胞可能有益于 防止疾病复发。我们在开发疫苗策略方面拥有丰富的经验，旨在 诱导I型炎症性004*T辅助免疫(THI)。诱导CD4*肿瘤特异性THI细胞的研究进展 与免疫策略相比，接种疫苗有几个明显的优势 主要是CD8‘’T细胞。细胞因子增强局部抗原提呈细胞(APC)的功能 并增强内源性抗原提呈。内源性肿瘤细胞的加工增加导致 表位扩散，对所表达的多个免疫原性蛋白的免疫反应的发展 在肿瘤里。此外，通过提供强大的004“Thi T细胞反应，肿瘤特异性CD8*T细胞将 内源性地诱导和增殖。最后，抗原特异性的CD4*T细胞将提供环境 随着时间的推移，需要增强和维持肿瘤特异性T细胞免疫反应。我们已经确定了 来自IGFBP-2的多个Th表位可用于多表位疫苗。我们会 IGFBP-2多表位疫苗免疫效力的评价 高表达IGFBP-2腹膜转移的动物模型。在临床前研究之后，疫苗 将用于针对IGFBP-2患者的辅助免疫的I期研究 已接受治疗的晚期卵巢癌患者的完全反应。 这项建议的具体目的是：(1)确定IGFBP-2与hGFP结合的特异性II类表位 亲和力跨越多个II类等位基因，并且不刺激PBMC产生转化生长因子-β(B)以包括在 多表位疫苗，(2)评价lGFBP-2类疫苗的免疫原性、治疗效果和安全性 高表达IGFBP-2腹膜转移小鼠模型的多表位DNA疫苗， (3)用IGFBP-2类II多表位质粒进行主动免疫的I期临床试验 DNA疫苗在晚期卵巢癌患者中的辅助设置。 相关性(请参阅说明)： 卵巢癌是免疫原性的，免疫可能会带来更好的预后。如果豁免权可以 大多数晚期卵巢癌患者在病程早期发生， 或许临床结果可能会有所改善。一种靶向免疫原性生物相关的疫苗 卵巢癌中的蛋白质可以提供这样的可能性。这项提议将解决相关的障碍 正在开发这样的疫苗，并将在第一阶段临床试验中测试疫苗。

We have identified insulin like growth factor binding protein 2 (IGFBP-2) as an ovarian cancer antigen. IGFBP-2 is emerging as a potentially important regulator of ovarian cancer invasiveness and metastatic potential. IGFBP-2 is over expressed in ovarian cancers and the level of overexpression is associated with invasive disease. Immunologic eradication of tumor cells overexpressiing IGFBP-2 could be beneficial in preventing disease relapse. We have extensive experience in developing vaccine strategies designed to elicit Type I inflammatory 004* T helper immunity (Thi). A focus on eliciting CD4* tumor specific Thi cells with vaccination has several distinct 'advantages over immunization strategies designed to elicit predominantly CD8'' T cells. Thi cytokines enhance the function of local antigen presenting cells (APCs) and augment endogenous antigen presentation. Increased processing of endogenous tumor cells results in epitope spreading, the development of an immune response to the multiple immunogenic proteins expressed in the tumor. In addition, by providing a robust 004" Thi T cell response, tumor-specific CD8* T cells will be elicited and proliferate endogenously. Finally, antigen specific CD4* T cells would provide the environment needed to enhance and sustain tumor specific T cell immune responses over time. We have identified multiple Th epitopes derived from IGFBP-2 which can be exploited in a polyepitope vaccine. We will evaluate the immunologic efficacy of a IGFBP-2 plasmid based polyepitope vaccine in an immune competent animal model of IGFBP-2 overexpressing peritoneal metastasis. Following pre-clinical studies, the vaccine will be manufactured for a Phase I study of adjuvant immunization against IGFBP-2 in patients with advanced stage ovarian cancer who have been treated to a complete response. The specific aims of this proposal are to: (1) identify IGFBP-2 specific class II epitopes that bind with high avidity across multiple class II alleles and do not stimulate TGF-beta (b) production in PBMC for inclusion in a polyepitope vaccine, (2) evaluate the immunogenicity, therapeutic efficacy, and safety of an lGFBP-2 class II polyepitope plasmid DNA vaccine in a mouse model of IGFBP-2 overexpressing peritoneal metastasis, and (3) conduct a Phase I clinical trial of active immunization with an IGFBP-2 Class II polyepitope plasmid DNA vaccine in patients with advanced stage ovarian cancer in the adjuvant setting. RELEVANCE (See instructions): Ovarian cancer is immunogenic, and immunity may confer a better prognosis. If immunity could be generated in the majority of advanced stage ovarian cancer patients early in the course of their disease, perhaps the clinical outcome could be improved. A vaccine targeting immunogenic biologically relevant proteins in ovarian cancer could offer such a possibility. This proposal will address the obstacles associated with developing such a vaccine and will test the vaccine in a Phase I clinical trial.