Vaccinating against IGFBP-2 to prevent ovarian cancer relapse

接种 IGFBP-2 疫苗可预防卵巢癌复发

• 批准号: 8322539
• 负责人: Mary L. Disis
• 金额: $ 43.77万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8322539
• 关键词: Active Immunization; Address; Adjuvant; Alleles; Animal Model; Antigen Presentation; Antigen-Presenting Cells; Antigens; Avidity; Binding; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Patient; Cancer Relapse; Cells; Clinical; DNA Vaccines; Development; Disease; Environment; Epitopes; Family; Goals; High-Risk Cancer; Home environment; Immune; Immune response; Immunity; Immunization; Immunologics; Immunosuppressive Agents; In complete remission; Inflammatory; Instruction; Insulin-Like Growth Factor Receptor; Malignant neoplasm of ovary; Neoplasm Metastasis; Outcome; Patients; Peripheral Blood Mononuclear Cell; Peritoneal; Peritoneum; Phase I Clinical Trials; Plasmids; Process; Production; Proliferating; Proteins; Recurrent disease; Safety; Serum; Staging; T cell response; T-Lymphocyte; Th1 Cells; Time; Transforming Growth Factor beta; Treatment Efficacy; Vaccinated; Vaccination; Vaccine Antigen; Vaccines; anticancer research; base; cancer invasiveness; cancer recurrence; cytokine; design; experience; human IGFBP2 protein; immunogenic; immunogenicity; improved; member; mouse model; neoplastic cell; novel vaccines; outcome forecast; overexpression; phase 1 study; plasmid DNA; preclinical study; prevent; tumor; vaccine development; vaccine evaluation

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.

我们已经确定胰岛素像生长因子结合蛋白2（IGFBP-2）为卵巢癌抗原。 IGFBP-2正在成为卵巢癌侵入性和转移性的潜在重要调节剂 潜在的。 IGFBP-2在卵巢癌中过度表达，过表达的水平与 侵入性疾病。过表达IGFBP-2的肿瘤细胞的免疫学消除可能对 防止疾病复发。我们在制定旨在旨在的疫苗策略方面拥有丰富的经验 引起I型炎症004* T辅助免疫（THI）。着重于引发CD4*肿瘤特异性Thi细胞 疫苗接种比旨在引发的免疫策略具有多个不同的优势 主要是CD8''T细胞。 Thi细胞因子增强了局部抗原呈递细胞（APC）的功能 和增强内源性抗原表现。内源性肿瘤细胞的加工增加导致 表位扩散，对表达多种免疫原性蛋白的免疫反应的发展 在肿瘤中。另外，通过提供强大的004“ Thi T细胞反应，肿瘤特异性CD8* T细胞将是 内源性引起和增殖。最后，抗原特异性CD4* T细胞将提供环境 需要随着时间的推移增强和维持肿瘤特异性T细胞免疫反应。我们已经确定了 源自IGFBP-2的多个表位，可以用多长期疫苗利用。我们将 评估IGFBP-2质粒基于免疫能力的多位素疫苗的免疫学疗效 IGFBP-2过表达腹膜转移的动物模型。遵循临床前研究，疫苗 将针对I期针对IGFBP-2的辅助免疫进行I期研究的患者 晚期卵巢癌已得到完全反应。 该提案的具体目的是：（1）确定与高结合的IGFBP-2特定II类表位 多个II类等位基因的亲和力，并且不刺激PBMC中的TGF-β（B）产生以包含在PBMC中 多聚调疫苗，（2）评估LGFBP-2类的免疫原性，治疗功效和安全性 在IGFBP-2的小鼠模型中，II多聚调质粒DNA疫苗过表达腹膜转移， （3）用IGFBP-2 II类多聚调质粒进行主动免疫的I期临床试验 辅助环境中晚期卵巢癌患者的DNA疫苗。 相关性（请参阅说明）： 卵巢癌具有免疫原性，免疫力可能会提供更好的预后。如果可以免疫 在大多数晚期卵巢癌患者疾病的早期患者中产生 也许可以改善临床结果。靶向免疫生物学相关的疫苗 卵巢癌中的蛋白质可以提供这种可能性。该建议将解决相关的障碍 通过开发这种疫苗并将在I期临床试验中测试疫苗。