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样生长因子结合蛋白2（IGFBP-2）作为卵巢癌抗原。 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，过度表达水平与卵巢癌的发生有关。 侵袭性疾病免疫清除过表达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， 引发I型炎性004* T辅助免疫（Thi）。聚焦于诱导CD 4 * 肿瘤特异性Thi细胞 与免疫策略相比， 主要是CD 8 + T细胞。Thi细胞因子增强局部抗原呈递细胞（APC）的功能 并增加内源性抗原呈递。内源性肿瘤细胞的加工增加导致 表位扩散，对所表达的多种免疫原性蛋白质的免疫应答的发展 在肿瘤中。此外，通过提供稳健的004-Thi T细胞应答，肿瘤特异性CD 8 * T细胞将被诱导。 内源性地引发和增殖。最后，抗原特异性CD 4 * 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细胞免疫应答。我们已经确定 衍生自IGFBP-2的多个Th表位，其可用于多表位疫苗。我们将 评价基于IGFBP-2质粒的多表位疫苗在免疫活性小鼠中的免疫功效。 IGFBP-2过表达腹膜转移的动物模型。经过临床前研究，疫苗 将生产用于在以下患者中进行IGFBP-2辅助免疫的I期研究： 晚期卵巢癌患者已接受完全缓解治疗。 该建议的具体目的是：（1）鉴定与高表达IGFBP-2结合的IGFBP-2特异性II类表位。 在多个II类等位基因之间的亲合力，并且不刺激PBMC中TGF-β（B）的产生以包含在 多表位疫苗，（2）评估IGFBP-2类疫苗的免疫原性、治疗功效和安全性， II多表位质粒DNA疫苗在IGFBP-2过表达的腹膜转移小鼠模型中的作用， 进行IGFBP-2 II类多表位质粒主动免疫的I期临床试验 DNA疫苗在晚期卵巢癌患者中的辅助治疗 相关性（参见说明）： 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 在大多数晚期卵巢癌患者的病程早期产生， 也许临床结果可以得到改善。靶向免疫原性生物学相关的疫苗 卵巢癌中的蛋白质可以提供这种可能性。该提案将解决与此相关的障碍， 开发这样的疫苗，并将在I期临床试验中测试该疫苗。