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.

我们已经确定了胰岛素样生长因子结合蛋白2 （IGFBP-2）作为卵巢癌抗原。