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.
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.
|Wang, Yifan; Krais, John J; Bernhardy, Andrea J et al. (2016) RING domain-deficient BRCA1 promotes PARP inhibitor and platinum resistance. J Clin Invest 126:3145-57|
|Norquist, Barbara M; Harrell, Maria I; Brady, Mark F et al. (2016) Inherited Mutations in Women With Ovarian Carcinoma. JAMA Oncol 2:482-90|
|Yu-Rice, Yi; Edassery, Seby L; Urban, Nicole et al. (2016) Selenium Binding Protein 1 autoantibodies in ovarian disorders and ovarian cancer. Reproduction :|
|Yumul, Roma; Richter, Maximilian; Lu, Zhuo-Zhuang et al. (2016) Epithelial Junction Opener Improves Oncolytic Adenovirus Therapy in Mouse Tumor Models. Hum Gene Ther 27:325-37|
|Wang, Yifan; Bernhardy, Andrea J; Cruz, Cristina et al. (2016) The BRCA1-Î”11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin. Cancer Res 76:2778-90|
|Andersen, M Robyn; Thorpe, Jason; Buist, Diana S M et al. (2016) Cancer Risk Awareness and Concern among Women with a Family History of Breast or Ovarian Cancer. Behav Med 42:18-28|
|Buas, Matthew F; Gu, Haiwei; Djukovic, Danijel et al. (2016) Identification of novel candidate plasma metabolite biomarkers for distinguishing serous ovarian carcinoma and benign serous ovarian tumors. Gynecol Oncol 140:138-44|
|Elias, Kevin M; Emori, Megan M; Westerling, Thomas et al. (2016) Epigenetic remodeling regulates transcriptional changes between ovarian cancer and benign precursors. JCI Insight 1:|
|Gregory, Mark T; Bertout, Jessica A; Ericson, Nolan G et al. (2016) Targeted single molecule mutation detection with massively parallel sequencing. Nucleic Acids Res 44:e22|
|Bernards, Sarah S; Norquist, Barbara M; Harrell, Maria I et al. (2016) Genetic characterization of early onset ovarian carcinoma. Gynecol Oncol 140:221-5|
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