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.
|Vragniau, Charles; Hübner, Jens-Martin; Beidler, Peter et al. (2017) Studies on the Interaction of Tumor-Derived HD5 Alpha Defensins with Adenoviruses and Implications for Oncolytic Adenovirus Therapy. J Virol 91:|
|Au-Yeung, George; Lang, Franziska; Azar, Walid J et al. (2017) Selective Targeting of Cyclin E1-Amplified High-Grade Serous Ovarian Cancer by Cyclin-Dependent Kinase 2 and AKT Inhibition. Clin Cancer Res 23:1862-1874|
|Liu, Joyce F; Palakurthi, Sangeetha; Zeng, Qing et al. (2017) Establishment of Patient-Derived Tumor Xenograft Models of Epithelial Ovarian Cancer for Preclinical Evaluation of Novel Therapeutics. Clin Cancer Res 23:1263-1273|
|Kroeger Jr, Paul T; Drapkin, Ronny (2017) Pathogenesis and heterogeneity of ovarian cancer. Curr Opin Obstet Gynecol 29:26-34|
|Yu-Rice, Yi; Edassery, Seby L; Urban, Nicole et al. (2017) Selenium-Binding Protein 1 (SBP1) autoantibodies in ovarian disorders and ovarian cancer. Reproduction 153:277-284|
|Zheng, Grace X Y; Terry, Jessica M; Belgrader, Phillip et al. (2017) Massively parallel digital transcriptional profiling of single cells. Nat Commun 8:14049|
|Liao, John B; Swensen, Ron E; Ovenell, Kelsie J et al. (2017) Phase II trial of albumin-bound paclitaxel and granulocyte macrophage colony-stimulating factor as an immune modulator in recurrent platinum resistant ovarian cancer. Gynecol Oncol 144:480-485|
|Labidi-Galy, S Intidhar; Papp, Eniko; Hallberg, Dorothy et al. (2017) High grade serous ovarian carcinomas originate in the fallopian tube. Nat Commun 8:1093|
|Kondrashova, Olga; Nguyen, Minh; Shield-Artin, Kristy et al. (2017) Secondary Somatic Mutations Restoring RAD51C and RAD51D Associated with Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma. Cancer Discov 7:984-998|
|Iwanicki, Marcin P; Chen, Hsing-Yu; Iavarone, Claudia et al. (2016) Mutant p53 regulates ovarian cancer transformed phenotypes through autocrine matrix deposition. JCI Insight 1:|
Showing the most recent 10 out of 185 publications