Vaccinating against IGFBP-2 to prevent ovarian cancer relapse (Abbrev: IGFBP-2 vaccine)
The ultimate goal of this project is to 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 prognosis1. If immunity could be generated in the majority of advanced stage ovarian cancer patients early in the course of their disease, perhaps clinical outcomes could be improved. A vaccine targeting immunogenic biologically relevant proteins in ovarian cancer could offer such a possibility. The development of a potentially therapeutic immune response via active immunization, a response that would result in the eradication of minimal residual disease in ovarian cancer patients, requires both an immune target that is expressed on the majority of ovarian cancers and a method of vaccination that has the potential to actively modulate the immunosuppressive factors at play in the ovarian cancer microenvironment.
We have identified insulin like growth factor binding protein 2 (IGFBP-2) as an ovarian cancer antigen. IGFBP-2 is a member of the insulin like growth factor receptor family and is a circulating protein that can be detected in the sera of ovarian cancer patients. 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 overexpressing IGFBP-2 could be beneficial in preventing disease relapse or tumor spread throughout the peritoneum.
In the course of this project we will (1) identify IGFBP-2 specific class II epitopes that bind with high avidity across multiple class II alleles and do not stimulate TGF-beta (β) production in PBMC for inclusion in a polyepitope vaccine, (2) evaluate the immunogenicity, therapeutic efficacy, and safety of an IGFBP-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.
Project 5 Publications
1. Behrens MD, Wagner WM, Krco CJ, Erskine CL, Kalli KR, Krempski J, Gad EA, Disis ML, Knutson KL. The endogenous danger signal, crystalline uric acid, signals for enhanced antibody immunity. Blood. 2008 Feb 1;111(3):1472-9. PMCID: PMC2214762
2. Disis ML. Translational oncology: Transforming cancer care. J Clin Oncol. 2007;25(7):750.
3. Balkwill FR, Ashworth A, Bast RC, Berek JS, Boyd J, Disis ML, Gabra H, Gore ME, Hamilton TC, Jacobs IJ, Kaye SB, Kohn EC, Mills GB, Urban ND. 10th Biennial Helene Harris Memorial Trust meeting. Cancer Res. 2006 Mar 15;66(6):2904-6.
4. Disis ML, Rivkin SE, Baron A, Markman M, Connolly D, Ueland F, Kohn E, Trimble E, Berek JS. Progress in ovarian cancer research: proceedings of the 5th Biennial Ovarian Cancer Research Symposium. Int J Gynecol Cancer. 2006; 16 (2):463-9.
5. Goodell V, Salazar LG, Urban N, et al. Antibody immunity to the p53 oncogenic protein is a prognostic indicator in ovarian cancer. J Clin Oncol. 2006;24:762-768.
6. Disis ML. Molecular targeting with cancer vaccines. J Clin Oncol 2005;23:4840-1.
7. Knutson KL, Disis ML. Tumor antigen-specific T helper cells in cancer immunity and immunotherapy. Cancer Immunol Immunother. 2005;54:721-728.
8. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L, Zou W. 6+Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004 Sep;10(9):942-9.
9. Disis ML, Goodell V, Schiffman K, Knutson KL. Humoral epitope spreading following immunization with a HER-2/neu peptide based vaccine in cancer patients. J. Clin Immunol. 2004 Sep;24(5):571-8.
10. Disis ML, Schiffman K, Guthrie K, Salazar LG, Knutson KL, Goodell V, dela Rosa C, Cheever MA. Effect of dose on immune response in patients vaccinated with an her-2/neu intracellular domain protein--based vaccine. J Clin Oncol. 2004 May 15;22(10):1916-25.
11. Disis ML, Rivkin S. Future directions in the management of ovarian cancer. Hematol Oncol Clin North Am. 2003 Aug;17(4):1075-85.
12. Disis ML, Schiffman K, Salazar LG, Knutson KL. Antigen specific cancer vaccines. In: Perry MC, ed. ASCO Educational Book. Alexandria, VA: American Society of C linical Oncology: 29-36, 2003.
13. Disis ML, Scholler N, Dahlin A, Pullman J, Knutson KL, Hellstrom KE, Hellstrom I. Plasmid-based vaccines encoding rat neu and immune stimulatory molecules can elicit rat neu-specific immunity. Mol Cancer Ther. 2003 Oct;2(10):995-1002.
14. Disis ML, Shiota FM, McNeel DG, Knutson KL. Soluble cytokines can act as effective adjuvants in plasmid DNA vaccines targeting self tumor antigens. Immunobiology. 2003;207(3):179-86.
15. Disis ML, Gooley TA, Rinn K, Davis D, Piepkorn M, Cheever MA, Knutson KL, Schiffman K. Generation of T-cell immunity to the HER-2/neu protein after active immunization with HER-2/neu peptide-based vaccines. J Clin Oncol. 2002;20(11):2624-32.
16. Disis ML, Knutson KL, McNeel DG, Davis D, Schiffman K. Clinical translation of peptide-based vaccine trials: the HER-2/neu model. Crit Rev Immunol. 2001;21(1-3):263-73
17. Disis ML, Schiffman K. Cancer vaccines targeting the HER2/neu oncogenic protein. Semin Oncol. 2001;28(6 Suppl 18):12-20.
18. Disis ML, Schiffman K. Issues on Clinical Applications of Cancer Vaccines. J Immunother. 2001;24(2):104-5.