Roswell Park Ovarian Cancer SPORE

总体总结-罗斯威尔公园卵巢癌孢子

Overall Summary – Roswell Park Ovarian Cancer SPORE This is the revised competing renewal application of the Roswell Park Ovarian Cancer SPORE. We have made significant progress on the translational objectives and human endpoints of each Individual Research Project (IRP). Our highly successful Developmental Research Program (DRP) and Career Enhancement Program (CEP) have catalyzed new translational ovarian cancer research projects, collaborations, and extramural funding for awardees. Our overarching goal remains unchanged: to conduct multidisciplinary, mechanism-based and collaborative translational research that will have the highest possible impact for women with ovarian cancer. Because immunotherapies have met with only modest success in ovarian cancer patients, we continue to uniquely focus on novel strategies for generating effective anti-tumor immunity by unraveling immune-resistance mechanisms and identifying novel proteogenomic biomarkers of responsiveness. After significant planning and guidance by our Internal and External Advisory Boards, and Patient Advocate Committee, we have leveraged our highly successful DRP and CEP to propose three bi-directional translational IRPs addressing basic and clinical research questions of importance in ovarian cancer. The new IRP1 and IRP2 evolved as a result of two DRP awards and the new IRP3 developed from a CEP award. IRP1 will test an oncolytic virus armed with a CXCR4 antagonist in combination with PDL1 blockade to abrogate tumor immune suppression and limit T cell exhaustion in a randomized Phase I/II clinical trial. IRP2 will test a novel strategy of rendering NY-ESO-1-reactive TCR transgenic T cells to be insensitive to the suppressive action of TGF and concomitantly neutralize M2- macrophages/myeloid-derived suppressor cells. IRP3 addresses the completely novel concept of identifying mismatch between immunopeptidomes of ovarian cancer cells versus dendritic cells and leveraging a computational approach of bypassing such mismatch. IRP1 commences with a planned clinical trial; the Phase I/II clinical trials in IRP2 and IRP3 will commence in year 3 following preclinical, IND-enabling translational studies. The program also continues to expand opportunities for new avenues of ovarian cancer translational research via its successful DRP and CEP. The four highly integrated, interconnected shared resource cores – Administration, Biospecimen & Pathology, Biostatistics & Bioinformatics, and Immunogenomics – bring innovative technology and resources to the SPORE and do not duplicate pre-existing shared resources available at Roswell Park. This application is strongly supported by nearly $4M institutional commitment to ensure its success of conducting highly innovative translational research that changes the clinical practice paradigm in ovarian cancer.