PROJECT SUMMARY – OVERALL This revised application of the Mayo Clinic SPORE in Ovarian Cancer (OC) builds on translational research con- ducted during Years 6-10 of funding. Our accomplishments over the past five years include i) identification of a unique vaccine strategy that, in a phase I study, led to 39% recurrence free survival at 49 months in high grade serous OC, ii) new understanding of the genomic and biochemical changes that limit the action of PARP inhibitors (PARPis) in OC, iii) distribution of over 9600 biospecimens for OC research, and iv) publication of 220 articles. The Developmental Research Program (DRP) has contributed to two of the four projects in this renewal; and the Career Enhancement Program (CEP) contributed to leadership of two projects. The overall goal of the SPORE remains to support innovative, interactive, translational OC research that leverages the expertise of bas- ic and translational investigators. This renewal contains four translational projects designed to investigate OC biology and enhance therapeutic response, building on recent clinical advances and promising preclinical results: • P1 (Development of a Th17-Inducing Dendritic Cell [DC] Vaccine for OC): Based on our study showing that DCs pulsed with Folate Receptor α peptides and matured to a Th17-inducing phenotype induced immune re- sponses in all patients and long-term recurrence-free survival in 39%, we will identify determinants of long- term vaccine response in a phase II trial and elucidate mechanisms of immune escape from this vaccine. · P2 (Next Generation TOP1 Inhibition for the Treatment of OC): Building on our observation that TOP1 inhib- itors are active in PARPi-resistant OC models and this activity can be enhanced by PARPi treatment even in the face of PARPi resistance, this project will identify determinants of sensitivity to TOP1 inhibitor/PARPi combinations and conduct a phase II trial of the ultra-long acting TOP1i PLX038 with the PARPi rucaparib. · P3 (Repurposing Ceritinib for OC Therapy): Based on the finding that ceritinib, a kinase inhibitor used for ALK- rearranged lung cancer, inhibits mitochondrial respiration, increases reactive oxygen species, and sensitizes OC cell lines and PDXs to PARPis independent of ALK status, we will identify pathways that mediate these effects and conduct a phase I trial of the ceritinib/olaparib combination. · P4 (Treatment of Advanced OC Using Gene-Edited CAR NK Cells): Building on a prior developmental research project, this team located at the University of Minnesota will apply advanced cellular engineering techniques to generate activated NK cells with enhanced tumor homing and persistence, then test the safety and efficacy of administering this allogeneic adoptive immunotherapy in a phase I clinical trial in platinum-resistant OC. These impactful projects are supported by four highly interactive cores: Core A (Administrative), Core B (Biospec- imens/Patient Registry), Core C (Biosta...