Abstract PR1: Development of new immune therapy combinations for ovarian cancer using genetically defined organoid platform

Abstract

Abstract High-grade serous ovarian cancer (HGSOC) is the most common, deadly subtype of ovarian epithelial cancer. HGSOC typically presents at an advanced stage, with widespread peritoneal metastasis. Surgical debulking and platinum/taxane-based chemotherapy can result in complete responses, but disease almost always recurs, eventually in drug-resistant form. The recent addition of Avastin and PARP inhibitors benefits a subset of patients, yet survival has improved marginally in the past 30 years. Responses to immune checkpoint inhibitors have been disappointing. Genomic studies (e.g., TCGA) show that HGSOC is a complex, diverse disease with widespread copy number abnormalities affecting multiple pathways. Nevertheless, most studies aimed at developing new therapies treat HGSOC as a single entity. The absence of genetically relevant, immune-competent HGSOC models poses a major barrier to developing new therapies. By exploiting a mouse fallopian tube organoid system that we developed, along with lentiviral gene transduction and/or CRISPR/Cas9 technology, we generated multiple new HGSOC models containing combinations of mutations seen in the human disease, including homologous recombination (HR)-proficient (Tp53-/-;Ccne1OE;Akt2OE and Tp53-/-;Ccne1OE;KrasOE) -deficient (Tp53-/-;Brca1-/-;Pten-/-and Tp53-/-; Brca1-/-;MycOE and unclassified (Tp53-/-;Pten-/-;Nf1-/-) models. These cells differ in proliferation, differentiation, and polarity/organoid structure in vitro, as well as tumorigenicity and metastatic spread upon orthotopic injection into syngeneic mice. Organoids with different mutations show differential sensitivity to current HGSOC drugs and evoke distinctly different immune microenvironments in vivo. Brca1-/- and CcneOE tumors show significant T-cell infiltration/Treg cells; the latter also have increased myeloid-derived suppressor cells (MDSCs). Pten-/- tumors have lower T-cell infiltration but high levels of MDSCs and macrophages. To test the utility of this platform for new therapeutic development, we focused on CcneOE tumors, because human CCNE-amplified HGSOC responds poorly to current therapy. CcneOE organoids were sensitive to gemcitabine (GEM), probably due to CCNE-evoked replication stress. GEM treatment reduced pro-MDSC cytokines in organoid-conditioned media, and decreased tumor burden in mice. Consistent with these in vitro data, residual tumors had decreased MDSCs (CD11b+Ly6CloLy6Ghi), but persistent Treg (CD24+CD25+FoxP3+) and “exhausted” CD8 T cells (CD8+PD1+). Intriguingly, a combination regimen aimed at attacking tumor cells (gemcitabine) and the residual microenvironment (CTLA4 and PDL1 antibodies) produced complete responses in mice with widespread metastatic disease. Our results argue that genotype-informed combination therapies will be necessary for better outcomes for this devastating disease. This abstract is also being presented as Poster A42. Citation Format: Shuang Zhang, Sonia Iyer, Hao Ran, Wei Wei, Robert A. Weinberg, Benjamin G. Neel. Development of new immune therapy combinations for ovarian cancer using genetically defined organoid platform [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr PR1.