Abstract B03: Immunotherapy of ovarian cancer with glycomimetic peptides

Abstract

Abstract Successful strategies for treating women with ovarian cancer remain elusive. Whereas chemotherapy with drugs such as paclitaxel and carboplatin extends survival, it bears a significant cost in toxicity. Immunotherapies with antibodies such as anti-PD-1, anti-PD-L1, or anti-VEGF have been successful in a fraction of patients. Inhibitors of poly(ADP-ribose) polymerase (PARP) have gained interest, particularly for the minority of patients who carry the BRCA-1/2 mutations. Ovarian cancer is highly inflammatory and recent reports described recruitment of monocytes, which then differentiate into a unique subset of dendritic cells (DCs) within the inflamed ascites environment. These monocyte-derived DCs (mo-DCs) have the potential to activate cytotoxic CD8+ T cells that attack tumor cells, but progression of disease is not abrogated without additional stimuli. We hypothesize that a means to actuate this role of mo-DCs will be an important component of a successful treatment of inflammatory tumors such as ovarian ascites. Mo-DCs along with CD1c+ DC2 subtypes express CD301, the Ca2+-dependent lectin domain family 10 member A (CLEC10A), which is a pathogen-recognition receptor specific for binding the ligand N-acetylgalactoasmine (GalNAc). A series of experiments were designed to test whether a novel peptide mimetic of GalNAc, designated sv6D, can enhance anticancer immune activity and limit the progression of ovarian cancer. CLEC10A is a type II transmembrane receptor that initiates a Ca2+ signal upon binding of sv6D and subsequent endocytosis. Production of IFN-γ by naïve T cells occurred when cultured with in vitro generated mo-DCs, which are similar to mo-DCs induced by inflammation, and 10 nM sv6D. In a syngeneic, orthotopic murine model of ovarian cancer, doses of 0.1 nmole/g of sv6D on alternate days completely suppressed ascites accumulation for several weeks, a measure of inhibition of tumor progression. Survival was also extended when sv6D was administered to mice previously treated with paclitaxel. Although treatment with anti-PD-1 was ineffective, i.p. injections of anti-PD-1 in combination with a tolerance-inducing treatment with sv6D provided maximal survival. Our studies demonstrate that 1) sv6D stimulates proliferation and differentiation of immune cells in the peritoneal cavity and serves as a trigger to promote the activation of CD8+ T cells by mo-DCs in ovarian ascites, 2) sv6D as a single agent inhibits progression of ovarian cancer and enhances survival in a mouse model of ovarian cancer, 3) sv6D in combination with paclitaxel or anti-PD-1 extends survival beyond that of either agent alone, and 4) sv6D is not antigenic and treatment with the peptide was not associated with evident toxicity. Taken together, these data demonstrate the potential for this novel approach of harnessing lectin receptors as a means toward an effective ovarian cancer treatment. Citation Format: Laura L. Eggink, J. Kenneth Hoober. Immunotherapy of ovarian cancer with glycomimetic peptides [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B03.