Abstract
Abstract Successful treatment strategies for women with ovarian cancer remain elusive. We hypothesize that novel means of activating anti-cancer immune activity will be an important component of a multifaceted approach to successful treatment. The present set of studies tests the hypothesis that novel peptide mimetics of C-type lectin receptor ligands, sv4L and sv6D, enhance anti-cancer immune activity and limit the progression of ovarian cancer in a mouse model. We further test the hypothesis that sv6D will function in synergy with additional immune modulators and conventional cytotoxic therapy. C-Type lectin receptors were targeted that are specific for N-acetylgalactosamine (GalNAc). Both svL4 and sv6D bind GalNAc-specific C-type lectin receptors including CLEC10A/CD301 with a KD in the low nanomolar range. CLEC10A is a transmembrane, endocytic receptor expressed on dermal dendritic cells, macrophages and immature dendritic cells. Further, studies with the B16 mouse melanoma model and spontaneous tumors (histiocytic sarcoma and mammary gland tumor) in dogs showed that treatment with svL4 correlated with reduced tumor-associated Treg cells. In the present studies subcutaneous injection of svL4 or sv6D every other day over 5 days stimulated a several-fold proliferation of immune cells in the peritoneal cavity of healthy mice. These results indicated that svL4 and/or sv6D might exhibit significant activity on peritoneal tumors. Efficacy of svL4 and sv6D each as a single agent and as a combination therapy with paclitaxel or anti-PD-1 was tested in C57BL6 female mice bearing ovarian ID8 intraperitoneal tumors. As a single agent, 0.1 nmole/g doses of svL4 or sv6D had a significant effect on suppressing ascites formation, a measure of tumor progression, and overall survival. Drug combination studies revealed a positive therapeutic interaction with sv6D and the cytotoxic paclitaxel. As single agents, sv6D and paclitaxel each had a significant effect on extending survival (median survival 140.5 and 150 days, respectively, vs. 122 days with no treatment). Survival was extended further with combination treatment when sv6D was administered to mice previously treated with paclitaxel (median survival 169 days). Also, a positive interaction was observed with sv6D and the check-point inhibitor anti-PD-1. Administration of sv6D following anti-PD-1 treatment resulted in a significant survival advantage compared to treatment with either agent alone. These data demonstrate 1) sv4L and sv6D mobilize immune cells in the peritoneal cavity, 2) svL4 or sv6D as single agents slow progression of ovarian cancer and enhance survival in a mouse model of ovarian cancer, 3) sv6D in combination with paclitaxel or anti-PD-1 extends survival past that of either agent alone. Taken together these date demonstrate the potential for this novel approach of harnessing lectin receptors as a means toward effective cancer treatment. Citation Format: Katherine F. Roby, Laura L. Eggink, J. Kenneth Hoober. An innovative immunotherapeutic strategy for ovarian cancer: Glycomimetic peptides [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 170. doi:10.1158/1538-7445.AM2017-170
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