Abstract 1588: PEGylated recombinant human hyaluronidase, PEGPH20, significantly enhances the anti-tumor activity of the combination of focal adhesion kinase Inhibitor and anti-PD-1 antibody by targeting CXCR4-expressing myeloid cells in a murine model of PDAC
Authors: Osipov Arsen , Wang Jianxin , Li Shiqi , Choi David , Henderson Mackenzie , Pachter Jonathan , Lee Jisook , Maneval Dan , Zheng Lei , Blair Alex 
Published: September 2020

Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is resistant to immunotherapy such as immune checkpoint inhibitors. One of the major resistance mechanisms is attributed to myeloid cells as an immunosuppressive element within the stroma of PDAC. It has been reported that focal adhesion kinase inhibitor (FAKi) can suppress immunosuppressive myeloid cells such as tumor associated macrophages and myeloid derived suppressor cells (MDSC), consequently sensitizing tumor to anti-PD-1 antibody therapy in mouse models of PDAC. Our group has previously shown that targeting the stroma via PEGPH20 enhanced the anti-tumor activity of the whole cell vaccine (GVAX) by targeting CXCR4-expressing myeloid cells. Here we are testing the hypothesis that PEGPH20 can synergize with FAKi by targeting myeloid cells in PDAC.
Experimental Design: An established murine pancreatic tumor model of hepatic metastases treated with and without anti-PD-1 therapy was used to assess the synergy and immune-modulating effect of FAKi and stromal degradation of hyaluronan via PEGPH20.
Results: FAKi and combination of FAKi with anti-PD-1 extends survival in the mouse metastasis model of PDAC. Adding PEGPH20 to the combination of FAKi and anti-PD-1 antibody significantly prolonged survival in this model. Comparing to the combination of FAKi and anti-PD-1 antibody, adding PEGPH20 significantly decreased the number of CXCR4-expressing myeloid cells in the tumor microenvironment (TME) of PDAC and consequently led to an increase in the amount of CCR7+ central memory T cells. Additionally, the amount of G-MDSCs, inflammatory resident monocytes and PD-L1 expressing myeloid cells in the TME of PDAC, was also decreased in PDAC treated with the triple combination of PEGPH20, FAKi and anti-PD-1 antibody compared to the dual combination of FAKi and anti-PD-1 antibody.
Conclusion: Stromal degradation of hyaluronan via PEGPH20 in combination with FAKi and anti-PD-1 antibody further depletes immunosuppressive cells in the TME including G-MDSCs, inflammatory resident monocytes and PD-L1 expressing myeloid cells, and appears to target the CXCR4 pathway through PEGPH20. These findings support testing the combination of FAKi and anti-PD-1 antibody with agents targeting CXCR4 directly or indirectly by PEGPH20 in human PDAC.
Citation Format: Arsen Osipov, Jianxin Wang, Shiqi Li, David Choi, Mackenzie Henderson, Jonathan Pachter, Jisook Lee, Dan Maneval, Lei Zheng, Alex Blair. PEGylated recombinant human hyaluronidase, PEGPH20, significantly enhances the anti-tumor activity of the combination of focal adhesion kinase Inhibitor and anti-PD-1 antibody by targeting CXCR4-expressing myeloid cells in a murine model of PDAC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1588.