Abstract 2206: Degradation of hyaluronan in the tumor microenvironment enhances oncolytic reovirus and anti-PD-L1 therapy in a murine syngeneic breast tumor model

Abstract

Abstract The extracellular matrix (ECM) structure heavily influences tumor growth, invasion and various steps of the cancer-immunity cycle. Hyaluronan (HA), a major component of ECM, is a glycosaminoglycan that accumulates in the tumor microenvironment (TME) of many solid tumor types, and HA accumulation can restrict T cell infiltration and promote immunosuppression. We have demonstrated in preclinical tumor models that enzymatic degradation of TME HA by intravenous PEGylated recombinant human hyaluronidase PH20 (Pegvorhyaluronidase alfa, PEGPH20) facilitates delivery of chemotherapeutics to tumors and enhances efficacy of current immunotherapy strategies including checkpoint inhibitors. In this study, we hypothesized that degradation of HA with PEGPH20 treatment may remodel the TME to improve the efficacy of oncolytic reovirus therapy (pelareorep) and checkpoint blockade therapy. To test this hypothesis, EMT6 murine breast tumor cells, which spontaneously accumulate HA and are sensitive to oncolytic activity of pelareorep were implanted orthotopically into the mammary fat pad of BALB/c mice. In this model, PEGPH20 treatment resulted in a reduction of HA measured by immunohistochemistry and induced tumor growth inhibition (30% TGI). Pelareorep plus anti-PD-L1 treatment also resulted in anti-tumor activity (44% TGI), and flow cytometric analysis of tumor infiltrating immune cells in pelareorep + anti-PD-L1-treated tumors demonstrated a significant increase in the numbers of cytotoxic CD8+ tumor infiltrating lymphocytes (TILs, p=0.0004), a decrease in regulatory T cells (T reg, p<0.0001) and an increase in CD8:Treg ratio (p=0.0018), indicating a robust antitumor immune response. Combination of PEGPH20 with pelareorep + anti-PD-L1 resulted in enhanced anti-tumor activity (71% TGI) compared to either PEGPH20 (30%TGI) or pelareorep + anti-PD-L1 (44% TGI). PEGPH20 in combination with pelareorep + anti-PDL1 also extended survival (median survival time, MST- 30 days, p<0.0001) in comparison with PEGPH20 alone (MST-21 days) or pelareorep + anti-PD-L1 (MST-22 days). Our data demonstrate the potential for matrix modeling through degradation of HA as a strategy to improve oncolytic reovirus + anti-PD-L1 immunotherapy. These findings are consistent with prior preclinical studies and support clinical evaluation of combining PEGPH20 with immune checkpoint inhibitors in HA-accumulating tumors. Citation Format: Jisook Lee, Grey A. Wilkinson, Trevor Kimbler, Barbara Blouw, Curtis B. Thompson. Degradation of hyaluronan in the tumor microenvironment enhances oncolytic reovirus and anti-PD-L1 therapy in a murine syngeneic breast tumor model [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 2206.