Abstract B30: Transient interferon suppression renders nerve sheath sarcomas susceptible to targeted viroimmunotherapy

Abstract

Abstract Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas resistant to most cancer treatments. Surgical resection remains the primary treatment; however, this is often incomplete, ultimately resulting in high mortality and morbidity rates. There has been a resurgence of interest in oncolytic virotherapy because of encouraging preclinical and clinical trial results. Oncolytic Herpes simplex virus (oHSV) selectively replicates in cancer cells, lysing the cell and inducing antitumor immunity. We previously showed that basal interferon (IFN) signaling increases interferon stimulated gene (ISG) expression, restricting viral replication in almost 50% of MPNSTs. The FDA-approved drug ruxolitinib (RUX) temporarily resets this constitutively active STAT signaling and renders the sarcoma cells susceptible to oHSV infection in cell culture. In the studies described, we translated our in vitro results into a syngeneic MPNST tumor model. Consistent with our previous results, murine MPNSTs exhibit a similar IFN- and ISG-mediated resistance mechanism and virotherapy alone provides no antitumor benefit in vivo. However, when mice are pretreated with ruxolitinib, this reduces ISG expression, making the tumors susceptible to oHSV infection. Ruxolitinib pretreatment improves viral replication and alters the oHSV-induced immune-mediated response. Our results show that this combination therapy increases CD8 T-cell activation in the tumor microenvironment and that this population is indispensable for RUX+oHSV antitumor benefit. Of note, animals treated with the combination therapy have developed a systemic circulating memory response against the specific tumor antigen. These data suggest JAK inhibition prior to oncolytic virus treatment augments both oHSV replication and the immunotherapeutic efficacy of viroimmunotherapy. Citation Format: Mohammed G. Ghonime, Kevin A. Cassady. Transient interferon suppression renders nerve sheath sarcomas susceptible to targeted viroimmunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B30.