Ewing's Sarcoma (EWS) is the second most common childhood bone cancer with high rate of metastasis (25%) and tumor recurrence (30~40%). Despite tremendous advances in the five-year survival rate of localized disease (70~80%), overall survival for patients with relapse or metastasis remains poor (<30%). Oncolytic virotherapy is an emerging anticancer treatment that utilizes attenuated viruses to selectively target and destroy tumor cells. Promotion of systemic anti-tumor immune responses by virotherapy holds great promise, as it has the potential to target distant metastasis and provide immunologic protection from tumor relapse. We tested the oncolytic herpes simplex virus (oHSV) rRp450 as a novel therapy for sarcomas using two human EWS cell lines 5838 and A673 in vitro and in mouse xenografts. Interestingly, our data showed a significant disconnect between the susceptibility of the EWS cell lines 5838 and A673 grown in vitro and the virus-induced antitumor efficacy in vivo. Although 5838 displayed much less virus replication and substantially weaker susceptibility to rRp450 in vitro, it displayed a superior in vivo therapeutic response to intratumoral rRp450 injection compared to tumors derived from the more susceptible A673 cell line. Analysis of these two tumor types demonstrated significant differences on baseline and virus-induced tumor microenvironment characteristics, including differences in cytokines, chemokines, and immune cell infiltrates. In the 5838 model, rRp450 treatment triggered higher inflammatory immune responses, including inductions of interferon-gamma (IFN-γ), Natural Killer (NK) cell chemokine CXCL10 and increased infiltration of NK cells and neutrophils in tumors. In addition, the number of pro-tumorigenic CD206+ M2-type macrophages also significantly decreased in rRp450-treated 5838 tumors. Blockade of NK cells or neutrophils alone had no effect on oHSV-induced antitumor efficacy, suggesting neither of these cell populations alone is crucial for virus-induced antitumor efficacy. Efforts to identify key mediator(s) to oHSV-induced antitumor efficacy are currently under investigation. Taken together, our study suggests that, rather than the persistence of virus replication, the oHSV-induced immune inflammatory response might determine the outcome of the oncolytic virotherapy in these models.
Citation Format: Chun-Yu Chen, Brian J. Hutzen, Pin-Yi Wang, Jennifer L. Leddon, Mark A. Currier, Nicholas Denton, Timothy Eubank, Timothy P. Cripe. Tumor-specific differences in virus-induced inflammation may determine therapeutic response to HSV virotherapy in sarcoma models. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B66.
- ©2015 American Association for Cancer Research.