Abstract 1545: Sensitivity of pancreatic adenocarcinoma to oncolytic vesicular stomatitis virus
Authors: Aaron U. Blackham, Scott A. Northrup, John H. Stewart
Journal: Cancer Research (2012)

Abstract Introduction: Oncolytic M protein mutant vesicular stomatitis virus (M51R-VSV) has potent oncolytic activity in a variety of cancer cells due to its ability to kill malignant cells with acquired defects in interferon (IFN)-mediated antiviral defenses. Herein we explore the sensitivity of pancreatic adenocarcinoma cells to recombinant wild-type virus (rwt-VSV) and M51R-VSV. Methods: Cell viability after VSV infection in Panc 1, MiaPaCa2, BxPC3, Panc 03.27, and Panc 10.05 cells was measured by MTS assay. Viral infectability was determined by flow cytometry using GFP labeled M51R-VSV. Responsiveness to extrinsic α-IFN in the setting of VSV infection was assessed by MTS assay. Xenografts were established in athymic nude mice and treated with intratumoral M51R-VSV. Results: Panc 1, MiaPaCa2, and BxPC3 were very sensitive to both rwt-VSV and M51R-VSV, displaying less than 20% cell viability at 48 hours after single-cycle infection (MOI 10 pfu/cell). Panc 10.05 cells remained moderately resistant at 48 hours but by 72 hours were completely sensitive to VSV under all conditions tested. In contrast, Panc 03.27 cells remained relatively resistant at 72 hours, displaying cell viabilities of 36±15 and 26±14% after rwt-VSV and M51R-VSV infection (MOI 10 pfu/cell) respectively. Similarly, sensitive Panc 1, MiaPaCa2, BxPC3, and Panc 10.05 cells permitted high levels of viral infectability by 24 hours post-infection even under multi-cycle infection conditions (MOI 0.1 pfu/cell) indicating that VSV replication and spread are feasible in these cell lines. Panc 03.27 cells, however, continue to resist M51R-VSV infection 24 hours after infection, even at extremely high MOIs (6.4±5.1% infectivity at MOI of 50 pfu/cell). Pre-treatment with α-IFN in sensitive pancreatic cancer cells demonstrated dose-dependent protection from VSV, suggesting that these cells possess defects in IFN-signaling which can be overcome by high doses of α-IFN. In contrast, the effect of high-dose α-IFN had a pro-apoptotic effect in resistant Panc 03.27 cells. M51R-VSV intratumoral treatment of established xenografts resulted in significantly reduced tumor growth relative to controls after 30 days in sensitive MiaPaCa2 tumors (1423±345% vs 164±136%, p&amp;lt;0.001), as well as in in vitro-resistant Panc 03.27 tumors (979±153% vs 50±56%, p=0.002). Conclusions: Pancreatic adenocarcinoma cells display varying degrees of sensitivity to VSV. Sensitive cell lines possess defects in IFN-mediated antiviral defenses which explain their sensitivity to VSV infection and killing while resistant cell lines appear to have intact anti-viral signaling. However, murine xenografts from resistant cells were sensitive to the oncolytic effects of VSV indicating that α-IFN from surrounding cells or natural killer cells may influence in vivo sensitivity. These data suggest that M51R-VSV is a promising future therapeutic option for patients with pancreatic adenocarcinoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1545. doi:1538-7445.AM2012-1545