Abstract
Abstract The Edmonston vaccine strain of measles virus (MV-Edm) is a promising oncolytic agent whose mechanisms of cytotoxicity, safety and efficacy are well established. A prerequisite for the clinical development of retargeted oncolytic viruses is the preclinical understanding of virus-host-tumor interactions in vivo. Unfortunately, this requirement has not yet been met in the measles virotherapy field, because of the lack of validated models and vectors able to target murine tumors or tissues. Our goals are to investigate the tumor selectivity and virus-host interactions of a novel oncolytic MV retargeted against murine uPA receptor in syngeneic immunocompetent cancer models. We have recently rescued and characterized novel oncolytic measles viruses fully retargeted against murine (MV-muPA) urokinase receptor. The murine specific virus offers the unique opportunity for in vivo characterization of virus-tumor-host interactions -as it relates to safety and efficacy-, in syngeneic models with an intact immune system. Efficient MV-muPA viral infection, replication and cytotoxicity were demonstrated in murine tumor cells (4T1, MC38 and CT26), whereas MV-muPA did not induce significant infection and cytotoxicity in B16F10 and TSA murine cancer cells. To validate MV-muPA as a therapeutic vector in syngeneic models, we assessed the antitumor effects of MV-muPA in immunocompetent models of murine colon cancer (CT26). Four intravenous administration of MV-muPA (2×10e6 PFUs) resulted in significant inhibition of tumor progression in treated animals. Successful tumor targeting after IV administration was demonstrated by IHC analysis of MV-N protein in resected tumors. No visible adverse events were observed in treated animals compared to controls. To characterize the biodistribution of MV-muPA in an immunocompetent model, 4T1 bearing BALB/C mice were treated with MV-muPA (2×10e6 PFUs) twice via tail vein. After five days virus treatment, tumors and major organs were removed for histological analysis (H&E) and for viral RNA quantification by qRT-PCR. MV-muPA preferentially concentrated in the primary tumor, as demonstrated by significantly higher RNA copy numbers of MV-N compared to other organs. While significant necrosis and inflammatory changes were observed in tumors from treated animals, non-tumor bearing tissues did not show histological signs of viral induced toxicity. In conclusion, our results demonstrated successful replication and antitumor efficacy of a fully retargeted measles virus in murine tumor cells in vitro and in vivo, and suggest targeting of tumor vasculature, and systemic administration of MV-muPA effectively targets tumor tissues without significantly affecting normal organs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5388. doi:10.1158/1538-7445.AM2011-5388
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call