169 SUNITINIB AUGMENTS ONCOLYTIC VIRUS MEDIATED ANTI-TUMOR IMMUNITY AGAINST RENAL CELL CARCINOMA - A NOVEL THERAPEUTIC PARADIGM?

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research (I)1 Apr 2013169 SUNITINIB AUGMENTS ONCOLYTIC VIRUS MEDIATED ANTI-TUMOR IMMUNITY AGAINST RENAL CELL CARCINOMA - A NOVEL THERAPEUTIC PARADIGM? Keith Lawson, Zhong-Qiao Shi, Jason Spurrell, Wenqian Chen, Jun Kawakami, and Don Morris Keith LawsonKeith Lawson Calgary, Canada More articles by this author , Zhong-Qiao ShiZhong-Qiao Shi Calgary, Canada More articles by this author , Jason SpurrellJason Spurrell Calgary, Canada More articles by this author , Wenqian ChenWenqian Chen Calgary, Canada More articles by this author , Jun KawakamiJun Kawakami Calgary, Canada More articles by this author , and Don MorrisDon Morris Calgary, Canada More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1549AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Here, we investigated the ability of the oncolytic virus, reovirus (RV), to prime both innate and adaptive immune responses against renal cell carcinoma (RCC). Moreover, based on clinical trials demonstrating sunitinib?s ability to reverse RCC induced immunosuppression, we sought to determine the utility of combining this agent with reovirus for superior anti-tumor immunity. METHODS Following RV infection of RCC cell lines (ACHN, 786-O, A498, RENCA) cytotoxicity, chemokine production and viral progeny were quantified by WST-1, luminex and plaque titration assays, respectively. In vivo, 8-9 week old Balb/c mice were inoculated with 2.5 x 106 RENCA cells subcutaneously to establish an immunocompetent murine model of RCC and treated with intraperitoneal (i.p) phosphate buffered saline (PBS), UV-irradiated RV (DV) intratumorally (i.t), RV (i.t), sunitinib (i.p) or a combination of these agents. Mice were followed for tumor size and overall survival. To determine the anti-tumor immune response, CD8+ splenocytes were isolated magnetically and stimulated with RV infected RENCA cells; IFN-ψ production was subsequently determined by ELISA assay. Additionally, Gr-1+/CD11b+ splenic myeloid derived suppressor cells (MDSC) were quantified from all mice by flow cytometry. Adoptive transfer of splenocytes from mice treated with RV, sunitinib or a combination these agents into treatment naive mice followed by subcutaneous RENCA tumor challenge was utilized to assess protective immunity. RESULTS In vitro, RV induced an oncolytic response associated with chemokine (RANTES, MIP-1α, MCP-1, KC, IP-10, MIG) production in all cell lines tested. In vivo, combination RV/sunitinib therapy decreased tumor burden and improved overall survival more significantly than either agent used as a monotherapy [132mm2 (PBS) vs. 61mm2 (RV) vs. 82mm2 (S) vs. 21mm2 (RV+S); p < 0.05]. This was associated with a downregulation of splenic MDSC and enhanced anti-tumor CD8+ splenocyte IFNκ response [p < 0.02]. Decreased tumor burden was observed in treatment naive mice receiving splenocytes from RV/sunitinib treated mice versus RV or sunitinib alone following RENCA tumor challenge [80mm2 (RV) vs. 74mm2 (S) vs. 35 mm2 (RV+S); p < 0.05]. CONCLUSIONS Our results demonstrate that reovirus has both direct oncolytic as well as immunotherapeutic activity against RCC. Moreover, we highlight that combination of this agent with sunitinib leads to decreased tumor burden, increased overall survival and improved protective immunity. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e69-e70 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Keith Lawson Calgary, Canada More articles by this author Zhong-Qiao Shi Calgary, Canada More articles by this author Jason Spurrell Calgary, Canada More articles by this author Wenqian Chen Calgary, Canada More articles by this author Jun Kawakami Calgary, Canada More articles by this author Don Morris Calgary, Canada More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...