MP54-02 DEVELOPMENT OF INTRAVESICAL HUMAN γΔT CELL BASED CHEMO-IMMUNOTHERAPY AGAINST URINARY BLADDER CANCER CELLS IN AN ORTHOTOPIC XENOGRAFT MODEL

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology I1 Apr 2018MP54-02 DEVELOPMENT OF INTRAVESICAL HUMAN γΔT CELL BASED CHEMO-IMMUNOTHERAPY AGAINST URINARY BLADDER CANCER CELLS IN AN ORTHOTOPIC XENOGRAFT MODEL Teruki Shimizu, Mako Tomogane, Masatsugu Miyashita, Osamu Ukimura, and Eishi Ashihara Teruki ShimizuTeruki Shimizu More articles by this author , Mako TomoganeMako Tomogane More articles by this author , Masatsugu MiyashitaMasatsugu Miyashita More articles by this author , Osamu UkimuraOsamu Ukimura More articles by this author , and Eishi AshiharaEishi Ashihara More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.1693AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Intravesical BCG treatment continues to play a central role in the treatment of non-muscle invasive urinary bladder cancer (UBC). There is currently no gold standard for salvage intravesical therapy after BCG treatment failure. To develop the substitute for BCG treatment failure, we focused on γδT cell immunotherapy. γδT cells exert potent cytotoxicity towards various cancer cells and can recognize isopentenyl pyrophosphate (IPP) through the TCRγδ receptor, and zoredronic acid (ZOL) pretreatment is widely used to induce IPP accumulation in cancer cells. In this study, we hilighted two issues; combined use of anticancer agents along with ZOL and a bladder instillation approach. The aims are to improve recognition of cancer cells by γδT cells and to increase E/T (Effector/Target) ratio. METHODS We examined the efficacy of ex vivo-expanded γδT cell immunotherapy. Flow cytometric analysis of CFSE/propidium iodide (PI) staining was used in in vitro cytotoxicity assays.After co-culture for 4 h, CFSE/PI double positive population was measured as apoptotic cancer cells. In in vivo experiment, the efficacy of ex vivo-expanded γδT cell immunotherapy was examined in an orthotopic xenograft model using In Vivo Imaging System (IVIS). RESULTS Ex vivo-expanded γδT cells showed potent cytotoxicity against UBC cells in in vitro assays. Combination treatment with standard anticancer agents showed that low dose gemcitabine pretreatment significantly enhanced the cytotoxicity of γδT cells by upregulating the expression of MICA and MICB (MICA/B), which are tumor-associated antigens recognized by γδT cells. These effects were abrogated by small interfering RNA-mediated knockdown of MICA/B in UBC cells. IVIS analysis revealed the potent cytotoxicity of weekly intravesical administration of γδT cells (Figure. 1), and weekly gemcitabine pretreatment enhanced the cytotoxicity of γδT cells in vivo. CONCLUSIONS Low dose gemcitabine pretreatment significantly enhanced the cytotoxicity of γδT cells by upregulating the expression MICA/B in in vitro. Intravesical γδT cell immunotherapy exerted potent cytotoxicity against UBC and intravesical γδT cell immunotherapy in combination with low dose gemcitabine may be a promising strategy in UBC. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e712 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Teruki Shimizu More articles by this author Mako Tomogane More articles by this author Masatsugu Miyashita More articles by this author Osamu Ukimura More articles by this author Eishi Ashihara More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...