MP65-07 TREATMENT WITH THE HISTONE DEACETYLASE INHIBITOR, CI-994, IN COMBINATION WITH PD-1 BLOCKADE LEADS TO REGRESSION OF INTRAVESICAL MURINE TUMORS (2017)

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology III1 Apr 2017MP65-07 TREATMENT WITH THE HISTONE DEACETYLASE INHIBITOR, CI-994, IN COMBINATION WITH PD-1 BLOCKADE LEADS TO REGRESSION OF INTRAVESICAL MURINE TUMORS Catherine Eden, Cynthia Perez-Fournier, Gopal Gupta, and Jose Guevara-Patino Catherine EdenCatherine Eden More articles by this author , Cynthia Perez-FournierCynthia Perez-Fournier More articles by this author , Gopal GuptaGopal Gupta More articles by this author , and Jose Guevara-PatinoJose Guevara-Patino More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2001AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES HDACs constitute a family of enzymes that deacetylate histones and cellular proteins resulting in regulation of transcription and cellular processes. HDAC inhibition has been shown to induce genes coding for MHC class I and class II molecules and immunologic activation molecules. Tissue microarray analysis of bladder cancer cell lines has demonstrated high HDAC expression in 40-60% of urothelial tumors. Our objective was to investigate the use of HDAC inhibitors on bladder tumors to stimulate immune mediated tumor cell destruction. METHODS In vitro human bladder cancer cell lines were cultured with exposure to various HDAC inhibitors and HLA matched human T cells. The murine urothelial cell line, MB49 was also cultured with HDAC inhibitors and activated murine splenocytes. MTT assay was performed to measure cell viability. We transduced the murine tumor line to carry Firefly luciferase to allow for bioluminescence monitoring post implantation and then implanted the cells intra-vesically using a 24Fr angiocatheter delivery method. Following implantation bioluminescence signals were monitored using IVIS Lumina imaging system. Our treatment arm consisted of a single intra-vesical instillation of CI-994 for 60 minutes on post-implantation Day 6 with intraperitoneal injection of PD-1 blockade, appropriate controls were also performed. Total flux was monitored by IVIS in the treatment and control arms. RESULTS In Vitro analysis showed a statistically significant decrease in viable tumor cells when treated with a short course of CI-994 and then exposed to activated human T cells (p 0.0025). There was an even greater response when the T cells had received PD-1 blockade (p 0.0003). MTT assay analysis of MB49 yielded similar positive results with CI-994 treatment and T cell exposure. In vivo mice who received intravesical CI-994 in combination with intraperitoneal PD-1 blockade showed a more immediate and durable response than mice in the control arms. The average bioluminescence signal for our combination treatment arm indicates minimal to no retained tumor burden. CONCLUSIONS HDACs are widely expressed in urothelial cancer and inhibition of the selective HDAC inhibitor CI-994 has shown promising results in vitro and in an in vivo orthotopic model at reducing tumor burden. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e854-e855 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Catherine Eden More articles by this author Cynthia Perez-Fournier More articles by this author Gopal Gupta More articles by this author Jose Guevara-Patino More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...