You have accessJournal of UrologyBladder Cancer: Basic Research IV1 Apr 2014MP39-08 A LISTERIOLYSIN EXPRESSING BCG WITH FAVOURABLE IMMUNOGENICITY AND PRECLINICAL TOXICITY AS A NOVEL TREATMENT FOR NON-MUSCLE INVASIVE BLADDER CANCER Cyrill Rentsch, Christian Wetterauer, Joel Gsponer, Heike Püschel, Alexander Bachmann, Leander Grode, Ankitha Minhas, Bernd Eisele, Doris Beherens, Willem de Blok, Nicole van der Wel, and Bas van Rhijn Cyrill RentschCyrill Rentsch More articles by this author , Christian WetterauerChristian Wetterauer More articles by this author , Joel GsponerJoel Gsponer More articles by this author , Heike PüschelHeike Püschel More articles by this author , Alexander BachmannAlexander Bachmann More articles by this author , Leander GrodeLeander Grode More articles by this author , Ankitha MinhasAnkitha Minhas More articles by this author , Bernd EiseleBernd Eisele More articles by this author , Doris BeherensDoris Beherens More articles by this author , Willem de BlokWillem de Blok More articles by this author , Nicole van der WelNicole van der Wel More articles by this author , and Bas van RhijnBas van Rhijn More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1323AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES VPM1002 is a genetically modified BCG vaccine in which all antibiotic resistance cassettes have been removed. The main genetic modification consists of the incorporation of the pore-forming toxin listeriolysin of Listeria monocytogenes. Listerolysin activity leads to the disruption of both, lysosomal and cell membranes and induces apoptosis. Consequently, this leads to optimised exposure of extracellular antigens to MHC class I receptors and to potential induction of cancer specific cytotoxic T cells. VPM1002 has been tested with favourable toxicity and immunogenicity profiles (Th1, Th17) in phase I and II trials as a vaccine for tuberculosis. Here we report preclinical data and a planned safety program for its use in non-muscle invasive bladder cancer (NMIBC). METHODS Systemic spread of mycobacteria after intrabladder (i.b.) instillation or intravenous (i.v.) bolus injection was assessed using VPM1002 or BCG-medac in female BL/6 mice to receive: 10e5 CFU of VPM1002 or 10e5 CFU of BCG-medac by 6 i.b. administrations/week and 10e5 CFU of VPM1002 or BCG-medac administered i.v. Mortality, symptoms, and microbial organ culture were assessed at week 1, 3, 5, 6. Toxicology studies in SCID mice and comparative single dose toxicity studies using the single i.b. administration are ongoing. Furthermore, a repeat dose toxicity study in mouse including three dose levels of BCG and VPM1002 will be performed and reported. RESULTS No local intolerance reactions in the mice treated with 10e5 CFU VPM1002 or BCG medac/animal i.b./iv. were observed. No test item-related deaths were noted at any tested dosing. The body weights of all animals were in the normal range throughout the course of the study. Repeated i.v. treatment with 10e5 CFU VPM1002 or BCG-medac/animal caused slightly to severely enlarged spleens and enlarged livers. Considerable CFU counts were noted in liver, lungs and spleen of the animals treated with 10e5 CFU BCG-medac/animal i.v. In contrast, no relevant CFU counts were noted in the examined organs of the animals treated with VPM1002 i.v. After 220 days all SCID mice receiving BCG-medac have died and all of the VPM1002 treated animals are still alive. CONCLUSIONS VPM1002 is the potentially first recombinant BCG suitable for future use as a new therapeutic in patients affected by NMIBC. The preclinical and clinical toxicity profiles from vaccination studies are encouraging. A phase I/II clinical trial in patients with BCG induction failure is currently being developed. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e428 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Cyrill Rentsch More articles by this author Christian Wetterauer More articles by this author Joel Gsponer More articles by this author Heike Püschel More articles by this author Alexander Bachmann More articles by this author Leander Grode More articles by this author Ankitha Minhas More articles by this author Bernd Eisele More articles by this author Doris Beherens More articles by this author Willem de Blok More articles by this author Nicole van der Wel More articles by this author Bas van Rhijn More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...