title: Bacillus Calmette-Guérin strain differences have an impact on clinical outcome in bladder cancer immunotherapy.
abstract: BACKGROUND
  Whether the commonly used bacillus Calmette-Guérin (BCG) strains Connaught and Tice confer different treatment responses in non-muscle-invasive bladder cancer (NMIBC) is unknown.
  
  
  OBJECTIVE
  To compare clinical efficacy, immunogenicity, and genetics of BCG Connaught and Tice.
  
  
  METHODS
  A prospective randomized single-institution trial with treatment of 142 high-risk NMIBC patients with BCG Connaught or Tice.
  
  
  METHODS
  Patients were randomized to receive six instillations of BCG Connaught or Tice. For experimental studies, BCG strains were compared in C57Bl/6 mice. Bladders and lymphoid tissues were analyzed by cytometry and the latter cultivated to detect live BCG. BCG genomic DNA was sequenced and compared with reference genomes.
  
  
  METHODS
  Recurrence-free survival was the primary end point of the clinical study. The Kaplan-Meier estimator was used for estimating survival and time-to-event end points. Nonparametric tests served for the analysis of the in vivo results.
  
  
  CONCLUSIONS
  Treatment with BCG Connaught conferred significantly greater 5-yr recurrence-free survival compared with treatment with BCG Tice (p=0.0108). Comparable numbers of patients experienced BCG therapy-related side effects in each treatment group (p=0.09). In mice, BCG Connaught induced stronger T-helper cell 1-biased responses, greater priming of BCG-specific CD8(+) T cells, and more robust T-cell recruitment to the bladder than BCG Tice. Genome sequencing of the BCG strains revealed candidate genes potentially involved in the differential clinical responses.
  
  
  CONCLUSIONS
  BCG strain may have an impact on treatment outcome in NMIBC immunotherapy.
  
  
  RESULTS
  We compared the efficacy of two commonly used bacillus Calmette-Guérin (BCG) strains for the treatment of NMIBC and found that treatment with BCG Connaught prevented recurrences more efficiently than BCG Tice. Comparison of the immunogenicity of the two strains in mice indicated superior immunogenicity of BCG Connaught. We also identified genetic differences that may explain the differential efficacy of the Connaught and Tice BCG strains.
  
  
  BACKGROUND
  NCT00003779.
authors.affiliation: Department of Urology, University Hospital Basel, Basel, Switzerland; Laboratory of Dendritic Cell Biology, Department of Immunology, Institut Pasteur, Paris, France; Center for Human Immunology, Institut Pasteur, Paris, France.
authors.forename: Cyrill A
authors.initials: CA
authors.lastname: Rentsch
authors.affiliation: Department of Urology, University of Bern, Inselspital, Bern, Switzerland.
authors.forename: Frédéric D
authors.initials: FD
authors.lastname: Birkhäuser
authors.affiliation: Laboratory of Dendritic Cell Biology, Department of Immunology, Institut Pasteur, Paris, France; Inserm U818, Paris, France; Mines ParisTech, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Biot
authors.affiliation: Department of Urology, University Hospital Basel, Basel, Switzerland; Laboratory of Dendritic Cell Biology, Department of Immunology, Institut Pasteur, Paris, France; Center for Human Immunology, Institut Pasteur, Paris, France.
authors.forename: Joël R
authors.initials: JR
authors.lastname: Gsponer
authors.affiliation: Laboratory of Dendritic Cell Biology, Department of Immunology, Institut Pasteur, Paris, France; Inserm U818, Paris, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Bisiaux
authors.affiliation: Department of Urology, University Hospital Basel, Basel, Switzerland; Laboratory of Dendritic Cell Biology, Department of Immunology, Institut Pasteur, Paris, France; Center for Human Immunology, Institut Pasteur, Paris, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Wetterauer
authors.affiliation: Immunotherapix BioTop, Institut Pasteur, Paris, France.
authors.forename: Micheline
authors.initials: M
authors.lastname: Lagranderie
authors.affiliation: Immunotherapix BioTop, Institut Pasteur, Paris, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Marchal
authors.affiliation: Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France.
authors.forename: Mickael
authors.initials: M
authors.lastname: Orgeur
authors.affiliation: PF1-Plate-Forme Génomique, Institut Pasteur, Paris, France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Bouchier
authors.affiliation: Department of Urology, University Hospital Basel, Basel, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Bachmann
authors.affiliation: Laboratory of Dendritic Cell Biology, Department of Immunology, Institut Pasteur, Paris, France; Inserm U818, Paris, France; Université Paris Descartes, Paris, France.
authors.forename: Molly A
authors.initials: MA
authors.lastname: Ingersoll
authors.affiliation: Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France.
authors.forename: Roland
authors.initials: R
authors.lastname: Brosch
authors.affiliation: Laboratory of Dendritic Cell Biology, Department of Immunology, Institut Pasteur, Paris, France; Inserm U818, Paris, France; Université Paris Descartes, Paris, France; Center for Human Immunology, Institut Pasteur, Paris, France.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Albert
authors.affiliation: Department of Urology, University of Bern, Inselspital, Bern, Switzerland. Electronic address: george.thalmann@insel.ch.
authors.forename: George N
authors.initials: GN
authors.lastname: Thalmann
mesh_terms: D000283:Administration, Intravesical; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001500:BCG Vaccine / Q000008:administration & dosage* / Q000145:classification; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000401:mortality / Q000473:pathology; D011446:Prospective Studies; D018570:Risk Assessment; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology
chemical_list: C087507:BCG Connaught; D001500:BCG Vaccine
keywords: Animal; BCG Connaught; BCG Tice; BCG vaccine; Flow cytometry; Immunotherapy; Intravesical drug administration; Models; Randomized controlled trial; Urinary bladder neoplasms