Bacillus Calmette-Guérin strain differences have an impact on clinical outcome in bladder cancer immunotherapy
| Autor: | Alexander Bachmann, Aurélie Bisiaux, Roland Brosch, Molly A. Ingersoll, Frédéric D. Birkhäuser, Gilles Marchal, Micheline Lagranderie, Mickael Orgeur, Joel R. Gsponer, Christian Wetterauer, Cyrill A. Rentsch, Matthew L. Albert, Christiane Bouchier, Claire Biot, George N. Thalmann |
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| Přispěvatelé: | Centre d'immunologie humaine (CIH), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunobiologie des Cellules Dendritiques, Department of urology, University of Bern, Fondation MINES ParisTech, BioTop Institut Pasteur, Pathogénomique mycobactérienne intégrée, Institut Pasteur [Paris], Génomique (Plate-Forme) - Genomics Platform, The Cancéropôle Île de France, Ligue Foundation, and the Association for Research on Cancer financed the experimental animal work. Support for the clinical studies was provided by the Swiss National Science Foundation Grant number PSAMP 129381 and by the 'Freiwillige Akademische Gesellschaft Basel.' Aurélie Bisiaux was funded by the French Foundation for Medical Research, and Molly A. Ingersoll by the LabEx Immuno-Oncology (Agence Nationale de la Recherche). Mickael Orgeur and Roland Brosch acknowledge support by the European Community's FP7 program under grant agreement number 241745, and FRM DEQ20130326471. Molly A. Ingersoll and Matthew L. Albert acknowledge support by La Ligue Contre le Cancer and Institut National du Cancer, France. The study was also supported by the Swiss Group for Clinical Cancer Research., Cyrill A. Rentsch thanks Stewart T. Cole for his encouragement in initiating this project. Matthew L. Albert thanks the Center for Human Immunology for their support of the work. The clinical study was initiated with the help of the Swiss Group for Clinical Cancer Research (SAKK), and we thank Qiyu Li (SAKK Coordinating Center, Bern, Switzerland) and K. Stucki (Institute of Mathematical Statistics and Actuarial Science, University of Bern, Switzerland) for the support with the statistical analysis of the clinical data. We also thank Wafa Frigui, Romain Veyron-Churlet, and Laurence Ma for their help in genomic DNA and/or library preparation., ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), European Project: 241745,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,NEWTBVAC(2010), European Project: FRM-DEQ20100318279,FRM, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP) |
| Rok vydání: | 2013 |
| Předmět: |
Male
medicine.medical_treatment MESH: Carcinoma Transitional Cell/mortality Intravesical drug administration 030232 urology & nephrology Kaplan-Meier Estimate BCG Connaught MESH: Risk Assessment law.invention MESH: Dose-Response Relationship Drug Mice 0302 clinical medicine MESH: Aged 80 and over MESH: Neoplasm Recurrence Local/pathology Randomized controlled trial law Models Clinical endpoint MESH: Animals Flow cytometry Prospective Studies MESH: Aged Aged 80 and over MESH: Statistics Nonparametric MESH: Middle Aged Immunogenicity MESH: Urinary Bladder Neoplasms/pathology Middle Aged 3. Good health Administration Intravesical 030220 oncology & carcinogenesis MESH: Survival Analysis MESH: Urinary Bladder Neoplasms/mortality MESH: BCG Vaccine/administration & dosage BCG Vaccine [SDV.IMM]Life Sciences [q-bio]/Immunology Female Immunotherapy MESH: Urinary Bladder Neoplasms/drug therapy MESH: BCG Vaccine/classification MESH: Carcinoma Transitional Cell/drug therapy Urology MESH: Neoplasm Recurrence Local/mortality MESH: Drug Administration Schedule complex mixtures Risk Assessment Disease-Free Survival Drug Administration Schedule Statistics Nonparametric 03 medical and health sciences In vivo MESH: Mice Inbred C57BL MESH: Carcinoma Transitional Cell/pathology medicine Animals Humans MESH: Mice MESH: Kaplan-Meier Estimate MESH: Administration Intravesical Aged Carcinoma Transitional Cell Bladder cancer MESH: Humans Dose-Response Relationship Drug business.industry Animal BCG Tice medicine.disease Survival Analysis MESH: Prospective Studies MESH: Male Mice Inbred C57BL Urinary Bladder Neoplasms Immunology MESH: Disease-Free Survival Neoplasm Recurrence Local business BCG vaccine MESH: Female MESH: Immunotherapy/methods CD8 |
| Zdroj: | European Urology European Urology, Elsevier, 2014, 66 (4), pp.677-688. ⟨10.1016/j.eururo.2014.02.061⟩ European Urology, 2014, 66 (4), pp.677-688. ⟨10.1016/j.eururo.2014.02.061⟩ Eur Urol |
| ISSN: | 1873-7560 0302-2838 1421-993X |
| Popis: | BACKGROUND: Whether the commonly used bacillus Calmette-Guerin (BCG) strains Connaught and Tice confer different treatment responses in non-muscle-invasive bladder cancer (NMIBC) is unknown. OBJECTIVES: To compare clinical efficacy, immunogenicity, and genetics of BCG Connaught and Tice. DESIGN, SETTING, AND PARTICIPANTS: A prospective randomized single-institution trial with treatment of 142 high-risk NMIBC patients with BCG Connaught or Tice. INTERVENTION: 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. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: 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. RESULTS AND LIMITATIONS: 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. PATIENT SUMMARY: We compared the efficacy of two commonly used bacillus Calmette-Guerin (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. TRIAL REGISTRATION: NCT00003779. |
| Databáze: | OpenAIRE |
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