The role of urinary microbiome in determining response to intravesical BCG-therapy in patients with high risk non-muscle invasive bladder cancer.

• Applicant: Dr. Jan Moritz Maas
• Subject Area: Reproductive Medicine, Urology ; Hematology, Oncology
• Term: from 2022 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 496073793

• Final Report Year: 2024

Final Report Abstract

Urothelial carcinomas of the bladder are classified into muscle-invasive (MIBC) and nonmuscle invasive carcinomas (NMIBC). While the former necessitate radical surgical methods, bladder-sparing therapy represents the gold standard for non-muscle invasive tumors. For patients with high-risk variants of NMIBC, intravesical therapy with Bacillus Calmette-Guérin (BCG), an attenuated form of Mycobacterium bovis, in addition to transurethral resection of the tumors is essential to reduce progression and recurrence rates. However, this therapy, which relies on a local inflammatory response for its anti-cancer effect, is ineffective in approximately 30-40% of patients, with inadequate immune response considered a contributing factor. Contrary to previous assumptions, the human urinary tract is not sterile but harbors a commensal microbiome comprising various bacteria, similar to the gastrointestinal tract. Dysbiosis of this microbiome results in altered immune responses, a factor deemed relevant in several non-urological diseases, as well as in certain urological conditions such as interstitial cystitis. Our hypothesis was that the urinary microbiome modulates the immune response induced by BCG therapy, thereby influencing its efficacy. To investigate this hypothesis, we collected urine and stool samples from 143 high-risk NMIBC patients across multiple centers (Vancouver, Toulouse, Helsinki) before and after BCG therapy. The goal was to examine the predictive role of the overall composition of each microbiome in response to BCG therapy, identify specific microorganisms associated with treatment success, and reciprocally evaluate the impact of BCG therapy on microbiome composition. To date, no predictive microbiome clusters in stool or urine have been identified. However, certain bacteria showed an association with a BCG response. The urinary microbiome demonstrated a higher predictive value than the stool microbiome. Specifically, Corynebacteria and anerobic cocci were associated with a positive BCG response, while Pseudomonades were frequently observed in cases of non-response to BCG. Furthermore, we demonstrated that BCG therapy significantly reduces the total number of bacterial species in urine. Interestingly, this reduction in the so-called alpha-diversity (number of bacterial species present) was also observed in the stool, a body compartment without direct contact with BCG. Divergent results between urine and stool were observed in betadiversity. Here, significant changes in composition were observed in urine samples, whereas stool samples did not exhibit such changes.

Publications

• A Peritoneal Purse-String Suture Prevents Symptomatic Lymphoceles in Retzius-Sparing Robot-Assisted Radical Prostatectomy. Journal of Clinical Medicine, 12(3), 791.
  Harland, Niklas; Alfarra, Mohammed; Erne, Eva; Maas, Moritz; Amend, Bastian; Bedke, Jens & Stenzl, Arnulf
  
• A Protocol for Organoids from the Urine of Bladder Cancer Patients. Cells, 12(17), 2188.
  Walz, Simon; Pollehne, Paul; Geng, Ruizhi; Schneider, Johannes; Maas, Moritz; Aicher, Wilhelm K.; Stenzl, Arnulf; Amend, Bastian & Harland, Niklas
  
• Combined positive score (CPS) and PD-L1 status in patients with high-risk non- muscle invasive bladder cancer are influenced by an intravesical therapy with Bacillus Calmette- Guérin (BCG)
  M. Maas; A. Hilsendecker; A. Pertoll; H. Bösmüller; V. Stühler; S. Walz; S. Rausch; A. Stenzl; J. Hennenlotter & S. Aufderklamm
  
• Development and initial evaluation of infigratinib-eluting seeds for localized treatment of non-muscle invasive bladder cancer (NMIBC)
  M. Maas; M. Reike; K. Yu; A. Contreras-Sanz; H. Bahlburg; A. Wang; H. Adomat; I. Moskalev; D. Lange; J. Kizkhakkedathu & P. Black
  
• Die intravesikale BCG Therapie beeinflusst den Combined Positive Score (CPS) sowie den PD-L1 Status im high-risk nicht-muskelinvasiven Urothelkarzinom der Harnblase
  M. Maas; A. Hilsendecker; A. Pertoll; H. Bösmüller; V. Stühler; S. Walz; S. Rausch; A. Stenzl; J. Hennenlotter & S. Aufderklamm
  
• Differential Expression and Clinical Relevance of C-X-C Motif Chemokine Receptor 4 (CXCR4) in Renal Cell Carcinomas, Benign Renal Tumors, and Metastases. International Journal of Molecular Sciences, 24(6), 5227.
  Maas, Moritz; Kurcz, Aymone; Hennenlotter, Jörg; Scharpf, Marcus; Fend, Falko; Walz, Simon; Stühler, Viktoria; Todenhöfer, Tilman; Stenzl, Arnulf; Bedke, Jens & Rausch, Steffen
  
• Impact of the extent of lymph node dissection on survival outcomes in clinically lymph node‐positive bladder cancer. BJU International, 133(3), 341-350.
  von Deimling, Markus; Furrer, Marc; Mertens, Laura S.; Mari, Andrea; van Ginkel, Noor; Bacchiani, Mara; Maas, Moritz; Pichler, Renate; Li, Roger; Moschini, Marco; Bianchi, Alberto; Vetterlein, Malte W.; Lonati, Chiara; Crocetto, Felice; Taylor, Jacob; Tully, Karl H.; Afferi, Luca; Soria, Francesco ... & del Giudice, Francesco
  
• Impact of urinary and gut microbiota on Bacillus Calmette-Guérin-induced response in non-muscle invasive bladder cancer
  D. Othman; T. Jalanko; M. Reike; I. Moskalev; B. Nelson; A. Hussein; C. Tin; M. Romigué; D. Ferreira; A. Contreras-Sanz; M. Maas; A. Miller; P. Black & D. Lange
  
• Nierenkarzinom – Experimentell, Diagnostik Analyse der immunologischen Marker BTLA, TIM3 und PD-L1 an der Invasionsfront und im Tumorzentrum des klarzelligen Nierenzellkarzinoms
  V. Stühler; B. Alemi; M. Maas; S. Walz; S. Rausch; A. Stenzl; M. Schwab; E. Schaeffeler & J. Bedke
  
• Radical Transurethral Resection of Bladder Tumor in Seemingly Organ-confined Muscle-invasive Bladder Cancer: Con. European Urology Focus, 9(2), 223-224.
  Maas, Moritz & Black, Peter C.
  
• Urine biomarkers in bladder cancer — current status and future perspectives. Nature Reviews Urology, 20(10), 597-614.
  Maas, Moritz; Todenhöfer, Tilman & Black, Peter C.
  
• Urothelkarzinom – Therapie invasiver Tumore An empirical survey on the adaption of neoadjuvant chemotherapy in muscle-invasive bladder cancer in Germany, Austria and Switzerland
  M.J. Reike; A. Reicherz; K.H. Tully; H. Bahlburg; M. Maas; M. Brehmer; C. Bolenz; J. Noldus; S. Berg & F. Roghmann
  
• Urothelkarzinom – Therapie invasiver Tumore The optimal number of cycles in clinically lymph node-positive bladder cancer
  M. von Deimling; L.S. Mertens; R. Li; M. Furrer; G. Ten Dijck; J. Tylor; F. Corcetto; M. Maas; A. Mari; R. Pichler; M. Moschini; K.H. Tully; D. D.’Andrea; G. Marcq; M. Velev; A. Gallioli; S. Albisinni; K. Mori; A. Khanna; M. Rink; M. Fisch; A. Minervini; P.C. Black; Y. Lotan; B. Kiss; P.E. Spiess; S.F. Shariat & B. Pradere
  
• Urothelkarzinom – Therapie nicht-invasiver Tumoren Development and initial evaluation of infigratinib-eluting seeds for localized treatment of non-muscle invasive bladder cancer (NMIBC)
  M. Maas; M. Reike; K. Yu; A. Contreras-Sanz; H. Bahlburg; A. Wang; H. Adomat; I. Moskalev; D. Lange; J. Kizkhakkedathu & P. Black
  
• Variabilität und prognostische Wertigkeit des combined-positive Scores (CPS) in Zusammenhanf mit einer intravesikalen BCG Therapie bei Patienten mit high-risk nichtmuskelinvasivem Urothelkaruinom (HR NMIBC)
  M. Maas; A. Hilsendecker; A. Pertoll; H. Bösmüller; V. Stühler; S. Walz; S. Rausch; A. Stenzl; J. Hennenlotter & S. Aufderklamm
  
• Upper Urinary Tract Urothelial Carcinoma (UTUC), Chapter 16, in The Ureter: A comprehensive review, Eds: M. Abdel-Gawad, B. Ali- El-Dein, J. Barry, A. Stenzl, Springer, ISBN-13 978-3031362118, expected March 2024
  S. Aufderklamm; M. Maas & A. Stenzl