Download PDF
Aktuelle Urol 2022; 53(02): 148-152
DOI: 10.1055/a-1677-0952
Originalarbeit

Adjuvante Instillationstherapie des nicht muskelinvasiven Harnblasenkarzinoms – neue Optionen abseits von BCG und Mitomycin

Adjuvant instillation therapy for non-muscle invasive bladder cancer – beyond BCG and mitomycin C
Georgios Gakis
1   Department of Urology and Pediatric Urology, University Hospital of Würzburg, Würzburg, Germany
› Author Affiliations
› Further Information
Also available at
    Permissions and Reprints

Zusammenfassung

Aufgrund der eingeschränkten Wirksamkeit der passiven Applikationsweise von BCG und Mitomycin-C (MMC) und in den letzten Jahren bestehenden BCG-Lieferengpässen ist eine Verbesserung der onkologischen Ergebnisse der adjuvanten Instillationstherapie beim nicht muskelinvasiven Harnblasenkarzinom (NMIBC) durch Entwicklung neuartiger Instillationsubstanzen und Applikationsweisen erforderlich.

Gemcitabin ist als generisch verfügbare Substanz in zahlreichen randomisierten Studien in den verschiedenen Risikokonstellationen untersucht worden und zeigt insbesondere im BCG-unresponsiven Stadium ein verbessertes rezidivfreies Überleben im Vergleich zur BCG-Rechallenge und MMC. Eine neuartige Instillationsform stellt das Gemcitabin-intravesical-releasing system (GemRIS) dar, welches in der Kombination mit dem systemisch wirksamen Checkpointinhibitor Cetrelimab in derzeit anlaufenden klinischen Studien getestet wird. Hyperthermes intravesikales MMC (HIVEC), welches extrakorporal erwärmt und in die Blase zirkuliert, führt zu einer Konzentrationssteigerung von MMC in der Blasenwand und wird im Rahmen klinischer Studie bereits getestet. Nadofaragene firadenovec (rAd-IFN-α/Syn3) ist ein rekombinantes Adenovirus zur Steigerung der Interferon-alpha-Konzentration im Urothel und bietet erstmalig die Möglichkeit eine intravesikale Gentherapie für die urologischen Praxis zu etablieren. Daten aus einer aktuellen Phase-III Studie legen im BCG-unresponsiven Stadium eine höhere Wirksamkeit bei günstigerem Nebenwirkungsprofil im Vergleich zu Studien mit einer PD-(L)1-Monotherapie nahe. Opportuzumab monatox ist ein rekombinantes Fusionsprotein, welche nach EpCAM-Binding zu einer Freisetzung von Pseudomonas aeruginosa Exotoxin führt, welches hiernach einen zytotoxischen Zellschaden einleitet. N-803 ist ein Interleukin (IL)-15 Superagonist, welcher im Kombination mit BCG in einer Phase Ib Studie ein dauerhaftes komplettes Ansprechen über 72 Monate bei 9 intermediate/high-risk Patienten zeigte und bereits 2019 eine Vorabzulassung durch die FDA erhalten hat.

Abstract

Due to limited local efficacy of BCG and mitomycin C and the worldwide shortage of BCG, there is a clinical need to develop novel intravesical agents and application forms in order to improve the oncological outcomes in non-muscle invasive bladder cancer (NMIBC). Gemcitabine has been investigated in various clinical trials. It has proven to be superior to BCG rechallenge and MMC in BCG-unresponsive high-risk NMIBC. GemRIS is an implantable novel form of intravesical drug delivery of gemcitabine and is currently being investigated with cetrelimab, a checkpoint inhibitor, in patients with high-risk NMIBC and MIBC. Hyperthermic intravesical chemotherapy (HIVEC) leads to increased concentrations of MMC in the bladder wall and is also being investigated in various NMIBC settings. Nadofaragene firadenovec (rAd-IFN-α/Syn3) is a recombinant adenovirus that induces release of interferon-alpha in the urothelium. In a randomised study on patients with BCG-unresponsive NMIBC, it has shown relatively superior efficacy and tolerability compared with studies evaluating the role of checkpoint inhibitor monotherapies. Opportuzumab monatox is a recombinant fusion protein which binds to EpCAM and induces release of exotoxins, resulting in cytotoxic cell death. N-803 is an interleukin (IL)-15 analogue, which has been investigated in a phase 1b study in combination with BCG and has shown durable complete response in all nine patients for 72 months. It was granted breakthrough designation status by the FDA in 2019.

Schlüsselwörter

TAR-200 - Chemohyperthermie - Nadofaragene firadenovec - Opportuzumab monatox - N-803

Keywords

TAR-200 - chemohyperthermia - Nadofaragene firadenovec - Opportuzumab monatox - N-803


Publication History

Received: 21 October 2021

Accepted: 18 January 2022

Article published online:
16 February 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • Referenzen

  • 1 Krebgesellschaft D. S3-Leitlinie Harnblasenkarzinom (Langversion). https://www.leitlinienprogramm-onkologie.de/fileadmin/user_upload/Downloads/Leitlinien/Blasenkarzinom/Version_2.0/LL_Harnblasenkarzinom_Langversion_2.0.pdf 2016
    Search in Google Scholar
  • 2 Kramer MW, Gakis G. Immuno-oncological therapeutic options in high-risk non-muscle invasive bladder cancer. Urologe A 2020; 59: 784-9
    CrossrefPubMedSearch in Google Scholar
  • 3 Witjes JA, Babjuk M, Bellmunt J. et al. EAU-ESMO Consensus Statements on the Management of Advanced and Variant Bladder Cancer-An International Collaborative Multistakeholder Effort(dagger): Under the Auspices of the EAU-ESMO Guidelines Committees. Eur Urol 2020; 77: 223-50
    CrossrefPubMedSearch in Google Scholar
  • 4 Gakis G, Efstathiou J, Lerner SP. et al. ICUD-EAU International Consultation on Bladder Cancer 2012: Radical cystectomy and bladder preservation for muscle-invasive urothelial carcinoma of the bladder. Eur Urol 2013; 63: 45-57
    CrossrefPubMedSearch in Google Scholar
  • 5 Jones G, Cleves A, Wilt TJ. et al. Intravesical gemcitabine for non-muscle invasive bladder cancer. Cochrane Database Syst Rev 2012; 1: CD009294
    CrossrefPubMedSearch in Google Scholar
  • 6 Shelley MD, Jones G, Cleves A. et al. Intravesical gemcitabine therapy for non-muscle invasive bladder cancer (NMIBC): a systematic review. BJU Int 2012; 109: 496-505
    CrossrefPubMedSearch in Google Scholar
  • 7 Bohle A, Leyh H, Frei C. et al. Single postoperative instillation of gemcitabine in patients with non-muscle-invasive transitional cell carcinoma of the bladder: a randomised, double-blind, placebo-controlled phase III multicentre study. Eur Urol 2009; 56: 495-503
    CrossrefPubMedSearch in Google Scholar
  • 8 Li R, Li Y, Song J. et al. Intravesical gemcitabine versus mitomycin for non-muscle invasive bladder cancer: a systematic review and meta-analysis of randomized controlled trial. BMC Urol 2020; 20: 97
    CrossrefPubMedSearch in Google Scholar
  • 9 Bendary L, Khalil S, Shahin A. et al. Intravesical gemcitabine versus bacillus Calmette-Guerin (BCG) in treatment of non-muscle invasive bladder cancer: a short term comparative study. J Urol 2011; 185: e664-5
    CrossrefPubMedSearch in Google Scholar
  • 10 Sylvester RJ, Brausi MA, Kirkels WJ. et al. Long-term efficacy results of EORTC genito-urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guerin, and bacillus Calmette-Guerin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol 2010; 57: 766-73
    CrossrefPubMedSearch in Google Scholar
  • 11 Porena M, Del Zingaro M, Lazzeri M. et al. Bacillus Calmette-Guerin versus gemcitabine for intravesical therapy in high-risk superficial bladder cancer: a randomised prospective study. Urol Int 2010; 84: 23-7
    CrossrefPubMedSearch in Google Scholar
  • 12 Di Lorenzo G, Perdona S, Damiano R. et al. Gemcitabine versus bacille Calmette-Guerin after initial bacille Calmette-Guerin failure in non-muscle-invasive bladder cancer: a multicenter prospective randomized trial. Cancer 2010; 116: 1893-900
    CrossrefPubMedSearch in Google Scholar
  • 13 Addeo R, Caraglia M, Bellini S. et al. Randomized phase III trial on gemcitabine versus mytomicin in recurrent superficial bladder cancer: evaluation of efficacy and tolerance. J Clin Oncol 2010; 28: 543-8
    CrossrefPubMedSearch in Google Scholar
  • 14 Grimberg DC, Shah A, Inman BA. Overview of Taris GemRIS, a Novel Drug Delivery System for Bladder Cancer. Eur Urol Focus 2020; 6: 620-2
    CrossrefPubMedSearch in Google Scholar
  • 15 Di Stasi SM, Giannantoni A, Massoud R. et al. Electromotive versus passive diffusion of mitomycin C into human bladder wall: concentration-depth profiles studies. Cancer Res 1999; 59: 4912-8
    PubMedSearch in Google Scholar
  • 16 Di Stasi SM, Giannantoni A, Giurioli A. et al. Sequential BCG and electromotive mitomycin versus BCG alone for high-risk superficial bladder cancer: a randomised controlled trial. Lancet Oncol 2006; 7: 43-51
    CrossrefPubMedSearch in Google Scholar
  • 17 Di Stasi SM, Giannantoni A, Stephen RL. et al. Intravesical electromotive mitomycin C versus passive transport mitomycin C for high risk superficial bladder cancer: a prospective randomized study. J Urol 2003; 170: 777-82
    CrossrefPubMedSearch in Google Scholar
  • 18 Di Stasi SM, Valenti M, Verri C. et al. Electromotive instillation of mitomycin immediately before transurethral resection for patients with primary urothelial non-muscle invasive bladder cancer: a randomised controlled trial. Lancet Oncol 2011; 12: 871-9
    CrossrefPubMedSearch in Google Scholar
  • 19 Pijpers OM, Hendricksen K, Mostafid H. et al. Long-term efficacy of hyperthermic intravesical chemotherapy for BCG-unresponsive non-muscle invasive bladder cancer. Urol Oncol 2021; 40: 62.e13-62.e20
    CrossrefPubMedSearch in Google Scholar
  • 20 Shore ND, Boorjian SA, Canter DJ. et al. Intravesical rAd-IFNalpha/Syn3 for Patients With High-Grade, Bacillus Calmette-Guerin-Refractory or Relapsed Non-Muscle-Invasive Bladder Cancer: A Phase II Randomized Study. J Clin Oncol 2017; 35: 3410-6
    CrossrefPubMedSearch in Google Scholar
  • 21 Boorjian SA, Alemozaffar M, Konety BR. et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Lancet Oncol 2021; 22: 107-17
    CrossrefPubMedSearch in Google Scholar
  • 22 Kowalski M, Guindon J, Brazas L. et al. A phase II study of oportuzumab monatox: an immunotoxin therapy for patients with noninvasive urothelial carcinoma in situ previously treated with bacillus Calmette-Guerin. J Urol 2012; 188: 1712-8
    CrossrefPubMedSearch in Google Scholar
  • 23 Rosser CJ, Tikhonenkov S, Nix JW. et al. Safety, Tolerability, and Long-Term Clinical Outcomes of an IL-15 analogue (N-803) Admixed with Bacillus Calmette-Guerin (BCG) for the Treatment of Bladder Cancer. Oncoimmunology 2021; 10: 1912885
    CrossrefPubMedSearch in Google Scholar