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

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

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