Interferon gene therapy with nadofaragene firadenovec for bladder cancer - from bench to approval

Sep 24, 2026

A mini review examines how interferon-a (IFNa) gene therapy using nadofaragene firadenovec (Adstiladrin®) reached approval for bladder cancer, addressing the translational pathway from foundational studies to clinical milestones. It explains why bladder cancer is suitable for gene therapy via direct bladder access and feasible monitoring using urine and tissue samples. Key technical barriers in gene transfer across the urothelium are discussed, including strategies such as modulating CAR expression and disrupting the urothelial barrier with Syn3. Clinical trial outcomes, ongoing research needs, and future directions for biomarkers, patient selection, vector optimization, and combination regimens targeting resistance mechanisms are summarized.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages6

Reading Time15 min

AccessFree to download

Introduction

Gene therapy: definitions and early development

TYPE Mini Review PUBLISHED 29 August 2023 DOI 10.3389/fimmu.2023.1260498 OPEN ACCESS EDITED BY Bryan E. Strauss, University of São Paulo, Brazil REVIEWED BY Howard L Kaufman, Massachusetts General Court, United States Steven Albelda, University of Pennsylvania, United States *CORRESPONDENCE Colin P. N. Dinney [cdinney@mdanderson.org](cdinney@mdanderson.org) RECEIVED 17 July 2023 ACCEPTED 01 August 2023 PUBLISHED 29 August 2023 CITATION Martini A, Tholomier C, Mokkapati S and Dinney CPN (2023) Interferon gene therapy with nadofaragene ﬁradenovec for bladder cancer: from bench to approval. Front. Immunol. 14:1260498 . doi: 10.3389/fimmu.2023.1260498 COPYRIGHT © 2023 Martini, Tholomier, Mokkapati and Dinney. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Interferon gene therapy with nadofaragene ﬁradenovec for bladder cancer: from bench to approval Alberto Martini, Cˆome Tholomier, Sharada Mokkapati and Colin P. N. Dinney* Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States Bladder cancer is a prevalent malignancy with limited therapeutic options, particularly for patients who are unresponsive to Bacillus Calmette-Gurin (BCG) . The approval of interferon-a (IFNa) gene therapy with nadofaragene ﬁradenovec (Adstiladrin®), the ﬁrst gene therapy for genitourinary malignancies, has provided a promising alternative. This article reviews the research and milestones that led to the development and approval of nadofaragene ﬁradenovec. Bladder cancer is well-suited for gene therapy due to direct access to the bladder and the availability of urine and tissue samples for monitoring. Early challenges included effective gene transfer across theurothelium, which was overcome initially by modulating the expression of coxsackie/adenovirus receptor (CAR) and, ultimately, by disrupting theurothelial barrier with Syn3 . Nadofaragene ﬁradenovec is a modiﬁed adenoviral vector carrying the IFNa gene. Clinical trials have shown promising results, with high response rates and manageable adverse events. Ongoing research focuses on improving patient selection, identifying biomarkers for response prediction, exploring alternative vectors for enhanced transfection efﬁciency, and developing combination strategies targeting resistance mechanisms. The approval of nadofaragene ﬁradenovec marks a signiﬁcant milestone in the ﬁeld of gene therapy for bladder cancer, and future developments hold promise for further enhancing its efﬁcacy and impact. KEYWORDS bladder cancer, gene therapy, immunogene therapy, BCG unresponsive bladder cancer, novel medications Introduction Bladder cancer (BLCA) is the seventh most common male malignancy, and the tenth worldwide overall (1) . Bladder cancer is classiﬁed according to the depth of invasion as either non-muscle invasive (NMIBC) or muscle invasive (MIBC) (2) . The former accounts for approximately 70% of newly diagnosed bladder cancers. The current standard of care Frontiers in Immunology 01 [frontiersin.org](frontiersin.org) for treatment of NMIBC is transurethral resection, followed by intravesical therapy. Bacillus Calmette-Gúerin (BCG) is the most effective intravesical therapy and is currently indicated for high-risk patients (3) . Unfortunately, over time most patients recur with BCG-unresponsive disease which is an inherently resistant disease with limited therapeutic options beyond radical cystectomy. However, many patients refuse or are not optimal candidates for this procedure. Prior to the approval of nadofa

FAQs

Why is bladder cancer considered well-suited for gene therapy in this review?

The review notes that the bladder can be accessed directly, allowing urine and tissue samples for monitoring, which supports assessment of therapeutic delivery and response.

What early barrier needed to be overcome for effective gene transfer?

Effective gene transfer across the urothelium was a key challenge; it was addressed by initially modulating CAR expression and ultimately by disrupting the urothelial barrier using Syn3.

What is nadofaragene firadenovec, and what do clinical trials suggest?

Nadofaragene firadenovec is a modified adenoviral vector carrying the IFNa gene. Clinical trials show promising efficacy signals with high response rates and manageable adverse events.

Sep 24, 2026

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