Integrating gene therapy into the treatment paradigm for non-muscle invasive bladder cancer.

INTRODUCTION: Approximately 75% of bladder cancer cases are non-muscle invasive at diagnosis. Drug development for non-muscle invasive bladder cancer (NMIBC) has historically lagged behind that of other malignancies. No treatment has demonstrated the ability to overcome drug resistance that ultimately leads to recurrence and progression. Gene therapy is emerging as a promising option for patients with NMIBC.

AREAS COVERED: This review summarizes the clinical application of gene therapy in NMIBC management and discusses recent clinical trials involving the adenoviral vector-based treatment nadofaragene firadenovec, and the oncolytic serotype 5 adenovirus, cretostimogene grenadenorepvec. Nadofaragene received approval by the Food and Drug Administration in December 2022, and cretostimogene has been granted Fast Track Designation and Breakthrough Therapy Designation. Ongoing trials are investigating strategies to augment efficacy and durability of these therapies.

EXPERT OPINION: Gene therapy may overcome resistance mechanisms of other NMIBC treatments, and data suggest a role for combination therapy with additive or synergistic agents. Significant differences in trial design limit comparability of agents across trials, highlighting the need for critical assessment of published findings. While initial investigations were in high-risk patients who recur despite frontline therapy with Bacillus Calmette-Guerin (BCG), there is growing interest in BCG-naïve and intermediate-risk populations.