A systematic review of gene-mediated therapy in BCG-unresponsive NMIBC: emerging evidence and future perspectives

BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC) represents a major therapeutic challenge, given the high risk of disease progression and the absence of validated bladder-sparing strategies. In this context, gene-mediated therapy has emerged as a promising bladder-sparing approach.

A systematic review of the literature available on Medline and Google Scholar was conducted to report the main oncological evidence, safety profile and future perspectives on gene therapies in BCG-unresponsive NMIBC. A total of 3157 records were screened and 13 references were included in our result section, including 8 articles from PubMed and 5 unpublished studies presented at conferences between 2023 and 2025.

Gene-mediated therapies are emerging as a promising therapeutic strategy, with complete responses rates ranging from 53.4% to 82.9% at 3 months and from 24.4% to 57.1% at 12 months. Median duration of response rate ranging from 9,7 to 28 months. The safety profile is promising, with overall adverse events ranging from 47% to 91%, including grade ≥ 3 adverse events in 4% to 14% of cases, and no treatment-related deaths. The recent Food and Drug Administration approval of Nadofaragene firadenovec, is expected to provide relevant real-world clinical data. However, precise patient selection, the lack of predictive biomarkers for response or monitoring, and the cost-related challenges of these treatments remain major limitations.

Gene therapies represent a novel and promising therapeutic approach for BCG-unresponsive NMIBC, with significant oncological efficacy and a favorable safety profile.