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

objectiveBCG-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.

methodsA 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records were screened and 13 references were included in our result section, including 8 articles from PubMed and 5 unpublished studies presented at conferences between 2023 and 2025.

resultsGene-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.

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