Introduction:

Roughly 30–40% of patients with non-muscle invasive bladder cancer (NMIBC) will develop BCG-unresponsive disease. Several alternative options exist, including the widely accepted off-label use of intravesical gemcitabine/docetaxel. Many of the newer agents used in this space are intravesical gene therapies that deliver immune system–enhancing DNA into host bladder cells through distinct mechanisms. These are: nadofarogene firadenovec-vncg, cretostimogene grenadenorepvec, and detalimogene voraplasmid. Our tertiary care academic medical center has participated in the clinical trials for all three of these drugs and possesses a large cohort of patients for whom descriptive sequencing and oncologic outcomes are available, presented herein.

Methods:

All included patients had provided informed consent for participation in the Emory University Bladder Cancer registry, which had local institutional review board approval. We performed chart review of all patients treated with gene therapy (GT) at our institution. Demographic and oncologic characteristics were collected on all patients. Information on use of intravesical gene therapy was recorded, including sequencing of agents. Descriptive oncologic outcomes are provided.  

Results:

Between January 2017 and June 2025, 51 patient received GT at our institution. The median age at the start of GT was 73.5 (range 59–87). Patients received a median of 12 doses of BCG before being determined BCG unresponsive, at a median 24 months from the time of original diagnosis. At the time of BCG-unresponsive disease, 38 patients (75%) had CIS and 12 (23%) had T1 disease. Nadofarogene firadenovec-vncg was the first GT for 72% of patients (37/51), cretostimogene grenadenorepvec was the first for 13% of patients (7/51), and detalimogene voraplasmid was the first for 15% of patients (8/51). Thirty-five patients (68%) experienced a high-grade recurrence after initial gene therapy, at a median of 4 months (range 2–63 months) from the start of GT. Twenty-one of the HG-recurrent patients (60%) were retreated with subsequent agent. Of these, 5 (24%) were retreated with the same agent and eight (38%) were treated with gemcitabine/docetaxel. Of the retreatments, 9 (42%) had subsequent HG recurrence. Overall, four patients have received multiple gene therapies (Figure 1). At the time of data collation, 11 patients (21%) had proceeded to cystectomy, 7 (13%) had developed metastatic disease, and 9 (17%) had died (4 from bladder cancer, 8%).

Conclusion:

In this single-institution experience, intravesical gene therapy offered a bladder-preserving option for patients with BCG-unresponsive NMIBC, including those with high-risk CIS and T1 disease. While high-grade recurrence remained common, treatment with an alternative GT agent offers durable disease control in a subset of patients, with additional salvage possible with the same GT agent or gem/doce in well selected patients.  These findings highlight the evolving role of gene therapy in the management of BCG-unresponsive NMIBC and the opportunity for future work to refine sequencing strategies and optimize long-term outcomes. 

Funding: N/A