Most cases of bladder cancer are diagnosed at early stages, when the tumor has not yet invaded the muscular layer. Such tumors are classified as non-muscle-invasive bladder cancer. The disease is usually treated with intravesical therapy – drugs are administered directly into the bladder. The main treatment approach for patients at high risk of recurrence is bacillus Calmette–Guérin (BCG) instillation.
However, even after BCG therapy, approximately 25% of patients develop recurrent high-grade tumors, and in some patients the disease progresses to muscle-invasive or metastatic cancer. In such cases, further intravesical therapy rarely provides substantial benefit, and patients are typically recommended radical bladder removal. This surgery can significantly impair quality of life and may not always be necessary for all patients.
As a result, urology has focused on developing bladder-preserving treatment approaches. An important milestone was the 2018 guidance from the U.S. Food and Drug Administration (FDA), which established the definition of BCG-unresponsive disease, enabling more accurate patient selection for clinical trials and accelerating the development of new therapies.
One result of this effort was the FDA approval of nadofaragene firadenovec-vncg in 2022. This intravesical therapy is intended for patients with high-risk BCG-unresponsive non-muscle-invasive bladder cancer.
The drug uses a nonreplicating adenoviral vector to deliver the interferon (IFN) gene into cells, thereby promoting tumor destruction. This approach enables localized antitumor activity directly within the bladder and is considered an alternative to cystectomy.
Interferon Gene Therapy in BCG-Unresponsive Bladder Cancer
Bladder cancer may evade immune surveillance by creating an immunosuppressive microenvironment. This is why BCG therapy remains effective – it activates innate and adaptive immune responses and induces tumor cell death. However, some tumors do not respond to BCG therapy.
An alternative therapeutic strategy involves administering IFN-α, a signaling protein that enhances antitumor immunity by activating NK cells and improving immune recognition of tumors. Despite promising preclinical results, intravesical administration of IFN-α2b protein demonstrated limited efficacy in clinical studies, especially in patients previously treated with BCG. The main reason was the short residence time of the drug in the bladder, usually only 1–2 hours.
To solve this problem, researchers developed a gene therapy approach: instead of delivering the interferon protein directly into the bladder, they delivered the IFN-α2b gene using an adenoviral vector. In preclinical studies, this strategy led to more sustained interferon expression and greater tumor reduction than IFN-α2b protein administration. These findings formed the basis for further clinical development of nadofaragene firadenovec-vncg.
Phase I and II studies demonstrated that intravesical administration of nadofaragene firadenovec-vncg resulted in prolonged, dose-dependent expression of IFN-α2b in the bladder. Interferon was detected in urine as early as 24 hours after treatment and persisted for up to 10–12 days in some patients, substantially exceeding the effect of IFN-α2b protein administration.
Mechanism of Action of Nadofaragene Firadenovec-vncg
Nadofaragene firadenovec-vncg suppresses tumors through multiple mechanisms simultaneously. IFN-α2b expression directly induces tumor cell death by activating apoptotic signaling pathways. This effect also extends to neighboring tumor cells, including those resistant to high concentrations of IFN-α2b.
Additionally, IFN-α induces endoplasmic reticulum stress, affecting an intracellular structure involved in protein synthesis and transport, thereby enhancing tumor cell damage and death while sparing normal urothelium. The drug also inhibits the formation of new blood vessels, which are required for tumor growth.
Beyond its direct effects, IFN-α activates antitumor immune responses by promoting dendritic cell maturation and enhancing antigen presentation, thereby facilitating T cell recognition and tumor destruction. IFN-α also stimulates NK-cell activity, enabling the elimination of tumor cells that evade immune detection due to reduced MHC I expression.
However, some tumors may remain resistant to therapy because IFN-α increases PD-L1 expression, potentially impairing immune recognition and reducing T-cell activity.
Contraindications
Nadofaragene firadenovec-vncg is contraindicated in patients with hypersensitivity to IFN-α or other components of the drug. The FDA also warns about the potential risk of systemic adenoviral infection in immunocompromised patients. Although the therapy is based on a nonreplicating adenoviral vector, it may theoretically contain trace amounts of replication-competent virus.
Clinical Efficacy
In phase I–III studies, nadofaragene firadenovec-vncg demonstrated clinical efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer.
In the phase I study, 41% of patients achieved complete remission at 3 months, and some remained disease-free for approximately 2.5 years. Disease recurrence within 3 months was common – 57% of patients ultimately required cystectomy, and one patient died 2 years after treatment initiation due to metastases.
In the phase II study, 35% of patients remained recurrence-free after one year, while some maintained response for up to 38 months. The study compared low and high doses of nadofaragene firadenovec-vncg. The proportion of patients without recurrence at one year was 33% and 37% in the low- and high-dose groups, respectively. Recurrence during the first year occurred in 35% of patients. Time to recurrence was longer in the high-dose group than in the low-dose group: nearly 12 months versus 3.5 months.
The most important findings were obtained in the phase III trial. Among patients with BCG-unresponsive carcinoma in situ – a superficial high-grade form of bladder cancer – complete remission was achieved in 53% of patients, and nearly half of them remained recurrence-free at 12 months. Tumor recurrence within one year was observed in 71% of patients, while cystectomy was required in 29% after a median of 9 months. Among patients with papillary tumors without carcinoma in situ, 60% remained recurrence-free after one year. Recurrence within 1 year occurred in 48% of patients, and cystectomy was required in 21% of patients, with a median time to cystectomy of 8 months.
Long-term follow-up demonstrated a low progression rate to muscle-invasive cancer – approximately 3% over 5 years. In addition, a substantial proportion of patients avoided cystectomy: 5-year bladder-preservation survival was 43% in patients with carcinoma in situ and 59% in patients without it.
Safety and Tolerability
Phase I–III studies showed that nadofaragene firadenovec-vncg was generally well tolerated. No dose-limiting toxicity or severe adverse events were reported.
The most common adverse effects included urinary urgency, bladder spasms, urethral discharge, and fatigue. Most adverse events were mild and transient, resolving within several days. Treatment discontinuation due to adverse effects was required in only 2% of patients.
Clinical Use of Nadofaragene Firadenovec-vncg
The FDA approved nadofaragene firadenovec-vncg for the treatment of patients with BCG-unresponsive non-muscle-invasive bladder cancer with carcinoma in situ – with or without papillary tumors – in whom cystectomy is not feasible or is undesirable.
Results from the phase III study showed that, in the absence of recurrence, repeated administration every 3 months for up to 4 years allowed some patients to maintain long-term disease control. However, therapy duration may be extended in patients with persistent treatment response, as in 8% of patients who continued therapy for 57 months.
In cases of recurrent high-grade tumors, patients are advised to consider cystectomy or participation in clinical trials investigating novel bladder-preserving therapies.
Conclusion
Nadofaragene firadenovec-vncg became the first approved gene therapy for bladder cancer and an alternative to cystectomy in patients for whom BCG therapy was ineffective.
The drug exerts antitumor effects by prolonging local IFN-α2b production in the bladder. This combines direct tumor cell killing with activation of antitumor immune responses.
The treatment acts locally within the bladder without systemic effects, resulting in a favorable safety profile and good tolerability.
The efficacy of nadofaragene firadenovec-vncg may depend on the immune response. In particular, increased levels of anti-adenoviral antibodies after treatment were associated with more durable remission.
One possible mechanism of resistance is increased PD-L1 expression, allowing tumors to evade immune responses. To overcome resistance, combination treatment strategies are being investigated, including nadofaragene firadenovec-vncg in combination with intravesical chemotherapy or systemic immunotherapy with pembrolizumab.
Reference
Intravesical interferon-α2b gene therapy with nadofaragene firadenovec-vncg: a contemporary review
