Demystifying Vector-Based Intravesical Gene Therapy for NMIBC: A New Frontier


Neal Shore, MD, FACS, is a U.S. Chief Medical Officer at GenesisCare USA and Medical Director of the Carolina Urologic Research Center. He also was an investigator on the Phase 2 and 3 studies in the clinical trial program for nadofaragene firadenovec-vncg.

Gene therapy is one of the more advanced medical breakthroughs, but with only 32 therapies approved by the U.S. Food and Drug Administration (FDA), it represents a small fraction of the therapeutic options available to patients, especially in oncology. As a result, gene therapy remains poorly understood by many clinicians and patients, inspiring both excessive enthusiasm for its potential efficacy and concern for possible unique and unknown adverse effects.

In urology, the availability of the first and only FDA-approved intravesical gene therapy (nadofaragene firadenovec-vncg) for non-muscle-invasive bladder cancer (NMIBC) unresponsive to standard therapy – Bacillus Calmette-Guerin (BCG) – unresponsive non-Muscle Invasive Bladder Cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors represents a breakthrough in the treatment paradigm for NMIBC patients. Demystifying the mechanism of action (MOA) of gene therapies like nadofaragene firadenovec-vncg is essential to help patients and clinicians make more informed, personalized treatment decisions.

The Mechanisms of Gene Therapies

The therapeutic potential for gene therapy is based on correcting a genetic defect either by replacing a disease-causing gene with a healthy one, inactivating an improperly functioning gene, or introducing a new or modified gene into the body. Among the types of gene therapies approved or in development are gene editing technology like CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats), which focuses on modifying a select region of the DNA, and the use of vectors to carry a gene or DNA segments into a host cell.

Viral vectors such as inactivated adenovirus are effective in delivering the desired genetic material into human cells. By nature, viruses can evade the body’s immune system to introduce their genetic material into cells. As the first DNA virus to be studied under a therapeutic program, adenovirus represents one of the more effective vectors given that most of human cells have adenovirus attachment receptors.1,2 The adenovirus has become one of the more commonly studied vectors in clinical trials, which continue to establish its safe use.2

One of the more highly expressed adenovirus receptors on human epithelial cells, including urothelial cells, is the coxsackievirus and adenovirus receptor (CAR).3 CAR plays a role in immune cell activation but also serves as a binding site for adenoviral infection. For viral-based vector gene therapy, the adenovirus is modified to inactivate their infection-causing ability.

Understanding the MOA of nadofaragene firadenovec-vncg

Nadofaragene firadenovec-vncg is a non-replicating adenovirus vector-based therapy containing the gene interferon alfa-2b (IFNα2b), a naturally occurring protein with antitumor activity.4,5 IFNα2b triggers tumor cell death via necrosis or endoplasmic reticulum stress and apoptosis.6 It is administered directly into the bladder and contains the Syn3 excipient, which helps to promote the transfer of the genetic material across the glycosaminoglycan (GAG) layer of the inner wall of the bladder.5,7,8 Inactivated adenovirus vector enters cells of the bladder wall releasing the gene encoding for the INFa2b protein into the nucleus, which is transcribed into mRNA.9 When the gene is incorporated into the cellular DNA of the bladder, it turns the bladder wall cells into essentially what could be considered as interferon microfactories.4,5,9 As a result, the bladder cell walls synthesize and secrete high quantities of IFNα2b protein, enhancing the body’s own natural defenses against the cancer.6

Clinical Evidence

The efficacy of nadofaragene firadenovec-vncg was demonstrated in an open-label, multicenter, single-arm Phase 3 trial involving adults (n=103) with BCG-unresponsive, high-risk, non-muscle invasive bladder cancer with carcinoma in situ (CIS) with or without papillary tumors following transurethral resection. The trial defined BCG-unresponsive high-risk NMIBC as persistent disease following adequate BCG therapy, disease recurrence after an initial tumor-free state following adequate BCG therapy, or T1 disease following a single induction course of BCG. Prior to enrollment, all patients had undergone transurethral resection of bladder tumor (TURBT) to remove all resectable disease. Participants received 75 mL (3 x 1011 vp/mL) nadofaragene firadenovec-vncg administered intravesically once every three months for up to 12 months.10

Among participants who had evaluable responses (n=98), more than half (51%, 50/98; 95% CI: 41% to 61%) of patients with CIS with or without concomitant high-grade Ta or T1 disease (CIS ± Ta/T1) achieved a complete response (CR) by month three of treatment. CR was defined by negative results for cystoscopy (with TURBT/biopsies, as applicable) and urine cytology. Of the patients who achieved an initial CR, 46% (n=23/50) continued to remain free of high-grade recurrence at 12 months.10

The safety of nadofaragene firadenovec-vncg was generally manageable with the most common (>10%) adverse reactions (ARs), including the following: laboratory abnormalities (>15%) including an increase in glucose, triglycerides, and creatine levels, and a decrease in phosphate levels; instillation site discharge; fatigue; bladder spasm; micturition (urination urgency); hematuria (blood in urine); chills; pyrexia (fever); and dysuria (painful urination). The majority of these adverse events were transient and generally mild to moderate in intensity.9 Serious adverse reactions occurred in 11% of patients who received ADSTILADRIN. Three patients (1.9%) discontinued treatment due to ARs.10 Importantly, high local expression of the IFNα2b protein was sustained typically for one to two weeks and did not build into the patient’s DNA.

In-Office Administration

Treatment with nadofaragene firadenovec-vncg is administered by catheter directly into the patient’s bladder once every three months in a clinical setting, outpatient setting, or hospital. The dosing is 75 mL at a concentration of 3 x 1011 viral particles (vp)/mL instilled once every three months into the bladder via a urinary catheter. This treatment option addresses the unique needs of urologists and patients, with an in-office administration that they are already familiar with enabling continuity of care.

The necessary equipment also is already available in the clinic. Aside from four thawed vials of nadofaragene firadenovec-vncg, instillation will require the following equipment:

  • Four vented vial adaptors suitable for a standard 20 mL vial;
  • Two standard 50 or 60 mL polypropylene Luer lock syringes or one Luer lock syringe equal to or greater than 75 mL (max 100 mL); and
  • Two Luer lock adaptors, including one straight, or intermittent, urethral catheter with a proximal funnel opening that will accommodate the Luer lock adapter. Clinicians should only use catheters made of vinyl/PVC (uncoated or coated with hydrogel), red rubber latex or silicone to instill nadofaragene firadenovec-vncg. Do not use catheters coated or embedded with silver or antibiotics.


In the U.S., there are approximately 260,000 patients with high-grade NMIBC on BCG therapy who are at an elevated risk of experiencing disease recurrence and progression.11 According to the AUA/SUO joint guidelines for NMIBC, up to 70% of newly diagnosed high-risk NMIBC patients experience recurrence within five years of starting BCG therapy; 10% to 45% of cases will progress to muscle invasive or metastatic bladder cancer within five years.11,12

For these patients, there is clearly a critical need for safe, efficacious treatment options following BCG treatment in patients who have persistent or recurrent disease.13,14,15 The FDA approval of nadofaragene firadenovec-vncg represented an important advancement in our current NMIBC treatment landscape, offering our patients and their families with a new alternative therapy.


ADSTILADRIN is a non-replicating adenoviral vector-based gene therapy indicated for the treatment of adult patients with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors.


CONTRAINDICATIONS: ADSTILADRIN is contraindicated in patients with prior hypersensitivity reactions to interferon alfa or to any component of the product.


  • Risk with delayed cystectomy: Delaying cystectomy in patients with BCG-unresponsive CIS could lead to development of muscle invasive or metastatic bladder cancer, which can be lethal. If patients with CIS do not have a complete response to treatment after 3 months or if CIS recurs, consider cystectomy.
  • Risk of disseminated adenovirus infection: Persons who are immunocompromised or immunodeficient may be at risk for disseminated infection from ADSTILADRIN due to low levels of replication-competent adenovirus. Avoid ADSTILADRIN exposure to immunocompromised or immunodeficient individuals.

DOSAGE AND ADMINISTRATION: Administer ADSTILADRIN by intravesical instillation only. ADSTILADRIN is not for intravenous use, topical use, or oral administration.

USE IN SPECIFIC POPULATIONS: Advise females of reproductive potential to use effective contraception during ADSTILADRIN treatment and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during ADSTILADRIN treatment and for 3 months after the last dose.

ADVERSE REACTIONS: The most common (>10%) adverse reactions, including laboratory abnormalities (>15%), were glucose increased, instillation site discharge, triglycerides increased, fatigue, bladder spasm, micturition (urination urgency), creatinine increased, hematuria (blood in urine), phosphate decreased, chills, pyrexia (fever), and dysuria (painful urination).

You are encouraged to report negative side effects of prescription drugs to FDA. Visit or call 1-800-332-1088. You may also contact Ferring Pharmaceuticals at 1-888-FERRING.

Please click to see the full Prescribing Information.


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  8. Benedict WF, et al. Intravesical Ad-IFNalpha causes marked regression of human bladder cancer growing orthotopically in nude mice and overcomes resistance to IFN-alpha protein. Mol Ther 2004;10(3):525–532.
  9. Boorjian SA, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: A single-arm, open-label, repeat-dose clinical trial. Lancet Oncol 2021;22(1):107–117.
  10. ADSTILADRIN. Package insert. Ferring Pharmaceuticals, Inc.; 2022
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