A gene therapy that stimulates interferon production within the body may prove to be effective against high-risk, early-stage bladder cancer when standard treatment fails.
For patients with high-risk non–muscle-invasive bladder cancer (i.e., Tis and high-grade Ta and T1 tumors) that persists or recurs despite standard treatment with bacille Calmette-Guérin (BCG), known as “BCG-unresponsive disease,” treatment options are currently limited. Because of the high risk of progression to muscle-invasive disease, the safest option is cystectomy; however, many patients are understandably reluctant to undergo removal of their bladder. An alternative is second-line medical therapy, but the only U.S. Food and Drug Administration (FDA)–approved drug for BCG-unresponsive disease, valrubicin, results in a durable complete response for only 8% of patients.
“There is currently no effective salvage therapy for patients with BCG-unresponsive, high-risk non–muscle-invasive bladder cancer that can safely delay cystectomy or direct patients away from cystectomy,” said Colin Dinney, M.D., a professor in and chair of the Department of Urology at The University of Texas MD Anderson Cancer Center. “So we and others are launching studies to try to find alternatives to cystectomy that are safe for patients.”
Within the next few years, patients may have a more effective second-line medical treatment option: a new adenovirus-mediated gene therapy that causes cells lining the bladder to produce interferon alfa-2b.
A long road to a new treatment
Although interferon alfa-2b is an established anticancer agent, instillation of interferon into the bladder has had only limited efficacy against bladder cancer because the drug is rapidly cleared from the body in urine. Gene therapy, in contrast, causes the cells lining the bladder to produce interferon, resulting in prolonged exposure.
A group that includes Dr. Dinney and William Benedict, M.D., a professor in the Departments of Genitourinary Medical Oncology and Urology, has been working for years to develop an effective gene therapy for bladder cancer. The researchers expected bladder tumors to be ideal targets for gene therapy because the vector containing the gene can be instilled easily into the bladder and retained in the bladder for several minutes, which should allow for good contact between the vector and the bladder wall, good transfer of the vector, and good gene activity. However, the researchers discovered that the bladder’s antibacterial and antiviral layer, which protects against infections, also prevents gene transfer.
A solution to this problem came in the form of Syn3, a surfactant that enhances the ability of the adenoviral vector to transduce cells in the bladder wall. Critical preclinical studies in mouse models developed by Dr. Benedict showed that delivering the gene vector together with Syn3 resulted in effective vector uptake and interferon production by both tumor cells and normal cells. “The bladder was working like a bioreactor to produce interferon, which it did for about a week,” Dr. Dinney said.
In the preclinical studies, the new gene therapy facilitated by Syn3 caused marked shrinkage of established bladder tumors, and three mechanisms of action were identified. First was a direct effect: some tumor cells that incorporated the gene became overwhelmed by the resulting production of interferon protein and died as a result. Second, the interferon-sensitive tumor cells—approximately 20%–25% of all tumor cells—underwent apoptosis because of their prolonged exposure to interferon in the bladder. Third and most important was a so-called bystander effect, in which a protein excreted into the urine was effective even against interferon-resistant tumor cells. The normal urothelial cells, although transduced by the vector and producing interferon, were not harmed by exposure to interferon.
The new gene therapy is the latest advance in an ongoing line of research, much of which is supported by MD Anderson’s Bladder Cancer Specialized Programs of Research Excellence (SPORE) grant from the National Cancer Institute.
Early clinical trials show promise
Building on the promising preclinical findings, researchers from several institutions conducted a phase I trial of recombinant adenovirus–mediated gene therapy with interferon alfa-2b plus Syn3 for patients with non–muscle-invasive bladder cancer that recurred after treatment with BCG. The 17 patients enrolled in this dose-escalation trial received a single intravesical instillation of the gene vector plus Syn3, which was retained in the bladder for 1 hour. Patients were monitored for adverse effects for 5 days after treatment and underwent cystoscopy at 3 months. Patients with a complete response at 3 months were allowed to receive 1 more dose of the gene therapy.
o dose-limiting toxic effects were observed in the trial. All adverse effects were grade 1 or 2, and the most common adverse effect, urinary urgency, was minimized by pretreatment administration of anticholinergics in all cases.
In all patients except those treated at the lowest dose, interferon alfa-2b was detectable in urine for up to 10 days after treatment, confirming effective gene transfer. The peak levels of interferon in the urine corresponded with the number of viral particles administered. And most exciting, cystoscopy 3 months after gene therapy demonstrated a complete response in seven of the 17 patients, including six of the 13 patients who were treated at a dose of at least 1 x 1010 viral particles/mL.
Encouraged by the results of the phase I trial, Dr. Dinney and others designed an industry-sponsored multi-institutional phase II trial. In this trial, patients with high-grade, non–muscle-invasive bladder cancer were randomly assigned to receive treatment with Syn3 plus the highest or second-highest dose of the interferon alfa-2b gene therapy vector from the phase I trial (3 x 1011 or 1 x 1011 viral particles/mL). Patients underwent an initial 1-hour intravesical instillation of the therapy, and patients who exhibited a complete response could receive up to 3 additional treatments at the same dose level at 3-month intervals, for a total of 4 doses. The trial was launched in November 2012, and accrual was completed in just over 1 year.
Of the 40 patients enrolled in the phase II trial, 23 had had disease that persisted despite BCG therapy, and 17 had been rendered disease free with BCG therapy but then had a recurrence. Unaudited interim results were reported in May at the American Urological Association’s annual meeting, and results are now available for all 40 patients.
The rate of freedom from high-grade recurrence, calculated on an intent-to-treat basis, was 56% at 6 months and 35% at 12 months and was similar in the two dose groups. The study also showed that the 12-month recurrence-free survival rate of the nine patients with papillary (Ta or T1) disease alone (55%) was higher than that of the 29 patients with a component of carcinoma in situ (30%). There were only three adverse events related to the treatment: a grade 2 uncomplicated urinary tract infection, a case of grade 3 diarrhea in a patient with a history of diarrhea, and a case of grade 3 acute renal failure resulting from dehydration due to a urinary tract infection.
Larger trial in the works
As a result of the phase II trial’s success, Dr. Dinney and others are currently working with the FDA to design a phase III registration trial of recombinant adenovirus–mediated interferon alfa-2b plus Syn3 in patients with BCG-unresponsive high-risk non–muscle-invasive bladder cancer. The trial, slated to begin in early 2016, is expected to enroll approximately 100 patients at 35 centers. The trial will have two unconventional features. First, it will have no control arm because outcomes with the currently approved second-line drug therapy, valrubicin, are relatively poor. Instead, all patients will receive gene therapy, and results will be compared with benchmarks approved by urologic oncologists and the FDA. Second, the trial will include a mixed population of patients with carcinoma in situ and patients with high-grade papillary disease, a patient combination the FDA has not allowed in previous phase III bladder cancer trials.
The criterion for determining whether the new gene therapy should be approved remains to be identified. Dr. Dinney expects this criterion to be a high-grade recurrence–free survival rate of at least 25% at 12 months. “That would be meaningful,” he said, “because valrubicin had a complete response rate of about 20% at 3 months and a durable response rate of about 8%.”
he planned phase III trial will also identify biomarkers linked to response to the new gene therapy. Currently, David McConkey, Ph.D., a professor in the Department of Urology, and Xifeng Wu, M.D., Ph.D., a professor in and chair of the Department of Epidemiology, are analyzing pretreatment and posttreatment urine and tissue samples from the phase II trial to identify potential biomarkers. “One of the possible biomarkers we’re looking at in the clinical trial specimens is whether or not adenoviral interferon caused upregulation of TRAIL (a cytotoxic cytokine) in urine or tumors or maybe both and whether the urine levels of TRAIL or the length of time TRAIL was detectable in urine correlates with clinical responses,” Dr. McConkey said. Any promising markers will be further studied in the phase III trial.
Also, work in Dr. McConkey’s laboratory has shown that interferon alfa upregulates the immune mediator programmed cell death ligand 1 (PD-L1) in human bladder cancer cells, so samples obtained before and after treatment will be analyzed to determine whether there is a change in the level of PD-L1 or its binding partner, programmed cell death 1 (PD-1). “We hypothesize that we might be able to get even better clinical activity if we combine adenoviral interferon with antibodies that block PD-L1 or PD-1, which might limit the immune response,” Dr. McConkey said.
There is a real unmet need for new treatments for BCG-unresponsive, high-risk non–muscle-invasive bladder cancer,” Dr. Dinney said. “The research we’re doing could change the field.”
For more information, contact Dr. Colin Dinney at 713-563-7465 or Dr. David McConkey at 713-792-8591.
OncoLog, August 2015, Volume 60, Issue 8