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Intravesical gene therapy with adenoviral-mediated interferon-alpha (Roferon A) led to complete responses in almost half of patients with bacillus Calmette-GuÃ©rin (BCG)-refractory transitional cell bladder cancer.
Seven of 15 evaluable patients had negative cystoscopy, biopsy, and cytology 3 months after treatment, first author Mark B. Fisher, MD, reported at the AUA annual meeting in Chicago. Five of the seven patients received a second dose of the gene therapy.
"Intravesical administration of adenoviral-mediated interferon-alpha is safe and well tolerated," said Dr. Fisher, who was a urologic oncology fellow at M.D. Anderson Cancer Center in Houston at the time of the study. "Effective gene transfer provides sustained urine interferon levels. Retreatment at 90 days is feasible and produced high urine interferon levels."
Overcoming early challenges
The rationale for use of interferon gene therapy to treat bladder cancer came from preclinical studies showing that interferon-alpha gene therapy inhibited tumorigenicity and metastasis by human bladder cancer in athymic mice. The inhibitory activity owed in part to various antiangiogenic effects that included endothelial cell apoptosis (Clin Cancer Res 2002; 8:1258-70).
"Unfortunately, early gene therapy trials have been disappointing, primarily because of challenges related to gene delivery," said Dr. Fisher, currently in group practice in Downers Grove, IL.
In an effort to overcome the challenges, investigators evaluated the proprietary novel excipient Syn3, which enhanced uptake and expression of recombinant adenovirus in bladder epithelium.
Preclinical studies using intravesical adenoviral-mediated interferon alpha-2a and interferon alpha-2b, in the presence of Syn3, markedly suppressed tumor growth and provided the impetus for the phase I study (Mol Ther 2004; 10:525-32).
Other research from the lab of study co-author William F. Benedict, MD, showed that interferon gene therapy had activity against interferon-resistant cells and in genetically altered urothelium. Additionally, studies have shown minimal toxicity in normal bladder tissue.
Phase II study anticipated
Dr. Fisher presented data from a phase I trial involving 16 patients with carcinoma in situ or stage Ta bladder cancer that had proven refractory to optimal BCG therapy or patients with T1 disease who had refused cystectomy. Each patient received a single dose of therapy, and biopsy was performed at baseline and on day 90. The primary endpoint of the ongoing trial is safety, and the secondary endpoint is interferon expression in urine from baseline to day 28.
Patients have received doses of 3x109 to 3x 1011 viral particles with 1.0 mg/mL Syn3. Total volume administered was 75 cc with a dwell time of 1 hour.
No dose-limiting toxicity has occurred thus far. Two patients had transient urinary urgency that prevented a 1-hour dwell time, but the remainder of the patients were treated successfully for 1 hour after pretreatment with anticholinergics. One patient developed urinary tract infection, and four had asymptomatic low-grade fever with transient decrease in neutrophil count. No patient had a change in AUA symptom score or bladder capacity.
It is expected that these initial results will soon be extended to a phase II study.