GENE THERAPY FOR ESOPHAGEAL CANCER

January 25, 2010 (Orlando, Florida) — In the first clinical trial in locally advanced esophageal cancer, gene therapy, administered concurrent with chemotherapy and radiotherapy, led to high pathologic complete response (pCR) rates and a doubling in survival over historic controls. The multicenter study was presented here at the 2010 Gastrointestinal Cancers Symposium by Kenneth Chang, MD, from the University of California Irvine Medical Center, in Orange.

The meeting is sponsored by the American Gastroenterological Association, the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

TNFerade Biologic is a second-generation replication-deficient adenovector carrying the transgene encoding human tumor necrosis factor (TNF)-α, which is regulated by the radiation-inducible promoter Egr-1. Intratumoral administration of TNFerade causes the secretion of TNF-α protein in tumors, which leads to the collapse of the tumor vasculature and the stimulation of proinflammatory and apoptotic pathways within the tumor. TNF-α also has a necrotizing and possibly immunomodulatory action, Dr. Chang said.

In a study of 24 patients, most with adenocarcinomas of T3 N1 stage, TNFerade was given weekly for 5 weeks by intratumoral injection under endoscopy or endoscopic ultrasound guidance, along with a 5.5-week course of cisplatin, 5-fluorouracil, and radiation (45 Gy total). Successive dosing cohorts received TNFerade at 4 × 10⁸, 4 × 10⁹, 4 × 10¹⁰, and 4 × 10¹¹ particle units weekly. Final follow-up data were available for all but the highest-dose group.

For the initial 3 dosing cohorts combined, the pCR rate was 36%, but reached 100% in some of the dosing cohorts. Two additional patients who were not resected had pCRs as well; these were shown radiographically. With their inclusion, the pCR rate was 47%. "They remain disease-free at 66 and 48 months," he noted.

"With these weekly injections, we were able to downstage the tumors," he said.

At 5 years, median overall survival was 56%, and median overall survival time was 47.7 months, he reported.

"This is in contrast to historic controls," Dr. Chang explained, "who have been shown to have median survival of 9.7 months, or up to 34 months at the most. This is much greater." He added that the 5-year survival rate is typically about 20%.

"[TNFerade] plus chemotherapy and radiotherapy yields an encouraging increase in survival over historic controls and warrants additional evaluation," Dr. Chang concluded.

During the discussion, however, Jaffer Ajani, MD, from the University of Texas M.D. Anderson Cancer Center in Houston, who participated in the study early on, raised questions about the toxicity of the treatment; these data were not presented by Dr. Chang. Dr. Ajani said the study had been discontinued because of treatment-related deaths. He also explained that the treatment "is a big production," because it requires a gastroenterologist to deliver the treatment weekly, and questioned whether a survival advantage could be determined in a study of 24 patients.

Dr. Chang responded that the drug continues to be in development, and that after much review, the deaths were not attributed to the injection of TNF. "It appears that as an adjunct to treatment it is safe," he said, "and given the preliminary data, a larger trial is warranted."

In an interview with Medscape Oncology, Mark Thornton, MD, PhD, senior vice president of product development for GenVec, in Gaithersburg, Maryland, which manufacturers TNFerade, explained that early in the study, 1 patient died from a pulmonary embolism. Pending further investigation, the US Food and Drug Administration halted the study, but the drug is still being studied in larger pancreatic cancer trials. "Rigorous assessment" in that setting, including a comparison between the TNFerade and control groups, has shown no difference in thromboembolic events. The product is now in phase 3 trials for pancreatic cancer. Encouraging preliminary results were presented at the 2009 American Society of Clinical Oncology annual meeting (Abstract 4605), Dr. Thornton noted.

"This concern is ancient history," he said, adding that further studies in esophageal cancer are now expected.

The authors of the study report receiving consulting fees, being employed by, or owning stock in GenVec. Dr. Ajani reports receiving research funding from Sanofi-Aventis, Taiho, NS Pharma, and Adherex.

2010 Gastrointestinal Cancers Symposium (GICS): Abstract 45. Presented January 22-24, 2010.