A Novel Gene Transfer Therapy Against Pancreatic Cancer (TNFerade) Delivered by Endoscopic Ultrasound (EUS) and Percutaneous Guided Fine Needle Injection (FNI)

Abstract

A Novel Gene Transfer Therapy Against Pancreatic Cancer (TNFerade) Delivered by Endoscopic Ultrasound (EUS) and Percutaneous Guided Fine Needle Injection (FNI) Kenneth J. Chang, Neil Senzer, Theodore Chung, J. Randolph Hecht, Stephen Vogel, Alexander Rosemurgy, John Nemunaitis, John Gibbs, Milind Javle, Tony Reid, Jennifer Macko, Paul Kessler, Mitchell C. Posner, James Farrell, L. Shane Grundy, Roy Soetikno, Irving Waxman, Nader Hanna We published two trials utilizing EUS-guided FNI for the delivery of immune therapy (Cancer 2000) and oncolytic viral therapy (Clin Cancer Res 2003) against pancreatic cancer. We now present a novel gene transfer therapy, TNFerade, delivered by EUS and percutaneous approaches (PTA) guided by ultrasound or computerized tomography (CT), in the treatment of unresectable, locally advanced adenocarcinoma of the pancreas (LAPC). TNFerade is a replicationdeficient adenovector containing human TNFa gene, regulated by a radiationinducible promoter Egr-1. Purpose: 1) Assess safety and efficacy of TNFerade plus chemoradiation in pts with LAPC. 2) Compare EUS and PTA as delivery modalities. Methods: Dose-escalating run-in design. Five-week treatment of weekly intratumoral injections of TNFerade (43 10 particle units (pu) in 2mL) via EUS or PTA (each institution allowed one preferred technique), continuous iv 5-FU (200 mg/m/d 3 5 days/wk) and radiation (50.4 Gy). TNFerade was delivered with a single needle pass at a single site in the tumor for PTA, while up to 4 injections were given by EUS. Endpoints: Safety and tumor response on spiral CT (core lab). Results: Of 37 pts, 17 had EUS and 20 had PTA (similar TNFerade doses). EUS vs PTA: T4 staging = 88% vs. 75%; N1 staging = 29% vs. 40%, mean tumor area (cm)= 18 vs.19; mean CA19-9= 4,396 vs. 1,707, meanKPS= 88 vs. 90. (p=NS for all). 1 dose limiting toxicity (gr 3 hypotension) in a PTApt; all other adverse events (AEs) potentially related to TNFerade were grade 1-2. Procedure related AEs were all grade 1-2 and were similar, except for injection site pain: 35% PTA vs 0% EUS (p = .01). Tumor responses and disease control were similar (Table 1). 4 patients underwent resection; one, an EUS patient, had a complete pathologic response. Conclusions: 1) TNFerade plus chemoradiation was well tolerated with maximum tolerated dose not reached; 2) indications of clinical activity were demonstrated by local tumor control and progression-free survival at up to 3 months; 3) EUS and PTA appear to be similarly safe and effective for delivery of TNFerade.