• Daniel H Sterman, Adri Recio, Richard G Carroll, Colin T Gillespie, Andrew Haas, Anil Vachani, Veena Kapoor, Jing Sun, Richard Hodinka, Jennifer L Brown, Michael J Corbley, Michael Parr, Mitchell Ho, Ira Pastan, Michael Machuzak, William Benedict, Xin-qiao Zhang, Elaina M Lord, Leslie A Litzky, Daniel F Heitjan, Carl H June, Larry R Kaiser, Robert H Vonderheide, Steven M Albelda, and Michelle Kanther.
• Thoracic Oncology Gene Therapy Program and Abramson Family Cancer Research Institute, University of Pennsylvania Medical Center, Philadelphia, PA 19104-4283, USA. sterman@mail.med.upenn.edu
• Clin Cancer Res. 2007 Aug 1;13(15 Pt 1):4456-66.

PurposeThis phase 1 dose escalation study evaluated the safety and feasibility of single-dose intrapleural IFN-beta gene transfer using an adenoviral vector (Ad.IFN-beta) in patients with malignant pleural mesothelioma (MPM) and metastatic pleural effusions (MPE).Experimental DesignAd.IFN-beta was administered through an indwelling pleural catheter in doses ranging from 9 x 10(11) to 3 x 10(12) viral particles (vp) in two cohorts of patients with MPM (7 patients) and MPE (3 patients). Subjects were evaluated for (a) toxicity, (b) gene transfer, (c) humoral, cellular, and cytokine-mediated immune responses, and (d) tumor responses via 18-fluorodeoxyglucose-positron emission tomography scans and chest computed tomography scans.ResultsIntrapleural Ad.IFN-beta was generally well tolerated with transient lymphopenia as the most common side effect. The maximally tolerated dose achieved was 9 x 10(11) vp secondary to idiosyncratic dose-limiting toxicities (hypoxia and liver function abnormalities) in two patients treated at 3 x 10(12) vp. The presence of the vector did not elicit a marked cellular infiltrate in the pleural space. Intrapleural levels of cytokines were highly variable at baseline and after response to gene transfer. Gene transfer was documented in 7 of the 10 patients by demonstration of IFN-beta message or protein. Antitumor immune responses were elicited in 7 of the 10 patients and included the detection of cytotoxic T cells (1 patient), activation of circulating natural killer cells (2 patients), and humoral responses to known (Simian virus 40 large T antigen and mesothelin) and unknown tumor antigens (7 patients). Four of 10 patients showed meaningful clinical responses defined as disease stability and/or regression on 18-fluorodeoxyglucose-positron emission tomography and computed tomography scans at day 60 after vector infusion.ConclusionsIntrapleural instillation of Ad.IFN-beta is a potentially useful approach for the generation of antitumor immune responses in MPM and MPE patients and should be investigated further for overall clinical efficacy.

44 keywords...

hide…