A Phase I Clinical Trial of Single-Dose Intrapleural IFN-ß Gene Transfer for Malignant Pleural Mesothelioma and Metastatic Pleural Effusions: High Rate of Antitumor Immune Responses

Clinical Cancer Research. 13, 4456-4466, August 1, 2007. [Link]

Sterman DH, Recio A, Carroll RG, Gillespie CT, Haas A, Vachani A, Kapoor V, Sun J, Hodinka R, Brown JL, Corbley MJ, Parr M, Ho M, Pastan I, Machuzak M, Benedict W, Zhang XQ, Lord EM, Litzky LA, Heitjan DF, June CH, Kaiser LR, Vonderheide RH, Albelda SM, Kanther M.

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


Purpose: This phase 1 dose escalation study evaluated the safety and feasibility of single-dose intrapleural IFN-ß gene transfer using an adenoviral vector (Ad.IFN-ß) in patients with malignant pleural mesothelioma (MPM) and metastatic pleural effusions (MPE).

Experimental Design: Ad.IFN-ß was administered through an indwelling pleural catheter in doses ranging from 9 x 1011 to 3 x 1012 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.

Results: Intrapleural Ad.IFN-ß was generally well tolerated with transient lymphopenia as the most common side effect. The maximally tolerated dose achieved was 9 x 1011 vp secondary to idiosyncratic dose-limiting toxicities (hypoxia and liver function abnormalities) in two patients treated at 3 x 1012 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-ß 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.

Conclusions: Intrapleural instillation of Ad.IFN-ß 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.