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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

Authors' Affiliations: ¹ Thoracic Oncology Gene Therapy Program and ² Abramson Family Cancer Research Institute, University of Pennsylvania Medical Center; ³ Virology Laboratory, Children's Hospital of Philadelphia; ⁴ Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania; ⁵ BiogenIdec, Cambridge, Massachusetts; ⁶ Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland; and ⁷ Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Daniel H. Sterman, Interventional Pulmonology Program, Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Medical Center, 833 West Gates Building, 3400 Spruce Street, Philadelphia, PA 19104-4283. Phone: 215-614-0984; Fax: 215-662-3226; E-mail: sterman{at}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.

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