title: A phase I trial of repeated intrapleural adenoviral-mediated interferon-beta gene transfer for mesothelioma and metastatic pleural effusions.
abstract: We previously showed that a single intrapleural dose of an adenoviral vector expressing interferon-beta (Ad.IFN-beta) in patients with malignant pleural mesothelioma (MPM) or malignant pleural effusions (MPE) resulted in gene transfer, humoral antitumor immune responses, and anecdotal clinical responses manifested by modified Response Evaluation Criteria in Solid Tumors (RECIST) disease stability in 3 of 10 patients at 2 months and an additional patient with significant metabolic response on positron emission tomography (PET) imaging. This phase I trial was conducted to determine whether using two doses of Ad.IFN-beta vector would be superior. Ten patients with MPM and seven with MPE received two doses of Ad.IFN-beta through an indwelling pleural catheter. Repeated doses were generally well tolerated. High levels of IFN-beta were detected in pleural fluid after the first dose; however, only minimal levels were seen after the second dose of vector. Lack of expression correlated with the rapid induction of neutralizing Ad antibodies (Nabs). Antibody responses against tumor antigens were induced in most patients. At 2 months, modified RECIST responses were as follows: one partial response, two stable disease, nine progressive disease, and two nonmeasurable disease. One patient died after 1 month. By PET scanning, 2 patients had mixed responses and 11 had stable disease. There were seven patients with survival times longer than 18 months. This approach was safe, induced immune responses and disease stability. However, rapid development of Nabs prevented effective gene transfer after the second dose, even with a dose interval as short as 7 days.
authors.affiliation: Section of Interventional Pulmonology and Thoracic Oncology, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104-4283, USA. Daniel.Sterman@uphs.upenn.edu
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Sterman
authors.forename: Adri
authors.initials: A
authors.lastname: Recio
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Haas
authors.forename: Anil
authors.initials: A
authors.lastname: Vachani
authors.forename: Sharyn I
authors.initials: SI
authors.lastname: Katz
authors.forename: Colin T
authors.initials: CT
authors.lastname: Gillespie
authors.forename: Guanjun
authors.initials: G
authors.lastname: Cheng
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.forename: Edmund
authors.initials: E
authors.lastname: Moon
authors.forename: Luana
authors.initials: L
authors.lastname: Pereira
authors.forename: Xinzhong
authors.initials: X
authors.lastname: Wang
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Heitjan
authors.forename: Leslie
authors.initials: L
authors.lastname: Litzky
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
authors.forename: Robert H
authors.initials: RH
authors.lastname: Vonderheide
authors.forename: Richard G
authors.initials: RG
authors.lastname: Carroll
authors.forename: Steven M
authors.initials: SM
authors.lastname: Albelda
mesh_terms: D000256:Adenoviridae; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D016899:Interferon-beta / Q000235:genetics*; D008175:Lung Neoplasms / Q000628:therapy*; D008297:Male; D008654:Mesothelioma / Q000628:therapy*; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000628:therapy*; D035422:Pleural Cavity; D016066:Pleural Effusion, Malignant / Q000628:therapy*
chemical_list: D016899:Interferon-beta