Abstract
We previously showed that a single intrapleural dose of an adenoviral vector expressing interferon-Β (Ad.IFN-Β) 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-Β vector would be superior. Ten patients with MPM and seven with MPE received two doses of Ad.IFN-Β through an indwelling pleural catheter. Repeated doses were generally well tolerated. High levels of IFN-Β 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.
Original language | English (US) |
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Pages (from-to) | 852-860 |
Number of pages | 9 |
Journal | Molecular Therapy |
Volume | 18 |
Issue number | 4 |
DOIs | |
State | Published - Apr 2010 |
Funding
Funding. This trial was funded by grants from the National Cancer Institute (NCI PO1 CA66726) and from Biogen Idec. We thank the following individuals at Penn for their assistance: Thomas Ferrara, Aaron Blouin, Kathleen Haines, and Ben Paramonte. We also thank Laurie Phillips and Katie Smith at Biogen Idec for their continued support and assistance, and Jorge Sanchez-Salazar (at Biogen Idec) for measuring IFN-β levels and neutralizing antibody titers. This trial was funded by grants from the National Cancer Institute (NCI PO1 CA66726) and from Biogen Idec.
ASJC Scopus subject areas
- Drug Discovery
- Genetics
- Molecular Medicine
- Molecular Biology
- Pharmacology