A Phase I Trial of Repeated Intrapleural Adenoviral-mediated Interferon-beta Gene Transfer for Mesothelioma and Metastatic Pleural Effusions

作者：Sterman Daniel H^*; Recio Adri; Haas Andrew R; Vachani Anil; Katz Sharyn I; Gillespie Colin T; Cheng Guanjun; Sun Jing; Moon Edmund; Pereira Luana; Wang Xinzhong; Heitjan Daniel F; Litzky Leslie; June Carl H; Vonderheide Robert H; Carroll Richard G; Albelda Steven M

来源：Molecular Therapy, 2010, 18(4): 852-860.

DOI：10.1038/mt.2009.309

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-alpha 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.

• 出版日期2010-4
• 单位Biogen Idec