A Phase I Trial of Repeated Intrapleural Adenoviral-mediated Interferon-β 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.

Management of malignant pleural effusion by suicide gene therapy in advanced stage lung cancer: a case series and literature review

“…Alternative treatment of MPE has been presented in previous studies with various results and techniques. 10,11,44 Here, we present results of regionally applied suicide gene therapy augmenting the chemotherapy effect in these two patients who were successfully treated. A secondary treatment pathway may involve the diffusion of the 5-FU cytotoxic metabolite through the pleura porous to the lymphatic circulation 46,47 , as it has been previously observed that different concentrations of administered drug formulations enter the lymphatic circulation through the pleura porous.…”

“…Moreover, after the second instillation, the detection for vector antibodies is recommended, as previous studies have demonstrated that antibodies are formed usually between the second and third administration. 43,44,74 In conclusion, the increased toxicity that follows the intrapleural gene therapy indicates the augmentation of anticancer effect of transformed pro-drug 5-FC to active 5-FU with Ad.CD. Intrapleural gene therapy may be a useful adjunct to chemotherapy in the management of MPE related to lung cancer in patients with good performance status.…”

“…70--72 However, recent data suggest that combination of immunotherapy with chemotherapy can overcome the inability to give multiple doses, resulting the boosting of the initial vaccination of the adenovirus. 44,73 This approach is currently being tested in a clinical trial using Ad.IFN in combination with cisplatin/gemcitabine and cisplatin/ pemetrexed in patients with mesothelioma and could be applied to other trials of viral immunogene therapy. 73 Following our first favourable observations of suicide gene therapy in the presented two cases of MPE secondary to lung cancer, we propose a protocol for local control of MPE.…”

“…(2010) 44 , it was investigated whether the administration of Ad. IFN-b twice (with 7 days and 14 days intervals) would be more beneficial for the patients with MPE.…”

Interferon-β lipofection II. Mechanisms involved in cell death and bystander effect induced by cationic lipid-mediated interferon-β gene transfer to human tumor cells

“…Both innate and acquired immunity toward adenovirus were described, a situation even more sensitive when the treatment should be repeated to reach a significant clinical outcome. In the case of a clinical trial for mesothelioma, 8 neutralizing antibodies against recombinant adenoviral particles carrying human hIFNb (hIFNb) gene prevented further rounds of transduction. Whereas safety and feasibility of the treatment were assessed, the clinical benefits resulted still poor.…”