Abstract
BackgroundThe hepatocyte growth factor (HGF)/c-Met signal pathway is up-regulated in human mesothelioma and suppression of the HGF/c-Met signaling with a competitive inhibitor, NK4 homologous to HGF in the structure, produced anti-tumor effects to mesothelioma in a preclinical study. Mesothelioma is highly resistant to a number of chemotherapeutic agents but distant metastasis to extra-thoracic organs is relatively infrequent until the late stage.Methods/designWe planned to conduct a clinical study of gene therapy with adenoviruses expressing the NK4 gene (Ad-NK4) to control the local tumor growth. The study is designed to inject Ad-NK4 into the intrapleural cavity with a dose escalation manner from 1010 to 1012 virus particles per patient and to examine safety and possible clinical benefits. The clinical investigation is a first-in-human trial to use the NK4 gene and to block the HGF/c-Met pathway with gene medicine. We conducted in vivo animal experiments to examine the safety level as one of the preclinical studies, and showed that Ad DNA administered in the pleural cavity was detected in many parenchymal organs. Biochemical and pathological analyses showed that liver damages were the major adverse effects with little toxicity to other organs. These studies firstly demonstrated biodistribution and transgene expression after an intrapleural injection of Ad vectors in an animal study, which contrasts with an intravenous injection showing relatively rapid clearance of Ad-NK4.DiscussionThe clinical study can also provide information regarding production of NK4 protein and antibody against NK4, and inhibition levels of the HGF/c-Met pathway by detecting dephosphorylation of c-Met in mesothelioma cells. These data will be crucial to judge whether local production of NK4 molecules can be an anti-cancer strategy.Trial registration: UMIN clinical trials registry, Japan. Register ID: UMIN15771
Highlights
The hepatocyte growth factor (HGF)/c-Met signal pathway is up-regulated in human mesothelioma and suppression of the HGF/c-Met signaling with a competitive inhibitor, NK4 homologous to HGF in the structure, produced anti-tumor effects to mesothelioma in a preclinical study
The clinical study can provide information regarding production of NK4 protein and antibody against NK4, and inhibition levels of the HGF/c-Met pathway by detecting dephosphorylation of c-Met in mesothelioma cells. These data will be crucial to judge whether local production of NK4 molecules can be an anti-cancer strategy
The average blood glucose value was lower in Ad-NK4injected than in phosphate-buffered saline (PBS)-injected mice on day 1 (P < 0.01), which could be associated with the temporal body weight loss on day 1
Summary
There are several points to investigate in the current clinical research, which includes antibody production, blocking of the HGF/c-Met signaling and clinical. A pleural effusion of the patient injected with Ad-NK4 is tested for the ability to dephosphorylate c-Met molecules in human mesothelioma cell lines or in patients-derived tumor cells if the samples are available It is uncertain at this moment whether anti-NK4 antibody is produced by Ad-NK4 administration since NK4 protein is naturally detected in human as a cleaved form of HGF. Cell death caused by Ad vectors can facilitate uptake of putative tumor antigens by professional antigen presenting cells and Ad vectors can work as an adjuvant together with cytokines released from recruiting inflammatory cells These immune responses in the previous studies did not induce serious adverse reactions, and pre-existing humoral and cellular immunity prior to the Ad administration did not inhibit subsequent Ad-mediated gene transduction (Molnar-Kimber et al 1998; Sterman et al 2005, 2007).
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