Human and mouse IFN-β gene therapy exhibits different anti-tumor mechanisms in mouse models

Abstract

Previously, we suggested that local human interferon-β (IFN-β) gene therapy with replication-defective adenoviral vectors can be an effective cancer treatment. Clinical trials to treat cancers with adenovirus expressing the human IFN-β gene (IFNB1) has been planned. As a continued effort to explore the mechanisms of action of human IFN-β gene therapy that can occur in the clinical setting, we tested mouse IFN-β gene therapy in human xenograft tumors in both ex vivo and in vivo models. Delivery of the mouse IFN-β gene (Ifnb) caused tumor inhibition; this effect was dependent on the indirect anti-tumor activities of IFN-β, notably a stimulation of natural killer cells. IFN-β does not show cross-species activity in its anti-proliferative effect and mouse IFN-β does not cause as significant an anti-proliferative effect on mouse tumor cells as human IFN-β causes on human tumor cells. Therefore, we believe that mouse models using either human IFN-β or mouse IFN-β gene transfer do not capture all aspects of the action of adenovirus-mediated human IFN-β gene therapy that may be present in the clinical setting. Due to its multiple mechanisms of action, human IFN-β gene therapy may be effective in treating human cancers that are either sensitive or resistant to the direct anti-proliferative effect of IFN-β.