Designing and building oncolytic viruses

Maroun, Justin; Muñoz-Alía, Miguel; Ammayappan, Arun; Schulze, Autumn; Peng, Kah-Whye; Russell, Stephen

Unlike secreted toxins, prodrug convertases do not pose a risk of increasing OV virulence because their toxic potential is manifest only in the presence of an exogenously added prodrug. For this reason, the approach has been extensively studied. Perhaps the most well-known convertase-prodrug combination is HSV TK, used with ganciclovir. TK converts ganciclovir to ganciclovir monophosphate which is further processed intracellularly to ganciclovir triphosphate, a DNA synthesis chain terminator that kills dividing cells as they enter S phase [138] . A major weakness of the TK-ganciclovir system, aside from its inability to kill nondividing tumor cells, is that it has very limited bystander killing potential. This is because ganciclovir monophosphate is not released from the cell in which it is generated, so does not impact uninfected tumor cells unless they are connected to the infected cell via gap junctions through which it can pass [139] . Encoding connexin, a gap junction protein, in the OV genome can enhance the bystander killing effect of TK, but attention is shifting to other convertases, most notably CD.