Disabled infectious single-cycle herpes simplex virus as an oncolytic vector for immunotherapy of colorectal cancer

New modalities of treatment for colorectal cancer are required to support a nd improve those currently available. One such approach is immunotherapy by transfer of immunostimulatory genes to tumor cells. Here, we report the us e of a herpes simplex virus (HSV) vector that is capable of a single round of infection (disabled infectious single-cycle [DISC]-HSV) as a gene transf er vehicle for colorectal cancer. This vector has potential advantages over other vectors for cancer immunotherapy in that it lyses infected tumor cel ls. Infection with DISC-HSV inhibited tumor cell growth both in vitro and i n vivo. In addition, DISC-HSV-mediated cell killing occurs by both apoptoti c and necrotic mechanisms. A range of colorectal tumor cell lines could be rapidly transduced with DISC-HSV/lacZ (14-90% in 4 hr), Both tumor preventi on and tumor therapy protocols showed clear antitumor effects with DISC-HSV /mGM-CSF, In the prophylactic approach, an infected/irradiated whole cell v accine protected up to 80% of mice from rechallenge. In addition, intratumo ral injection of established tumors with DISC-HSV/GM-CSF caused rejection i n 40% of mice and generated some protection from subsequent rechallenge. In both cases, however, it is clear that a dominant therapeutic effect of the DISC-HSV vector derives from its oncolytic properties, irrespective of the transduced gene. As a prelude to taking these studies forward to human cli nical trials, we demonstrate that tumor cells could be successfully grown f rom freshly obtained human colorectal cancer resections (within 1 week of s urgery), mere transduced with DISC-HSV/hGM-CSF, and secreted the cytokine, This study provides the preclinical basis for trials of immunotherapy of co lorectal cancer using DISC-HSV.