Targeting the tumor vasculature to improve the efficacy of oncolytic virus therapy.

Virus-mediated oncolysis is not a new concept. The idea goes back to the early 1900s, when it was noted that a flu-like disease coincided with a substantial drop in the number of tumor cells in a leukemic patient (1) and that rabies vaccination was followed by regression of cervical cancer (2). Additional anecdotal observations followed, but early attempts at viral therapy for cancer were unsuccessful (3 , 4). In principle, to be an effective weapon against cancer, an oncolytic virus must infect and kill cancer cells while sparing normal cells (5 , 6). Recent advances in biochemistry, molecular biology, and genetic engineering have brought oncolytic virus therapy back into focus. Some viruses that preferentially infect tumor cells that overexpress receptors for virus entry have been identified; other viruses have been genetically engineered to exploit specific characteristics of tumor cells, such as the expression of tumor antigens, tumor suppressor proteins, or altered signaling pathways (5 , 6). Although the in vitro results have been encouraging , preclinical animal models and early clinical trials have demonstrated little efficacy with oncolytic virus therapy and only limited spread of the virus infection beyond the primary site (6 – 10). Because safety reasons have dictated that oncolytic viruses be attenuated for clinical use, a concern has been raised that they may have largely lost their ability to effectively spread and kill the tumor tissue (6). Another concern is that innate host immunity may limit oncolysis and the spread of oncolytic viruses to the tumor tissue (5 , 6). There is evidence that the acute immune response that follows an initial oncolytic viral infection limits tumor oncolysis and viral replication, resulting in diminished antitumor efficacy (5). Indeed, depletion of complement activity or the use of the immu-nosuppressant drug cyclophosphamide was found to enhance virus oncolytic effects (11 – 13), and addition of interferon gamma or the activation of the cytokine interleukin 10 inhibited the replication of oncolytic virus in rat glioma cells (5 , 12). In this issue of the Journal, Kurozumi et al. (14) sought to target the tumor vasculature to reduce tumor infl ammation and improve the antitumor effi cacy of oncolytic virus therapy. In their elegant studies, the authors treated established intracranial gliomas in rats with an oncolytic virus derived from type I herpes simplex virus. They observed that at 3 days after treatment, the tumor vessels had increased permeabililty and the tumor …