Combinatorial strategies for oncolytic herpes simplex virus therapy of brain tumors

Abstract

Oncolytic viruses, such as the oncolytic herpes simplex virus (oHSV), are an exciting new therapeutic strategy for cancer as they are replication competent in tumor cells but not normal cells. In order to engender herpes simplex virus with oncolytic activity and make it safe for clinical application, mutations are engineered into the virus. Glioblastoma multiforme (GBM) is the most common and deadly primary brain tumor in adults. Despite many advances in therapy, overall survival has not been substantially improved over the last several decades. A number of different oHSVs have been tested as monotherapy in early-phase clinical trials for GBM and have demonstrated safety and anecdotal evidence of efficacy. However, strategies to improve efficacy are likely to be necessary to successfully treat GBM. Cancer treatment usually involves multimodal approaches, so the standard of care for GBM includes surgery, radiotherapy and chemotherapy. In preclinical GBM models, combinations of oHSV with other types of therapy have exhibited markedly improved activity over individual treatments alone. In this review, we will discuss the various combination strategies that have been employed with oHSV, including chemotherapy, small-molecule inhibitors, antiangiogenic agents, radiotherapy and expression of therapeutic transgenes. Effective combinations, especially synergistic ones, are clinically important not just for improved efficacy but also to permit lower and less-toxic doses and potentially overcome resistance.