Herpesviruses as oncolytic agents

A number of tumors or their metastases are not accessible to surgical resection, and/or respond poorly to radiation, chemotherapy, cytokine or antibody therapy. Although these represent a minority of tumors, their burden worldwide is nonetheless of great impact. Quite often, they are characterized by the worst prognosis and highly impact on the quality of life. These tumors require more sophisticated therapeutic approaches. Many viruses, including herpesviruses are highly specialized machines for killing cells. Oncolytic virotherapy exploits the ability of certain viruses to infect and kill tumor cells, and represents a novel approach to reduce cancer burden, and at least delay tumor progression. Genetically engineered oncolytic viruses are in clinical trials. The objective of genetic engineering of candidate viruses, subject to current technology, is to attenuate wild-type viruses and make their replication dependent on dividing tumor cells. Because the range of cells susceptible to infection remains unaltered, safety is achieved to the detriment of potency. At low doses, these agents are frequently ineffective. At high doses, they can be toxic rather than therapeutic. Martuza and Markert were the first to employ herpes simplex virus (HSV) as a possible treatment for glioblastoma, the most common malignant brain tumor. Since then, herpes simplex viruses (HSVs) have become among the best candidate oncolytic agents for several reasons. In general, they are mild pathogens in humans. They replicate and spread efficiently, and cause cell lysis. A lot is known regarding the molecular basis of the their life cycle and the molecules they encode. They are amenable to genetic engineering. Large genome space is available for insertion of heterologous genes designed to modulate virus replication in specific host cells, or the host response to virus infection. Multiple gene deletions allow conditional replication of HSV-1 in tumor cells. Recombinants differing in the level of attenuation may be created. Importantly, specific anti HSV-1 therapy (Acyclovir, Valacyclovir) is available, and can be used, should emergencies arise. We will review here the main properties of the oncolytic HSVs under clinical experimentation and the ongoing efforts to improve them, a field to which Bernard Roizman and his collaborators contributed pivotal discoveries.