Oncolytic viruses as therapeutic agents.

The concept of using viruses as oncolytic agents has a long history. However, relatively new developments are the use of these viruses as gene delivery vehicles and the restriction of viral replication and lysis to tumour cells. The latter is attempted by the use of tumour-specific promoters, which transcriptionally target viral genes involved in replication, or by deletion of viral functions dispensable for replication in tumour cells but essential for productive infection of normal cells. In addition, retargeting of the viral tropism towards tumours by capsid modifications has been examined. Although much progress has been made in developing oncolytic vectors for clinical use, there is still a long way to go to determine which combinations of virus, gene therapy, surgery, radiation, and/or chemotherapy will provide improved therapy for the control and eradication of a variety of human cancers. First controlled clinical trials with an oncolytic adenovirus in combination with chemotherapy have shown encouraging antineoplastic activity. For future vector developments it will be crucial to achieve maximum vector distribution and transgene expression within tumours, to trigger a specific systemic immune effector response against treated and untreated lesions, and to modulate the immune system to avoid immune-mediated inactivation or destruction of the virus. In the context of replication-competent vectors, suicide genes might be used as fail-safe mechanism in the case of a runaway infection.