Viruses as anticancer drugs

Abstract

Oncolytic viruses are being developed as anticancer drugs. They propagate selectively in tumor tissue and destroy it without causing excessive damage to normal non-cancerous tissues. When used as drugs, they must meet stringent criteria for safety and efficacy and be amenable to pharmacological study in human subjects. Specificity for neoplastic tissue is the key to safety, and this goal can be achieved through a variety of ingenious virus-engineering strategies. Antiviral immunity remains a significant barrier to the clinical efficacy of oncolytic viruses but this is being addressed by using novel immune-evasive delivery strategies and immunosuppressive drugs. Noninvasive pharmacokinetic monitoring is facilitated by engineering marker genes into the viral genome. Clinical data on the pharmacokinetics of oncolytic viruses will be the key to accelerating their development and approval as effective anticancer drugs. This review introduces concepts relevant to the use of viruses as anticancer drugs, emphasizing targeting mechanisms as well as safety and efficacy issues that are currently limiting their clinical success.

Figure 1

Mechanisms of tumor targeting by oncolytic viruses. (a) Transcriptional targeting. An essential viral gene is placed under the control of a tumor-specific promoter (some virus promoters are naturally tumor specific). Typically, the selected gene encodes an early viral protein that is essential for successful completion of the virus life cycle. This is applicable only to DNA viruses (excluding poxviruses) and retroviruses. (b) Translational targeting. The virus is engineered (or adapted) to disable viral proteins that antagonize the cellular interferon (IFN) response. Normal cells then release interferon upon infection, causing neighboring cells to shut-off translation. Infected cancer cells are impaired in their ability to release or respond normally to interferon. (c) Pro-apoptotic targeting. The virus is engineered (or adapted) to disable viral proteins that prevent apoptosis. Normal cells then die quickly upon infection before progeny viruses can be produced. Infected cancer cells are impaired in their ability to undergo apoptosis. Hence, the virus can generate progeny and spread only in the cancer cells. (d) Transductional targeting. The virus gains entry to its target cells through a receptor expressed more abundantly on tumor cells than on normal cells. The natural receptors for several viruses fall into this category. Alternatively, the attachment specificity of the virus can be reprogrammed towards tumor antigens by the display of single-chain antibodies or other polypeptide-binding ligands on the viral surface.

Figure I

Virus replication. (a) Viral invasion of the cell. (b) The cellular response to viral infection and the suppression of this response by viral accessory proteins. Abbreviations: RIG, retinoic-acid-inducible protein-1; TLR, Toll-like receptor.