Oncolytic herpes viruses, chemotherapeutics, and other cancer drugs

Abstract

Oncolytic viruses are emerging as a potential new way of treating cancers. They are selectively replication-competent viruses that propagate only in actively dividing tumor cells but not in normal cells and, as a result, destroy the tumor cells by consequence of lytic infection. At least six different oncolytic herpes simplex viruses (oHSVs) have undergone clinical trials worldwide to date, and they have demonstrated an excellent safety profile and intimations of efficacy. The first pivotal Phase III trial with an oHSV, talimogene laherparepvec (T-Vec [OncoVex(GM-CSF)]), is almost complete, with extremely positive early results reported. Intuitively, therapeutically beneficial interactions between oHSV and chemotherapeutic and targeted therapeutic drugs would be limited as the virus requires actively dividing cells for maximum replication efficiency and most anticancer agents are cytotoxic or cytostatic. However, combinations of such agents display a range of responses, with antagonistic, additive, or, perhaps most surprisingly, synergistic enhancement of antitumor activity. When synergistic interactions in cancer cell killing are observed, chemotherapy dose reductions that achieve the same overall efficacy may be possible, resulting in a valuable reduction of adverse side effects. Therefore, the combination of an oHSV with "standard-of-care" drugs makes a logical and reasonable approach to improved therapy, and the addition of a targeted oncolytic therapy with "standard-of-care" drugs merits further investigation, both preclinically and in the clinic. Numerous publications report such studies of oncolytic HSV in combination with other drugs, and we review their findings here. Viral interactions with cellular hosts are complex and frequently involve intracellular signaling networks, thus creating diverse opportunities for synergistic or additive combinations with many anticancer drugs. We discuss potential mechanisms that may lead to synergistic interactions.

Keywords: combination studies; herpes simplex virus; oncolytic virus; virotherapy.

Figure 1

HSV-1 can overcome normal cells protective block in protein synthesis: 1. HSV-1 enters the host cell and begins replication. 2. Complementary RNA anneal to produce dsRNA. 3. PKR binds dsRNA, dimerizes resulting in activation and autophosphorylation. 4. Phosphorylated PKR selectively phosphorylates elF2α. 5. Phosphorylated elF2α causes the host cell to shutdown translation thereby preventing viral replication. 6. HSV produced ICP34.5 which forms a protein complex with PP1α. 7. The ICP34.5 PP1α complex dephosphorylates elF2α so the viral replication (8) can continue unchecked. Abbreviations: HSV, herpes simplex virus; PKR, protein kinase R; eIF2α, eukaryotic initiation factor 2; PP1α, protein phosphatase 1 alpha; ICP, infected cell polypepetide; P, phosphorylation.

Figure 2

Increasing replicative capacity of the virus: (A) in normal cells the virus does not replicate. (B) In a cancer cell the virus replicates, lyses the cell and produces viral progeny that go on to infect further cancer cells. (C) In the presence of certain drugs the virus can produce more viral progeny. Upon lysis more progeny virus are released – potentially increasing the number of cells that can be infected.

Figure 3

Anti-viral host response mediated by IFN (interferon) induces apoptosis of surrounding cells. By using drug to block innate antiviral defence mechanism the infected cell will not signal other nearby cells to ‘warn’ them about the virus, hence viral replication will occur.

Figure 4

Herpes simplex virus (HSV) replication cycle HSV-1 is a double stranded DNA virus which encodes for around 100 transcripts and contains three main structural components. The central capsid (or nucleocapsid) contains the viral DNA. This is surrounded by an envelope. The tegument is located between the envelope and the capsid. HSV enters the host cell at either the cell surface or via pH dependent endocytosis through a process involving envelope glycoproteins. The tegument proteins are released into the cell and the capsid is transported to the nucleus where viral DNA is released into the nucleus. There are three classes of viral genes that are transcribed and translated in a specific order: Immediate Early (IE) genes, which encode for proteins that promote expression of viral genes and also have a role in innate immune invasion, Early (E) are responsible for the replication of viral DNA and lastly Late (L) genes which include capsid, tegument and envelope proteins.