Abstract
Oncolytic viruses (OVs) target and destroy cancer cells while sparing their normal counterparts. These viruses have been evaluated in numerous studies at both pre-clinical and clinical levels and the recent Food and Drug Administration (FDA) approval of an oncolytic herpesvirus-based treatment raises optimism that OVs will become a therapeutic option for cancer patients. However, to improve clinical outcome, there is a need to increase OV efficacy. In addition to killing cancer cells directly through lysis, OVs can stimulate the induction of anti-tumour immune responses. The host immune system thus represents a “double-edged sword” for oncolytic virotherapy: on the one hand, a robust anti-viral response will limit OV replication and spread; on the other hand, the immune-mediated component of OV therapy may be its most important anti-cancer mechanism. Although the relative contribution of direct viral oncolysis and indirect, immune-mediated oncosuppression to overall OV efficacy is unclear, it is likely that an initial period of vigorous OV multiplication and lytic activity will most optimally set the stage for subsequent adaptive anti-tumour immunity. In this review, we consider the use of histone deacetylase (HDAC) inhibitors as a means of boosting virus replication and lessening the negative impact of innate immunity on the direct oncolytic effect. We also discuss an alternative approach, aimed at potentiating OV-elicited anti-tumour immunity through the blockade of immune checkpoints. We conclude by proposing a two-phase combinatorial strategy in which initial OV replication and spread is maximised through transient HDAC inhibition, with anti-tumour immune responses subsequently enhanced by immune checkpoint blockade.
Highlights
Oncolytic viruses (OVs) preferentially infect, replicate in, and destroy tumour cells while sparing normal cells
The boosting effect of MS-275 on virus replication was dependent on the continuous administration of this compound and vanished as the drug was withdrawn. These results provided first evidence that by transiently blocking the IFN response, histone deacetylase inhibitors (HDACIs) may function as reversible switches to control the extent of virus replication within the tumour
Clinical responses elicited by OVs remain highly heterogeneous, calling for the combination of these viruses with other therapeutics to overcome some of the obstacles that may hamper efficacy
Summary
Oncolytic viruses (OVs) preferentially infect, replicate in, and destroy tumour cells while sparing normal cells. Clinical benefit was demonstrated: the treatment met its primary endpoint with a 16% durable response rate and increased median overall survival rate by 4.4 months [5] Based on these results, a Food and Drug Administration (FDA) advisory panel recommended product approval, which was granted in the U.S on October 2015 under the brand name Imlygic [6]. OVs with a natural tropism for cancer cells include rodent protoparvoviruses (PV; family Parvoviridae), myxoma virus (Poxviridae), Newcastle disease virus (NDV; Paramyxoviridae), reovirus (Reoviridae) and Seneca valley virus (Picornaviridae). These viruses are normally non-pathogenic in humans. Genetic engineering has improved OV safety through attenuation of viral pathogenicity factors, increased virus selectivity for cancer cells at both entry and transductional levels, and enhanced efficacy through the insertion of therapeutic transgenes, such as GM-CSF, into the viral genome [3,11]
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