Vesicular stomatitis virus as a flexible platform for oncolytic virotherapy against cancer

Abstract

Oncolytic virus (OV) therapy is an emerging anti-cancer approach that utilizes viruses to preferentially infect and kill cancer cells, while not harming healthy cells. Vesicular stomatitis virus (VSV) is a prototypic non-segmented, negative-strand RNA virus with inherent OV qualities. Antiviral responses induced by type I interferon pathways are believed to be impaired in most cancer cells, making them more susceptible to VSV than normal cells. Several other factors make VSV a promising OV candidate for clinical use, including its well-studied biology, a small, easily manipulated genome, relative independence of a receptor or cell cycle, cytoplasmic replication without risk of host-cell transformation, and lack of pre-existing immunity in humans. Moreover, various VSV-based recombinant viruses have been engineered via reverse genetics to improve oncoselectivity, safety, oncotoxicity and stimulation of tumour-specific immunity. Alternative delivery methods are also being studied to minimize premature immune clearance of VSV. OV treatment as a monotherapy is being explored, although many studies have employed VSV in combination with radiotherapy, chemotherapy or other OVs. Preclinical studies with various cancers have demonstrated that VSV is a promising OV; as a result, a human clinical trial using VSV is currently in progress.

Oncolytic viruses: From bench to bedside with a focus on safety

“…Hastie & Grdzelishvili published an excellent overview of abovementioned strategies and resulting oncolytic VSVs in 2012. 88 A recent study in purpose-bred beagle dogs showed that a dose up to 10 10 TCID 50 of VSV-hIFNb was well tolerated, with mild adverse events with the exception of one dog that received 10 11 TCID 50 which developed severe hepatotoxicity and shock leading to euthanasia. 93 A following study testing VSV-hIFNb on rhesus macaques via intrahepatic injection did not result in neurological symptoms and is considered to be safe enough to proceed into phase I clinical trials, which are currently ongoing in humans and pet dogs.…”

“…91,92 All 3 strategies previously described (conditional replication, arming, and targeting) have been employed to increase efficacy of VSV. 88 Furthermore, combination therapy has been described with different other therapies. Finally, optimizing delivery and distribution of oncolytic VSVs has been evaluated using cell-based carriers and aptamer or PEGylation of virions.…”

“…Secondly, VSV produces high virus yields in a wide range of cell types, it replicates intracytoplasmatic without risk of genomic integration, it harbors a small and easy to manipulate genome, and there is no pre-existing immunity in humans. 88 VSV infection in humans is generally asymptomatic and limited to people having direct contact with VSV. 88 A single case of VSV strain Indiana related encephalitis in humans has been reported.…”

“…88 VSV infection in humans is generally asymptomatic and limited to people having direct contact with VSV. 88 A single case of VSV strain Indiana related encephalitis in humans has been reported. 89 VSV oncoselectivity is based largely on defective or reduced type I IFN responses in tumor cells, 90 although abnormal translation machinery and other cellular proteins have also been shown to play a role.…”

“…88 Compared with other oncolytic viruses, VSV has some distinct advantages: first of all a well-studied biology with relative replication independency of cell cycle and a specific receptor. Secondly, VSV produces high virus yields in a wide range of cell types, it replicates intracytoplasmatic without risk of genomic integration, it harbors a small and easy to manipulate genome, and there is no pre-existing immunity in humans.…”