Overview

It has long been hypothesised that viruses may have a role in treating cancer. From the mid-1800s, there has been documentation of patients undergoing spontaneous cancer remission following severe infection, and by the start of the 20th century, a temporary complete remission of acute leukaemia was observed in a patient suffering from influenza.1 Over the course of the last century, rodent cancer models have demonstrated tumour regression following virus treatment,1 2 and these promising results led to clinical trials in the 1960s–1970s using ‘anti-cancer’ viruses, which were unfortunately somewhat hampered by their high rate of infectious complications secondary to wild-type virus use.1 2 Over the past three decades, the introduction of genetically engineered viruses that can specifically target cancer cells while leaving normal cells unharmed has opened up an exciting new era of oncolytic virotherapy (the use of viruses to treat cancer), with the advent of a wide spectrum of early phase clinical trials for a range of malignancies.2 3 Importantly, these trials have been safely delivered and well tolerated by patients with cancer with a range of clinical presentation.2 3 More recently, talimogene laherparepvec (an attenuated herpes simplex virus expressing human granulocyte-macrophage colony-stimulating factor for immunostimulation) has demonstrated a major breakthrough in the field, becoming the first oncolytic virus to reach regulatory approval in the USA, Europe and Australia, having shown positive results for patients with advanced melanoma in phase III study.4 5 Although research is still relatively in its infancy for paediatric malignancies and limited to preclinical laboratory work and a handful of phase I studies,1 6 oncolytic virotherapy clearly holds promise as a potential novel therapeutic strategy for poor prognosis children’s cancers and certainly warrants further evaluation, including in combination with other treatment modalities.

How does oncolytic virotherapy work?

Oncolytic viruses can selectively infect and lyse cancer cells, while leaving normal tissue unharmed2 7 (figure 1). Such tumour tropism results from a variety of mechanisms, such as overexpression of viral entry receptors on cancer cells, faulty antivirus intracellular defence mechanisms and aberrant stress responses that viruses are able to exploit in order to gain entry into cancer cells.3 Oncolytic viruses may be naturally occurring or they may be genetically engineered to improve their safety and tumour specificity or to enhance their immunostimulatory properties.2 3

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Figure 1

Oncolytic viruses are tumour selective. Oncolytic viruses can selectively replicate in cancer cells, leaving normal cells unharmed. Oncolytic viruses can act as both direct cytotoxic agents and immunotherapeutics. Adapted from Kirn et al 10 and Prestwich et al.7

Once a virus has entered a cancer cell, it aims to take advantage of cellular resources to replicate and synthesise new viruses, which can then be released to perpetuate further cancer cell infection within a tumour mass.2 3 Following successful replication, oncolytic viruses induce host cell death, and this may be achieved by one of several mechanisms, including apoptosis, necrosis, pyroptosis (inflammatory-mediated cell death) and autophagy.2 3 There has recently been a shift in the oncolytic virotherapy paradigm to suggest that oncolytic viruses also generate tumour cell killing by enhancing the immunogenicity of the tumour microenvironment, thus activating innate and subsequently adaptive immune responses against infected tumour cells3 7 (figure 1). The ability of oncolytic viruses to act as both direct cytotoxic agents and immunotherapeutics highlights a dual mechanism of action that can be exploited to maximise cancer cell killing and may be enhanced when used in combination with other anticancer therapies.8

What type of viruses have been used in the clinical arena and are they safe?

Translation of oncolytic virotherapy from bench to bedside is clearly gathering steam. A vast array of viruses have been evaluated in clinical trials, including herpes simplex virus, adenovirus, Coxsackie virus, measles virus, Newcastle disease virus, parvovirus, polio virus, reovirus, Seneca Valley virus, retrovirus, vaccinia virus and vesicular stomatitis virus.2 (Viruses printed in italics have been modified for safety and tumour specificity.) In 2016, approximately 40 oncolytic virotherapy clinical trials were observed to be recruiting patients for a range of cancer diagnoses including solid and intracranial malignancy.5 Oncolytic virotherapy with herpes simplex virus, reovirus, Seneca Valley virus and vaccinia has been evaluated in case series as well as phase I studies for paediatric patients with recurrent malignant brain tumours, such as high-grade glioma, and relapsed or refractory extracranial solid tumours, such as neuroblastoma, hepatoblastoma, rhabdomyosarcoma and Ewing sarcoma.6 9 Overall, tolerability in adult and paediatric trials to date has been excellent; no transmission to patient contacts has been documented and viral mutation to original pathogenic form has not been seen.2

How can oncolytic virotherapy be delivered?

Viral delivery to tumours still remains a significant challenge. Systemic delivery is limited to the intravenous or intranasal route, with no oral formulations currently available.8 Additionally, systemically delivered oncolytic virus may be neutralised by the patient’s own immune system before it reaches the tumour target.8 In an attempt to overcome this problem, intratumoural oncolytic virus injection has been evaluated in clinical trials and is also capable of generating a systemic reaction through activation of the adaptive immune system, with response seen in non-injected tumours.8 However, use of intratumoural injection limits the number of opportunities for treatment and may be particularly difficult to achieve on a regular basis, especially in the paediatric setting. Penetration of the blood–brain barrier remains a problem for intracranial tumour delivery, and novel approaches to deliver virus directly into brain tumours using positive pressure infusion techniques, such as convection enhanced delivery, are currently under investigation.8

What are the future challenges for oncolytic virotherapy?

The next phase for oncolytic virotherapy development is to maximise therapeutic efficacy, testing for synergistic effects with other treatment modalities that may enhance tumour cell killing, immunogenicity and sensitivity of cancer cells to chemotherapy and radiotherapy.8 Laboratory cancer models have demonstrated enhanced therapeutic responses when oncolytic viruses are combined with either chemotherapy or radiotherapy, and combinations of virus with novel small targeted molecular inhibitors or immune checkpoint blockers are showing promise.8 As with all cases of drug development, there is a fine balance that needs to be addressed between enhancing therapy and minimising toxicity. Additionally, within the paediatric arena, cost, competition with other novel therapies, limited patient numbers and paucity of preclinical models are all barriers to development. In summary, oncolytic virotherapy clearly has the potential to become an exciting tool in our armamentarium against cancer, boosted by the current rage for immunotherapy, and may be able to improve outcomes for poor prognosis adult and paediatric tumours.