Oncolytic virotherapy could dramatically expand scope of locoregional therapy

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Steven Rose
Steven Rose

“I believe that it behooves the interventional radiology audience to at least be aware of oncolytic virotherapy, so that when the time and situation is right, they could be well positioned to adopt it,” Steven C Rose, professor of Clinical Radiology and section chief, Interventional Oncology University of California, San Diego Health Sciences told Interventional News.

Why should interventional radiologists be excited about the role of oncolytic viruses in cancer therapy?

 

I believe that interventional radiologists should be excited about oncolytic virotherapy because it appears that image-guided delivery of the virus is central to getting an adequate dose of the viral particles to the tumour in order to effect meaningful tumour infection and resultant tumour cell lysis. The human immune system is very effective at killing and eliminating systemically administered and circulating viruses. Viral delivery has been shown, both with transcatheter arterial and with direct interstitial intratumoural techniques.

 

What does your research on hepatic artery infusion of oncolytic viruses show?


Published and presented early data are encouraging. Across the board, nearly all patients experience a flu-like syndrome that lasts less than 24 hours. Grade three toxicities are very uncommon and grade four and five toxicities
are rare. To date, this therapy appears to be very safe in appropriately screened patients.


The efficacy data are less robust. One small multicentre, single-arm trial of arterially administered adenovirus (Onxy-015) in patients with liver metastases from gastrointestinal primary adenocarcinomas demonstrated partial tumour response by imaging criteria in 43% of patients. These patients who had tumour responses had a median survival of 475 days compared to 143 days in the non-responders (p<0.0001). In another small, prospective, randomised controlled trial of intratumourally-injected Vaccinia virus (JX-594) in patients with advanced hepatocellular carcinoma, a standard dose (1x109pfu) arm was compared to a low dose (1x108pfu) arm. The median survival in the standard dose arm was 13.7 months, compared to 6.4 months in the low dose arm (HR=0.41; p=0.025). The Kaplan-Meier survival curve for the low-dose arm was nearly identical to the control arm in two large randomised, prospective controlled trials that proved survival benefit for sorafenib. The survival benefit of the standard dose JX-594 arm far exceeded the survival benefit for sorafenib. Clearly, much larger randomised controlled trials for virotherapy are warranted, and in fact some are ongoing. In addition, other viral strains need to be developed and tested, and the effects studied in other tumour cell lines and in organs besides the liver. Of note, some preliminary work has been done using Herpes simplex I viruses injected intratumourally into unresectable adenocarcinomas of the pancreas.

Where do you most see the potential value of oncolytic viruses?

If the promise seen in early reports is borne out by large trials, I foresee oncolytic virotherapy potentially expanding the scope of locoregional therapy dramatically. For example, image-guided thermal or chemical focal ablative therapy is highly dependent on small tumour size (preferably less than 3cm), number (usually no more than three or four), and location.

Direct intratumoural injection of virus has effectively treated tumours in the order of 10–12cm. Proximity to nearby critical non-targeted structures is moot, because the virus is incapable of replication in non-tumoral tissues. Intra-arterial regional delivery of patent cytotoxic agents such as Yttrium 90 radioembolization carries a risk of severe gastrointestinal ulceration due to delivery into hepatosplanchnic arteries such as right gastric or supraduodenal arteries. Non-target delivery of viral particles is irrelevant because, once again, the viruses cannot replicate in tissues other than cancer. In addition, there is some anecdotal evidence of viral activity in distant metastases due to secondary tumour infection from the viruses shed after the initial tumour cell lysis. Finally, since the mechanism of cell death is replication-mediated cell lysis rather than apoptosis, viral agents likely will be effective in patients with chemorefractory tumours.


What is the central message of your talk at CIRSE 2012 on oncolytic viruses in cancer therapy?

 

My central message is that therapy has great promise, but needs validation with trials that offer higher levels of evidence. I believe that it behooves the audience to at least be aware of this therapy, so that when the time and situation is right, they could be well positioned to adopt it. I suspect multiple members of the audience may be from centres that will be enlisted to participate in some of the expanded, ongoing trials.


What are the special considerations?

 

When selecting patients for potential use of virotherapy, some special considerations need to be taken. Patients who are immunocompromised (eg past or future organ transplantation, concurrent chemotherapy) may be at risk of widespread viral dissemination. Patients or household members who have active eczema can develop a serious, potentially fatal complication of eczema vaccinatum if administered live Vaccinia virus. Many patients, especially those with hepatocellular carcinoma, are being treated with antiviral agents (eg, HBV, HCV, and HIV) that may interfere with the effectiveness of the therapeutic oncolytic virus.