Friending A Virus: Understanding Virotherapy Through Reolysin

Not unlike the word "cancer", the word "virus" has never carried any positive connotations.

We may refer to a popular video as having gone viral but if we say "It's a virus," that changes everything. Even as an adjective, "viral" is limited: a person's laugh, for instance, is never viral; at best it's infectious. If anything about them is viral, odds are you want nothing to do with that.

In a new development, however, one of the more promising fields in medical research is giving both virus and viral a second chance.

Oncolytic virotherapy uses replication competent viruses to selectively infect and then destroy cancer cells. [1]

Viruses as Cancer Killers

One of the most remarkable cancer stories of 2014 featured oncolytic virotherapy. A team of researchers at the Mayo Clinic conducted a proof-of-principle trial involving two patients with advanced-stage cancer. They injected each patient with 100 billion units of a specially engineered measles virus.

That is enough to treat 10 million people.

One patient died. The other patient, who had been through multiple treatments including a pair of stem cell transplants, nearly died but then recovered. Within a few weeks, she had no detectable cancer in her body. [2]

She is not the first patient to be successfully treated with virotherapy, but she is the first well-documented case of a cancer patient with advanced disease experiencing complete remission.

Viruses as Harmless to Humans

While the Mayo Clinic patients and others have been treated with a virus known to cause illness, the reality is that most viruses aren't like that at all.

"The vast majority of viruses – between 85 to 90 percent of known viruses – do not cause illness in humans when infected," says Dr. Brad Thompson, Chairman, President and CEO of Oncolytics Biotech. "But nobody knows for sure how many there are because they're never studied. Back when I was doing hands-on research, if I had applied for a grant to research a virus that didn't cause a disease I wouldn’t have gotten any money for it. The medical community has rightfully focused its time and energy on viruses that actually cause illness."

The lead product candidate for Oncolytics Biotech is Reolysin. Reolysin is a modified version of a very common virus known as the reovirus, an acronym that stands for Respiratory Enteric Orphan Virus. By the time most humans reach adulthood, they have been exposed to the reovirus.

Oncolytics have launched or completed around 20 clinical trials involving Reolysin for studies on ovarian cancer, pancreatic cancer, melanoma, myeloma, head and neck cancer, breast cancer, colorectal cancer and malignant glioma, among others.

This past December, the company filed for Orphan Drug Designation from both the EMA (Europe) and the U.S. FDA for Reolysin to treat pancreatic and ovarian cancers. It was announced today that the FDA has granted Orphan Drug Designation to Reolysin for ovarian cancer.

In The Emperor of All Maladies, Siddhartha Mukherjee explains this technical aspect of viral infection:

Normally viruses infect cells ... produce more viruses ... but they do not directly affect the genetic makeup of the cell. Influenza virus, for instance, infects lung cells and produces more influenza virus, but it does not leave a permanent fingerprint on our genes; when the virus goes away, our DNA is left untouched. [5]

Not until 1958 was it first discovered that unlike influenza virus, some viruses actually do physically attach themselves to the DNA of a cell and change the genetic makeup of that cell. This lead to the discovery of the role of viruses in causing cancer (rather, it led to the acceptance of this theory). Today experts estimate that about one quarter of all cancers are caused by viral infection (viral culprits include Epstein-Barr, HBV, HPV, HTLV-1, HIV, and HHV8). Some, like evolutionary biologist Paul Ewald, believe that one day we'll realize that 95 percent of cancers have a viral origin. [6]

Viruses and DNA

Cancer is a disease of genes. [7] Every cell in the body, driven and directed by its genetic code, is pre-programmed to die. When a virus gets inside the cell and attaches itself to the DNA, depending on what genes the virus brings, that cell may be under new management. It can then turn off the cell's prior instructions to die by allowing cancer-causing genes to start working while silencing the function of cancer-suppressing genes.

A similar process is at work when DNA is exposed to known carcinogens like radiation or benzene. These elements leave their own mark on DNA by damaging it, thus rending the cell incapable of dying. Even though the end game for a cancer-causing virus is the death of its host, the death is slow enough for the virus to replicate billions and billions of times over.

Understanding the Role of the Immune System

"Anyone who says they understand the immune system doesn't understand the immune system," says Thompson. "All viruses have techniques either to hide themselves from the immune system or to suppress a response from that system. The reovirus hitchhikes on most blood cell types and becomes invisible. So you inject this into a patient, it attaches itself to almost any blood cell except red blood cells, and those cells deliver it to the tumor."

That isn't to say there is no immune response. The immune system does respond to reovirus, but it is unable to neutralize it.

So how does the virus kill a cancer cell?

Well, the same way that influenza virus kills lung cells. Once inside the cell, the virus replicates, making more and more versions of itself until the cancer cell explodes.

You might expect the engineered reovirus to do this same thing in healthy cells. In healthy cells, however, the reovirus is unable to replicate. In as many as half of all cancers, a cancer-causing gene known as RAS is activated. The activation of this pathway enables the reovirus to run amok.

It replicates until it can no longer be contained and the cell bursts. In doing so, that one cell now releases as many as 50,000 progeny virus particles, each of which can now infect another cancerous cell. This bounty of virus particles allows Oncolytics to keep the amount of Reolysin they administer below what might be considered toxic, unlike the enormous and toxic measles virus levels given the myeloma patient.

"In all drugs you run into toxicity limits, limits of what people can tolerate," said Thompson. "With Reolysin we haven't actually ever reached a maximum tolerated dose. We reach the amount where we clearly are able to get the virus inside the tumor."

Once that point is reached, the virus does the rest of the work.

A Final Pro-Virus Argument

As for that 'permanent fingerprint on our genes' left behind by some viruses, Thompson says many of the viruses that do integrate into the genome do so silently, without causing illness. As a result, they still may have much greater value than one might ever imagine.

"Viruses introducing new genetic material ... this is a driving element in evolution," said Thompson. "Up to a quarter of your genetic material came from viruses infecting your ancestors, dating back hundreds of millions of years."

FOOTNOTES

1. Russell Sj, Peng K-W, Bell JC. Oncolytic Virotherapy. Nature Biotechnology 2012;30(7):10.1038/nbt.2287.
2.Engineered measles virus puts myeloma patient into remission. Lymphomainfo.net.
5. Mukherjee, Siddhartha. The Emperor of All Maladies.. Scribner. New York, 2010.
6. Grant, Andrew. The Big Idea That Might Beat Cancer and Cut Health Care Costs by 80 Percent. Discover Magazine, Sept 2009.
7. Ridley, Matt. Genome: The Autobiography of a Species in 23 Chapters. HarperCollins. New York, 2000.