Topic: REOLYSIN® - A new experimental treatment for brain tumors.
Interview conducted by:
Al Musella, DPM
President, Musella Foundation
|Matt Coffey, Ph.D.
Vice-President, Product Development
A co-founder of Oncolytics Biotech Inc., Dr. Coffey's current responsibilities include directing the clinical trial program and protecting Oncolytics' intellectual property position. Prior to joining Oncolytics, Dr. Coffey completed his doctorate degree in oncology at the University of Calgary with a focus on the oncolytic capabilities of the reovirus. The results of his research have been published in several respected scientific journals, including Science, Human Gene Therapy, and The EMBO Journal.
- What is REOLYSIN® and how does it work?
REOLSYIN® has been developed from the naturally-occurring reovirus. Reovirus (Respiratory Enteric Orphan Virus) is a common virus that most people (70% to 100%) have been exposed to in their lifetime. The virus is considered asymptomatic, meaning that there are no particular symptoms associated with it. Unlike other viruses that continue to reside in the body after infection, the body will eliminate reovirus within two weeks. Because it is considered such a "safe" virus, it has been used for decades by research institutions and individuals studying viral replication structure. In 1998, graduate students (including myself) working in a laboratory at the University of Calgary discovered that this particular virus seemed to be able to replicate itself in cancer cells that have what is called an activated Ras pathway, one of the most common family of genetic defects leading to cancer. Up to two-thirds of all human cancers, including many brain cancers, are Ras-activated, and are therefore a target for reovirus therapy.
Here's how it works: Viruses on their own cannot replicate. They need to borrow a host cell's manufacturing equipment. A virus particle will enter a cell, borrow the manufacturing equipment, and replicate itself within the cell until the cell dies, or the body's natural defenses kill the virus particles. If the virus is successful in killing the cell, the progeny virus are then free to infect and kill surrounding cells.
When the reovirus enters a normal cell and attempts to borrow the cell's manufacturing equipment to replicate itself, an anti-viral protein called PKR is able to quickly neutralize the virus. In a Ras-activated cancer cell, however, this anti-viral response is turned off. The reovirus is able to replicate itself within the cancer cell, resulting in that cancer cell's death. The cycle of infection, replication and cell death will be repeated until there are no longer any cancer cells available.
- How is REOLYSIN® administered to patients?
Currently, REOLYSIN® is administered by a single injection directly into cancer tumours. The company is also completing the toxicology work required to gain approval for a systemic trial, which could commence early in 2003.
- I know it is too early to talk about humans, but how did it work on tumors in animal studies? Did you run any animal trials involving gliomas?
I'll answer this question in two parts; First, it's not too early to talk about humans. We completed a Phase I human study late in 2001, and announced final results in March, 2002. We enrolled 18 late-stage, terminal cancer patients who had a variety of cancers. Our two endpoints were safety and tumour response. There were no serious adverse events noted. In addition, 11 of 18 patients (60%) had evidence of viral activity, with tumour regression ranging from 32% to 100%. Remember, these were patients for whom all other cancer treatments had failed, so we were quite excited about these results.
Second, Oncolytics did not run any animal trials involving gliomas, but researchers at the University of Calgary did. (http://www.fp.ucalgary.ca/unicomm/news/Jun_01/brain_research.htm).
Mice implanted with human gliomas were given a single, intralesional injection of reovirus. In the study, 20 of 23 animals had their tumours regress 100%. In addition, the animals gained weight and appeared healthy at the end of the trial.
- Historically, one of the biggest problems that localized treatments had was getting to the tumor. How do you know that the REOLYSIN® gets to the intended areas? Does it diffuse easily in brain tissue? Do you use any special techniques like convection enhanced delivery?
The procedure is actually quite simple. We use what is called a stereotactic needle to deliver REOLYSIN® to the tumour. While patients are conscious, an opening is created in the skull. The surgeon then inserts the stereotactic needle into the tumour and delivers three injections to various parts of the tumour. In theory, you would need only one injection, as the virus will replicate itself quickly if the cancer is ras-activated. However, because tumours are also made up of healthy connective tissues, it is possible that the virus could be stopped from spreading if it is surrounded by normal tissues, or necrotic (dead) areas. This approach gives us the best opportunity to get REOLYSIN® to as much of the tumour as possible. As we explore different dosages and additional methods of delivery, however, we may consider other techniques to enhance delivery.
- What brain tumor trials of REOLYSIN® are open now (anywhere in the world)? What phase? Where are they and what are the qualifications?
Right now, the only trial ongoing is the Phase I/II trial for recurrent malignant glioblastoma being conducted right here in Calgary, through the Tom Baker Cancer Centre. It is anticipated that once we gain FDA approval, the trial will expand to other sites, including the U.S. But the maximum number of patients that will be enrolled in Canada and the U.S. is 38, so it will not be a large trial. For a list of the criteria, click on the following link. (http://www.oncolyticsbiotech.com/clinical.html). It is important to note that Oncolytics has no influence over who is chosen to participate in the trial, and not all eligible patients may be selected. To become a candidate, patients must take the list of criteria to their oncologist, neurosurgeon or physician, who will determine if they are indeed a candidate. If the doctor believes they might be a candidate, he or she should contact Oncolytics directly, and we will put him or her in touch with the appropriate principal investigator.
REOLYSIN® is also being tested in a T2 prostate cancer trial that began in spring, 2002, and has been tested through our Phase I human trial in a variety of other cancers including breast and pancreatic.
- Is there any way to get REOLYSIN® on a compassionate use basis?
To date, no one has been able to access REOLYSIN® through a compassionate use basis. Health Canada does have a Special Access Program (SAP). Patients would need to contact Health Canada to find out more.
- What types of tumors does this therapy have the potential to treat?
The potential is quite broad. Because reovirus attacks Ras-activated cancer cells, it has the potential to treat up to two-thirds of all human cancers. Brain, pancreatic, breast, prostate and lung are just a few of the cancers it has the potential to treat. This doesn't mean, however, that REOLYSIN® has the potential to treat 100% of these types of cancers. Not all brain, breast or prostate cancers are Ras-activated, and some cancers are only partly Ras-activated. What makes this potential therapy different from other conventional therapies is that it appears to kill cancer cells only - without harming normal, healthy cells.
- How does it differ from other viral-based therapies?
Reovirus is naturally occurring, and requires no genetic modification. This is important, as many other viruses that can kill cancer cells also have potentially harmful side effects, and must be genetically modified to remove those harmful characteristics. Reovirus appears to be effective in its natural state.
- Why do humans get cancer then, if most of us have been exposed to reovirus?
That's a good question. Reovirus is usually confined to the gastrointestinal or respiratory tracts in humans, so it would not have access to tumours growing elsewhere in the body, nor in the amount required to impact the tumours.
- Do you feel that this has the possibility of being a cure, or will it just keep cancer at bay for a while?
I think most would agree that either of those outcomes would be excellent for cancer patients who have run out of options, particularly those with recurrent, malignant glioblastoma. REOLYSIN® looks promising for a number of indications, including glioblastoma, but we're too early in our clinical program to know what the final outcome will be. At the very least, however, REOLYSIN® is a promising new tool against cancer, and those kinds of tools don't come along very often.
For more information:
Oncolytics Biotech Inc.
210, 1167 Kensington Crescent NW
Calgary, Alberta, T2N 1X7
Oncolytics Biotech Inc. is a Calgary-based biotechnology company developing REOLYSIN® as a potential therapy for Ras-activated cancers.