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Hope and fear: Part III

The promise of viral therapies

From Thursday's Globe and Mail

At any other moment in Brad Thompson's life it might have sounded too strange.

But when University of Calgary researchers approached the entrepreneur in 1998 about the potential of using a common stomach bug to fight cancer, their timing was uncanny.

Dr. Thompson had lost his mother to lung cancer that year, his uncle to esophageal cancer and he himself had been diagnosed with melanoma.

"I was open to thinking about cancer, and thinking about it in a new way," said the microbiologist, who was working with a biotech firm on bowel diseases at the time.

"I'm awfully glad they came to see me."

Eight years later, Dr. Thompson, now CEO of Calgary-based Oncolytics Biotech, is in the vanguard of one of the more promising, if unconventional, approaches to treating cancer patients: deliberately infecting them with viruses.

Cancer cells, it so happens, are particularly vulnerable to viral invasion and the century-old concept has cured laboratory mice, pushed some end-stage cancer patients into long-term remission and raised hopes for a new generation of cancer therapies.

Hundreds of patients in clinical trials in Canada, the United States and Europe have volunteered to catch a cold, a stomach bug, a mutant form of herpes and even a chicken flu.

Researchers have found cancer cells lack the defences that healthy cells have to protect themselves from infection. Flipped into overdrive, a cancer cell never shuts down the pathway that allows a viral intruder to waltz in, replicate and wreak havoc.

Several viruses have now passed Phase 1 human safety tests with encouraging results and larger Phase 2 trials to test their efficacy are in the works.

But getting a new medicine to market is never easy and those involved say that transforming a virus into a viable drug presents more obstacles than usual. For one, it can be tricky to control a dose when the drug has the power to replicate itself.

"This is a much more complicated kind of drug, if you can even call it a drug," said David Stojdl, a scientist working at the Ottawa Regional Cancer Centre in the field.

As well, despite years of university research, the field still labours to alter its fringe image. Some academic scientists are struggling to attract the interest of drug companies with pockets deep enough to continue development. Not everyone has been as receptive as Dr. Thompson to the idea of using one disease to fight another.

"Industry is much more conservative, and for them this can be too much," said John Bell, an Ottawa scientist and long-time pioneer in the field.

But the need for private-sector investment is critical, he said: "You can treat mice with government funding, not people."

Earlier this year, China became the first country to approve a viral therapy, giving the nod to a modified version of the common cold to treat cancers of the head and neck. Yet the cold bug now being sold by a Shanghai biotech firm is a copycat of a virus first developed by a U.S. company, which despite encouraging results from mid-stage clinical trials, dropped it in favour of a more conventional drug.

Yet most experts feel it's time to look beyond convention.

"As an industry, we haven't been very successful in new approaches to treating to cancer," Dr. Thompson said. "Most of the advances have been the result of better diagnosis . . . survival times have improved with earlier detection."

He, for example, credits his own quick melanoma diagnosis to his beloved dog, Mozart, who sniffed so steadily at the malignant mole on his leg that he rushed to the doctor to have it checked.

Dr. Thompson knows from experience that "the therapies we use to treat cancer are still the same ones we've had for years.

"Viral therapies are promising, they're safe, they target the cancer cells and there's not much collateral damage."

It began as one of those weird medical observations. An Italian doctor in the early 1900s noticed that after he gave a prostitute a rabies vaccine to treat a dog bite -- a shot that contains viral material -- her cervical cancer regressed.

The mysterious connection -- bolstered by anecdotes about cancer patients getting better when they battled a cold, flu or other infection -- led to a few experiments. Reports from the 1940s suggested that measles might somehow help to quell lymphoma. In the 1950s, doctors in the Soviet Union literally fed poliovirus to cancer patients.

But not until the early 1990s did virologist Patrick Lee and colleagues at the University of Calgary piece the puzzle together.

They showed that in a cancer cell, a pathway crucial for growth and survival is stuck in the "on" position. Like a porch light that never shuts off, this defective mechanism that makes a cell malignant also allows a virus to find the door easily.

Once inside that cell, the viral intruder makes so many copies of itself they bust the host from the inside out and set off to find another.

Dr. Lee had centred his work on the reovirus, a bug so common it usually triggers at least one bout of diarrhea in most people by the age of 3, but it helped to spread wide interest in the viral field.

Researchers at McMaster University in Hamilton and others in Britain, for example, have homed in on the anti-cancer powers of herpes. Researchers at Duke University in North Carolina are running with a crippled poliovirus, and at Minnesota's Mayo Clinic it's a modified form of measles. University of Ottawa scientists, meanwhile, have been studying a range of microbes with an eye to tailoring them to be a tumor's worst enemy.

On a recent blustery morning at the Ottawa Regional Cancer Centre, Dr. Bell and his team crammed into his cluttered office to discuss the learning curve.

Dr. Bell, an affable, silver-haired man in black jeans, is a senior scientist with Cancer Care Ontario and a co-founder of the Canadian Oncolytic Virus Consortium, which is establishing standards in the field.

It was, for example, once thought that a virus might simply be injected into a tumour. But since cancer usually kills when it spreads, Dr. Bell said, it's clear viruses have to be given intravenously to flush the system, "if they are going to be useful."

Research suggests that 80 per cent of cancer cells have a defect that makes them susceptible to a virus. But "just as viruses have evolved ways to enter our cells," he said, "our immune system has evolved to stop them."

Figuring out how to keep the body's immune system from killing viruses that have been dispatched to kill the cancer is one of the field's key issues.

"It's been a matter of finding that balance between attenuating a virus to minimize side effects and yet not to the point where it's losing its anti-cancer punch."

Most safety trials have not even reached a maximum-tolerated viral dose in patients, he suspects, because they have involved either less virulent strains, or those genetically tweaked to be less toxic.

Dr. Bell's initial investigations focused on the Newcastle virus, a flu bug that strikes chickens. Since few patients are likely to have been exposed to the fairly obscure virus, he estimates it has "a two-week window to attack tumour cells before [a patient's] immune system gears up to destroy it."

A few years ago, Dr. Bell teamed up with a Maryland company called Provirus Inc., to run clinical trials of Newcastle virus. Thirty patients with a range of advanced cancers were enrolled in Ottawa and another 18 in Hamilton in 2001.

McMaster professor Sébastien Hotte, a medical oncologist at the Juravinski Cancer Centre, said the Phase 1 testing and follow-up was designed only to determine safe doses of the virus, but it also showed promising results in six of the 18 patients, who had all exhausted standard treatments.

Dr. Hotte, author of the report that is soon to be published, said the virus was delivered by IV twice a week for three weeks. If the treatment was well tolerated, the infusions continued over several months.

The first dose prompted "flu-like" symptoms, but they disappeared with subsequent doses as the body acclimatized to the treatment.

"We were quite happy," Dr. Hotte said, "some patients had signs of disease regression."

The most dramatic example involved a woman in her 40s with end-stage cervical cancer who received the viral infusions for nine months. Some months after treatment ended, surgeons operating to remove a benign growth on her bladder discovered her cancer had disappeared. More than three years later, Dr. Hotte said, the woman is still alive.

He said the therapy is "not ready for prime time," but noted that larger trials of the virus in patients with cervical and colorectal cancers are to begin in Hamilton next year.

"Given that we have a lot of people who are drug averse, [patients] find this approach very attractive. It's not a chemical, it's not chemotherapy, and that," he said, "is appealing to them."

It was Calgary virologist Dr. Lee, along with his postdoctoral student Jim Strong and his graduate student Matt Coffey, who first paid Dr. Thompson a visit in 1998.

Since then, the garden-variety reovirus that led to their breakthrough has become the cornerstone of Oncolytics.

So far, 100 patients have received treatment with Reolysin in six preliminary safety trials, three of them in Alberta. The company has also been testing it on cancer patients in England and recently received approval to expand the trials.

"About half the patients have no side effects at all," Dr. Thompson said. "The most common side effects in the other half are mild fever . . . mild joint or muscle pain . . . and a bit of tiredness."

As well, a few patients in the trials who were not expected to live long are still alive, he said.

The U.S. National Cancer Institute is so intrigued by the company's strategy that earlier this year it announced it will pay for a multicentre clinical trial to test Oncolytics' stomach bug on patients with melanoma and ovarian cancer. "That's a big endorsement," Dr. Thompson said.

Dr. Bell is no longer involved with the Maryland company developing the Newcastle virus. With the Ottawa teams' hopes of genetically tweaking viruses to increase their ability to selectively target tumour cells, there was a parting of ways.

Said David Stojdl, who was once a postdoctoral student in Dr. Bell's lab: "We can engineer them to do whatever we want." Currently, he is working out ways to specifically arm viruses to break into tumour cells only, but still "trip the alarm" that will bring immune guards to protect healthy cells.

It's also possible, Dr. Bell said, that they could design a virus primed to attack cancer stem cells, which have recently been revealed as the engines driving several types of tumours.

But in the meantime, he sees a major challenge to the field: finding and keeping private-sector investment. Grants from government agencies such as Cancer Care Ontario help, he said. But academic grants are barely a sliver of what is needed to run clinical trials.

The Ottawa group has most recently been exploring a partnership with a California company to focus on vaccinia, a cowpox relation best known as an ingredient in the smallpox vaccine.

Dr. Bell understands that using live viruses as a medical treatment naturally raises concerns. In 1999, for example, Jesse Gelsinger, an 18-year-old American who suffered from a rare metabolic disorder, died after doctors injected him with a weakened cold virus as a means of delivering a corrective gene to his ailing liver.

"People are fearful, perhaps," Dr. Stojdl agreed, "that you don't have control of its distribution throughout the body."

Harold Atkins, a medical oncologist who has worked with Dr. Bell for eight years, also noted that the virus field doesn't follow the traditional course of other therapies.

"With chemical drugs," Dr. Atkins said, "there's 40 to 50 years of understanding how drugs interact with the body and find their target, and with this, it's not clear those lessons apply."

Still, the Ottawa group is forging ahead. In a tower that overlooks the cancer centre, a small, stark white biofactory of negative air-pressure rooms is under construction where the researchers hope to produce their cancer-fighting viruses for clinical trials.

"Our purpose here," Dr. Bell said, "is to get it far enough along so that it's not viewed as a fringe concept."

From the vantage point of a private-sector player, Dr. Thompson is more optimistic. The drug industry may have been initially reluctant, he agreed, because of safety concerns. But safety trials have gone well.

"[Pharmaceutical companies] have never really lost interest. They've always been watching over our shoulders."

Industry's main concerns, he said, are, "Can you produce enough and will it work well?"

Viruses like the common cold and stomach bug may be ubiquitous in nature, but producing enough of them for use in treatment is a challenge.

Dr. Thompson explained that 10 trillion viral particles are needed for one IV treatment, and a patient may receive as many as 45 treatments over a nine-month period.

After a six-year investigation, Oncolytics has turned to a European manufacturer to grow Reolysin in human cell lines, where the virus can replicate itself and then be harvested.

Dr. Thompson suspects the interest from big companies will follow from the next phase of trials, which he said is preferable as an initial investor: "You are rewarded for the risk you undertake."

*****

Series schedule

Nov. 20 Drugs and dollars:

The pressure of high costs on care

Nov. 21 So tired of waiting:

Treatment is still taking too long

Nov. 22 Canada's research chasm: A nation falls behind

Nov. 23 PET scan scandal: High tech sits idle

Nov. 24 Screen test: Beating the

colorectal killer

Nov. 25 in Focus English lessons: The quest for a national strategy

Nov. 25 in NewsThe science of stem cells: A new way of looking

at cancer

Nov. 28 The end of chemo: There must be a better way

Today Can a shot of the flu cure cancer?

Saturday In his shoes:

Eight-year-old Spencer fights to live

Wednesday, Dec. 6 It's everywhere: Is the environment killing people?

Saturday, Dec. 9 "C-type" mentality: The psychology of survival

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