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Breakthroughs in cancer research have a long history of being overhyped. But the enthusiasm for immunotherapy is different. It's exciting because increasingly it works. And it just might become the most important therapy of all

With Stage 4 melanoma, Air Force Captain Trent Krajaefski agreed to the experimental treatment that had him come to Toronto from Ottawa for an intravenous infusion every three weeks or so. ‘I was at the point where you say yes to anything,’ he says. (Dave Chan for The Globe and Mail)

Trent Krajaefski didn’t just get cancer, he was ambushed by it. It was March, 2011, and the 32-year-old Air Force captain was just back from a run when the vision in both his eyes dissolved into a formless shade of grey.

The change was as abrupt as it was terrifying. But the real shock came later that night when an emergency-room brain scan revealed the underlying cause: Captain Krajaefski had a tumour eating into his optic nerve. It was a Stage 4 melanoma – the deadliest form of skin cancer. Undetected, the cancer had taken root in his lower abdomen, metastasized and spread to his lungs, brain and elsewhere.

“I had no idea,” he says. “There were no prior signs that I recognized.”

Although much of his eyesight would be restored after surgery, Krajaefski knew he faced a bleak prognosis: About 10 per cent of patients with metastatic melanoma survive more than five years. His cancer was aleady well advanced and it proved resistant to chemotherapy.

Then his luck turned. That resistance qualified him to participate in a clinical trial involving a form of immunotherapy, an approach that enlists the body’s own natural defences to fight cancer cells like they would fight an infectious agent.

He jumped at the chance.

In technical parlance, he was given a PD-1 checkpoint inhibitor, a drug that bypasses tumour cells and acts instead on the body’s T cells – the immune system’s foot soldiers. In many patients, tumour cells carry the ability to switch off T cells by presenting them with a signal, like a secret handshake that lets tumour cells appear as normal cells. The new drug latches onto T cells at just the right place to block that handshake and keep the T cells in attack mode.

For Krajaefski it proved to be a winning strategy. His cancer has diminished. He is still working and still running. The fact he has come this far counts him as one of immunotherapy’s success stories.

His physician, Dr. David Hogg, a senior scientist at Princess Margaret Cancer Centre in Toronto, says the case is an example of how immunotherapy is rewriting the rule book on melanoma – a type of cancer where grim disappointment has been the norm.

“We’ve gone from having nothing to having a really effective therapy,” Hogg says.

The transformation has put immunotherapy in the spotlight after years in the medical wilderness. In recent weeks a spate of studies published in Nature and The New England Journal of Medicine document promising early stage results with the use of checkpoint inhibitors in certain types of bladder, lung and kidney cancers, as well as Hodgkin’s lymphoma. Researchers are also looking to exploit other ways – beyond the use of checkpoint inhibitors – of priming the immune system to fight tumours. Immunotherapy is now poised to take a place alongside the traditional triad of cancer treatments: chemotherapy, surgery and radiation.

If the latest efforts are successful, immunotherapy may well prove to be the most important therapy of them all.

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Last month, the federal government jumped on the bandwagon, announcing its support for a $60-million initiative called BioCanRx (Biotherapeutics for Cancer) that aims to boost Canada’s role in the immunotherapy revolution. Though modest on the scale of global cancer research, the program is strategic in its goal of accelerating the most promising avenues for immunotherapy already under development in Canadian labs, and getting them to patients faster.

The incentive is two-fold, says Dr. John Bell, a senior scientist at the Ottawa Hospital Research Institute who is leading the effort. “If you can educate your immune system to view cancer as foreign, not only do you have anti-cancer activity – which will reduce a tumour and hopefully eliminate it – you have long-term immune surveillance so the cancer can’t come back.”

While cancer breakthroughs have a long tradition of being overhyped, the growing buzz around checkpoint inhibitors carries an important distinction: Positive early results are continuing to hold up after randomized studies involving thousands of patients. And survival rates are doubling or tripling.

In other words, immunotherapy is gaining attention now “because it works,” says Dr. James Allison, a researcher at the MD Anderson Cancer Center in Houston, who conducted the pioneering work that would ultimately lead to the first checkpoint inhibitor.

Releasing the brakes

Although he lost his mother to lymphoma at the age of 11, as a scientist Allison did not at first set out to cure cancer. Rather, he hoped to achieve a better understanding of how the immune system works. In the mid-1990s, it was the pursuit of this more fundamental question that led him to discover that a particular receptor found on the surface of T cells can work like a brake pedal on the immune system. By blocking that receptor, the right drug can “take the brakes off” whenever T cells encounter tumour cells, Allison explains.

Dr. James Allison, a researcher at the University of Texas MD Anderson Cancer Center who landed Canada's top medical prize, a Gairdner Award, for his work in immunology, says 'we need to get beyond melanoma.' (Fred Lum/The Globe and Mail)

The significance of the find was not appreciated immediately, but the gravelly voiced Texan – an accomplished harmonica player who once shared the stage with Willie Nelson – persevered. The work led to a drug known as ipilimumab (Yervoy), which was approved by the U.S. Food and Drug Administration in 2011 and just last September by Health Canada as a first-line treatment for malignant melanoma.

Now a second generation of checkpoint inhibitors that act in similar ways on different T cell receptors is coming online. One of them, pembrolizumab (Keytruda), is the drug that worked for Krajaefski. In September it also received a green light from the FDA for use in melanoma patients who have exhausted other options.

In October, Allison was in Toronto to collect a Gairdner Award, Canada’s most prestigious medical prize. At a related symposium organized to highlight new developments in cancer research, Allison and others at the front lines of immunotherapy shared their latest results. The scene offered a remarkable contrast to how the field was once viewed by mainstream cancer researchers.

Dr. Pamela Ohashi, director of the Immune Therapy Program at Princess Margaret Cancer Centre, is launching an early phase trial in which ovarian cancer patients' T cells are reproduced and re-injected to fight tumours en masse. (Fred Lum/The Globe and Mail)

And that, says Dr. Pamela Ohashi, a researcher at the Princess Margaret who has been working in immunotherapy for more than two decades, comes down to knowledge base. While immunologists have long recognized the potential of the immune system to fight cancer, they were at first missing the detailed understanding that would allow them to harness it effectively.

“People got really skeptical about it,” she says. And by the time the knowledge was finally there, “it took a really long time to get clinicians on board.”

The flamboyance advantage

Now there is widespread acceptance. But risks remain. The new therapies amount to “poking the immune system through the bars of a cage,” Hogg says. If the immune response is overstimulated, the therapy runs the risk of triggering inflammation or autoimmune conditions like colitis. Worries about side effects recently led Hogg to take Krajaefski off his trial, now that his cancer appears to be at bay.

Researchers say that while side effects must be taken seriously, the overriding conundrum is the fact that immunotherapy does not appear to work for everyone. Finding out why has become a key motivator of many ongoing studies.

Ultimately, the significance of immunotherapy will hinge on how widely applicable it proves to be. So far melanoma has played the role of poster child because it is a form of cancer in which tumour cells tend to exhibit a large number of mutations. This makes them more obvious to the immune system – an effect that Hogg compares to the tumour cells wearing a flamboyant Halloween costume.

“One of the things that’s impressive about immunotherapy is that it looks as though it has a lot of persistence. That’s very exciting.”
Dr. Harold Varmus, director of the U.S. National Cancer Institute, in Bethesda, Md.

Recent work by Dr. Brad Nelson and colleagues at the BC Cancer Agency suggest that cancers with fewer mutations can also be attacked with immunotherapy. In a study published last year, the group looked at tumour samples banked from cancer patients over many years. In cases where patients tended to recover, no matter what the cancer type, the study showed that immune cells were actively engaged in infiltrating the cancer.

“What’s really clear from our work is that patients who have a strong immune response have a far better survival rate than those who don’t,” Nelson says.

What has energized the field is that when immunotherapy does work, it seems to do more than simply delay the progress of cancer for a short time.

“One of the things that’s impressive about immunotherapy is that it looks as though it has a lot of persistence. That’s very exciting,” says Dr. Harold Varmus, director of the U.S. National Cancer Institute, in Bethesda, Md.

This sets immunotherapy apart somewhat from another area of active research, known as targeted therapy, which involves tailoring the treatment of an individual patient’s cancer with drugs that target that cancer’s unique set of genetic mutations. While targeted therapy continues to be an important player, its key drawback is that cancer cells are not all genetically identical. Those that survive the initial targeting may later proliferate, allowing the disease to regain momentum.

If the body’s entire immune system is doing the fighting rather than a lone drug, it has a better chance of hitting the full genetic range of tumour cells with a better long-term outcome. And unlike chemotherapy, a chemical treatment which bombards all cells that divide rapidly, whether they are cancerous or not, immunotherapy is less taxing on the body.

Exploiting the immune system

While successes with checkpoint inhibitors have won respect for immunotherapy, they represent only one way in which researchers are looking to channel the power of the immune system against cancer.

The full spectrum is apparent in the approach taken by BioCanRx, which is divided into three areas of research. One theme is dedicated to identifying and developing antibodies, such as checkpoint inhibitors, that can assist the body’s immune response to cancer. Another uses so-called oncolytic viruses that preferentially infect cancer cells and, in doing so, can trigger a more robust immune response.

A third theme is adoptive cell therapy, which involves extracting and reproducing a patient’s T cells in the lab and then injecting them back into a patient, in the billions, to go after tumour cells en masse.

Graphic: Immunotherapy three ways

A new Canadian network seeks to accelerate promising developments in immunotherapy, which involves harnessing the body’s immune system to fight tumour cells, in three areas:

      Ohashi, a participant in BioCanRx, is among those pursuing this third approach. This month she will begin an early phase trial, the first of its kind, to attempt adoptive cell therapy with ovarian-cancer patients. Like melanoma, it’s another form of the disease where options for treatment are limited, and there is potential for immunotherapy to make a big impact.

      “You can feel there’s just this huge enthusiasm and excitement to push different trials forward,” Ohashi says.

      More tantalyzing is the prospect of combining different immune therapies with one another to elicit a more powerful response. Such a combination approach is reminiscent of the way HIV/AIDS was eventually transformed from a near-certain death sentence to what, for many, is a chronic condition that can be managed for years. (The approach has the downside of driving up costs, so BioCanRx is also looking for ways to make therapies more cost effective.)

      But whichever particular version of immunotherapy proves most useful in different settings, top researchers echo a common theme: The recent progress is a sign that years of toil in the basics of immunology are finally paying off, not with a single cure but with a panoply immune-based methods. The result will help some people live longer. It may also change our relationship with cancer as a disease.

      “There’s not going to be one cure for cancer,” says Dr. Jedd Wolchok, an immunotherapy researcher at the Memorial Sloan Kettering Cancer Center in New York. “There are going to be a lot of treatments used together that are going to control the disease, changing it from something that patients die from to something that they live with – or live without.”