For more than half a century, the war on cancer has been fought mainly with three weapons.

The oldest and most reliable of these has been the simplest — a scalpel, to cut out as much of the deadly mass as possible. Any stragglers left behind are then scorched with radiation.

Finally, the cancerous bits that manage to escape the first two weapons are poisoned with chemicals, although often with serious and unpleasant side-effects.

As those three weapons have been improved and expanded, overall survival rates continue to inch up year by year.

Nearly two out of three Canadians diagnosed with cancer can expect to live at least five years, up from about a 50 per cent survival rate two decades ago.

And yet, there's something missing from this arsenal.

"Slowly but surely we've improved our chances of people living longer with better surgical techniques, better radiation techniques, better chemotherapy and more specific chemotherapy along the way," said Dr. Rosalyn Juergens, a researcher at Hamilton's Juravinski Cancer Centre.

"But talking to my patients, they often say 'Gosh, we kinda thought you guys would hit a home run and that we could do better.'"

Cancer researchers have long believed that a fourth weapon must exist — the human body itself, with the help of the immune system's soldiers.

It's a puzzle that has long baffled scientists.

The immune system has developed some very sophisticated weapons to fight off harmful foes, no matter if they're foreign or domestic.

Cancer cells are obviously harmful. Over time, they kill the body.

Yet when cancer comes calling, for some reason the immune system is tricked into turning a blind eye to the threat.

So why can't the body's natural defences mount an attack against these rogue cells?

Can the sleeping giant be roused into action?

The answer, it appears, is yes and the implications are massive.

It's early days yet but immunotherapy — the science of developing treatments that awaken the body's immune system — is showing signs of turning the tables once and for all.

"This has changed everything," said Dr. Jonathan Bramson, a McMaster University researcher and one of Canada's leading cancer immunology experts.

"Now, it's no longer some esoteric idea.

"It's no longer scientists in a laboratory playing with mice," he added. "This is now scientists in a clinic treating patients and getting responses in patients that are unheralded."

Immunotherapy is the leading edge of a wave of sophisticated new directions in cancer treatment that attack the disease with remarkable precision.

It's led to an explosion in options that are available, or soon might be.

Using just the terms "tumour" and "immunotherapy" on the U.S. government's clinical trials registry, there are 338 trials actively recruiting patients.

The U.S. Food and Drug Administration is aware of more than 700 cancer drugs in the pipeline. If even a quarter of those actually makes it to the marketplace, it represents a massive influx of new treatments, considering there were only eight new cancer drugs approved in the U.S. in 2014.

It may also be an unsustainable tidal wave from a financial point of view as the new cancer immunotherapy treatments now routinely exceed $100,000 per patient per year (See Day 2: Cancer's Costly Conundrum).

That's become more of an issue for provincial governments as some patients survive longer and longer on these expensive new treatments.

At first glance, the numbers reported by clinical trials might not seem overly impressive. For some of the new immunotherapies, the average improvement in overall survival might be a matter of months compared to the previous best option.

But there's a bigger story hiding in the statistics.

When some of the treatments have been used against advanced lung cancer and melanoma, up to 20 per cent of the patients have shown a long-term response.

That might not sound like much but keep in mind these trials involved final-stage patients who had run out of treatment options. Not long ago, the long-term survival rates for that type of patient would have hovered closer to zero per cent.

"So how can we get that 20 per cent closer to 100 per cent?" asked Dr. Sebastien Hotte, a medical oncologist and head of the Juravinski Cancer Centre's Phase I research program.

"Hopefully over time we're going to be able to afford to be a lot more picky, in that a response rate of 20 per cent or living two months longer is just not going to be acceptable," said Hotte. "It has been acceptable in large part because that was as good as it got."

The solution to better survival rates will likely be a combination of attacks — surgery, radiation and chemotherapy to reduce the bulk of cancerous cells and then an immunotherapy agent to finish the job. Or perhaps a combination of immunotherapy drugs that attack different checkpoints.

"What we've learned over the past 35 years in the war against cancer is that you cannot beat cancer with a single line of therapy," said Bramson. "You'll only beat it if you come in with multiple lines of attack rapidly before it has a chance to change."





Cancer and the immune system The basics of how your immune system works The immune system is an incredibly complex defence network designed to protect the body from harm. It depends on an elaborate communication system of specialized cells circulating through the body.

Some of these cells act as scouts, on the lookout for suspicious objects. What makes something suspicious or not depends on what types of chemical markers are attached to the outside of a cell.

When these scouts see something they don’t like, they race back to the factories where white blood cells are made — lymph nodes, the spleen, bone marrow, the thymus — and present examples of the markers that seem suspicious.

The factories then produce soldiers that are specifically designed to go looking for any targets displaying those markers. Depending on the type of soldier — T cells, B cells, macrophages, granulocytes — they will either disable the intruder or just chew one of these targets up.

The immune system also keeps a stock of memory cells, so when it sees that same intruder in the future, it can easily ramp up production of the right attackers.

One of the trickiest jobs for the immune system is to figure out what is “self” — a normal cell that belongs in the body — and what is “non-self” — something dangerous that doesn’t belong.

Most of the time, we think about foreign invaders such as a cold virus or a bacterial infection, but the immune system also has to be able to recognize domestic threats.

The circulating scout cells need to have the ability to recognize when a normal cell has undergone some kind of change that makes it an abnormal cell that needs to be killed off. When the immune system detects that kind of abnormality, it switches on a process of programmed cell death called apoptosis.

“The tricky part is the domestic,” said Juravinski Cancer Centre researcher Dr. Rosalyn Juergens. “How do you figure out when it’s time to say, ‘OK, you’re just too bizarre, it’s time to cut you off.’”

What goes wrong with cancer

Cancer cells are abnormal cells that have tricked the immune system into thinking they’re still normal.

“People often think of the immune system being soldiers that have guns and it’s just one way, that they just shoot,” said McMaster researcher Dr. Jonathan Bramson.

“But in fact, they’re being shot at as well,” he added. “So everything that the immune system fights is fighting back.

“A cancer that emerges in a 50-year-old or a 60-year-old could have been there for 40 or 50 years, always going back and forth until finally it found the angle and got past the immune system.”

Once again, it can be a case of what types of chemical structures are sticking out from the surface of the cancer cell.

The cancer cell can have a marker sticking out that switches off the immune system’s process of programmed cell death. Or the cancer cell can release little bits of chemicals that are recognized by the immune system as signals to shut down a response.

In some cases, the immune system does recognize cancer cells as a foe but it can’t mount a strong enough attack.

“If you look inside the tumour, you can see that in some of these patients there are clearly immune cells that are inside the tumour,” said Bramson.

“You can tell that they’re fighting,” he added. “The tumour’s winning but they’re fighting.”

Immunotherapy pushes your immune system to fight back

Researchers are learning more about the chemical markers that are erected on the surface of cancer cells and which ones can be exploited by the immune system.

One method is to block the signals being sent by the cancer cells that turn off the immune response.

Another method showing great promise is to find ways to keep the programmed cell death process from being deactivated.

In some cases, the new immunotherapy agents are designed to act on the cells of the immune system and not the cancer cells directly. For example, the drug will block a receptor on the immune system’s killer cells so that the programmed cell death function stays switched on.

One emerging line of research is to remove some of a cancer patient’s own white blood cells and then engineer them with certain receptors that will cause them to recognize the tumour. The engineered cells are then multiplied and injected back into the patient.

The challenge with immunotherapy — and other types of chemotherapy, for that matter — is that the genetic material in cancer cells is unstable to begin with, constantly mutating and changing just enough that some of the cells can become resistant to the treatment.

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The goal is to overwhelm the tumour before it can change fast enough to outrun the immune system.

“It comes down to a numbers game,” said Bramson, who uses the analogy of how beaches were taken during the Second World War.

“You send out a thousand troops, the gunners take them all down,” said Bramson. “You send out 10,000 troops, the gunners take down most of them but they run out of bullets eventually and those that survive get up the ridge and they take it.

“An awful strategy from the point of view of human life,” he added. “Not a bad strategy from the point of view of the immune system because these cells are expendable and they can be re-created.”

Right now, the immunotherapy successes have been with types of cancer that build up lots of mutations — melanoma, from the constant bombardment of the sun, and lung cancer, because of the constant exposure to the toxic chemicals in cigarette smoke.

The more mutations that occur, the better the chance that these mutations will show up as strange markers on the outside of the cancer cell that can then be used as a target for the immune system.

As treatments progress and diagnostic tests become more sophisticated, cancer will be defined less by the body site where it arises and more by the types of abnormalities found on the outside of the cancer cell or the types of pathways that can be interrupted inside the cancer cell.

Part one Arming ourselves against cancer

Part two Cancer's costly conundrum

Part three Latest advances in treatment

Part four Hamilton's top researchers

Part five Deadly diagnosis

Introduction to the series

Click to enlarge

The newest directions in cancer treatment

Monoclonal antibodies Monoclonal antibodies are complex chemical creations built in the laboratory and designed to attach to very specific structures located on the surface of a cell, much the way a key fits into a lock.

They can be built to attach to certain receptors on the outside of cancer cells, causing them to act like a red flag that tells the immune system to kill this cell. Or they can lock on to the cancer cell and prevent it from responding to a growth signal.

In some cases, the monoclonal antibody actually locks on to the healthy cells of the immune system, to keep them switched on so they attack the cancerous cells.

Monoclonal antibodies can now be engineered with some sophisticated added features.

For example, they can have a radioactive particle attached and when the antibody binds to the cancer cell, the radiation is activated. In this way, only cancer cells are affected.

Or the antibodies can come with a chemotherapy agent attached that is only released when the antibody attaches to the surface of the cancer cells.



Small molecule therapies Small molecule therapies are sometimes also referred to as targeted therapies.

The trick in cancer treatment is to find some function that has gone haywire in the cancer cell that doesn’t happen in a normal cell, and then find a compound that disrupts only the process that has gone wrong so that normal cells are unaffected.

Monoclonal antibodies are too large to slip inside a cancer cell so they do their work by attaching to the cell surface. In contrast, small molecule therapies are tiny enough that they can pass through the cell surface and then work on targets inside the cell that cause the cancer cell to go haywire.

One of the advantages of small molecule therapies is that the pathways being disrupted by the small molecule treatments are usually specific to a cancer cell, so normal cells aren’t harmed.



Oncolytic virus McMaster University, in partnership with the University of Ottawa and Toronto’s University Health Network, is at the forefront of research into the use of an oncolytic virus to fight cancer.

In this case, a virus that infects Brazilian sand flies is modified to go searching for cells that have a specific structure called the MAGE-A3 protein attached to the outer surface.

This protein is found on about one-third of all cancers, including melanoma, colorectal, ovarian and some types of lung cancer.

When the virus finds a cell with MAGE-A3 protein, it slips inside, begins replicating and causes the cancer cell to burst open. The virus then moves on to the next cancer cell it finds with the MAGE-A3 protein.

There’s an added bonus too. The virus also stimulates the body’s own immune system to begin destroying cancer cells with that protein.

There is a significant downside, though. The only normal cells that display the MAGE-A3 protein are the sperm-producing cells of the testes, so infertility is potential side-effect in men.



Therapeutic vaccines Most people think of a vaccine as something that’s administered to prevent a disease from developing. A therapeutic vaccine is something administered after a disease has developed in the hope of stimulating the immune system to jump into action.

In the case of therapeutic cancer vaccines, the goal is to inject a marker — or antigen — that will be recognized as a dangerous invader by the immune system, which will then send out killers to attack the cancer cells that show the marker.

The key is to find a marker that is specific to cancer cells so that normal cells are left untouched.



Anti-angiogenesis Tumours need fuel to grow, and blood vessels are the pipelines that provide the fuel. To grow beyond a millimetre or two in size, a tumour will have to develop its own network of blood vessels, a process called angiogenesis.

Anti-angiogenesis drugs prevent the tumour from growing new blood vessels. The idea is to keep the tumour from expanding rather than attacking cancer cells directly.

Unfortunately, successes to date have been limited.

Bevacizumab (brand name Avastin) is the most promising anti-angiogenesis agent so far.