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Ed Williams never saw the “weird little spot” that started his cancer journey.
It was square in the middle of his back, and no matter how he twisted and turned, he couldn’t find it in the mirror. His wife, Isabelle, discovered it in the summer of 2011.
“It didn’t worry me at first,” says Williams, a middle school teacher from Russell with a keen interest in science.
During his annual physical, he raised the issue with his doctor, who ordered tests, and in January, Williams was diagnosed with Stage 3 melanoma: The cancer had already spread to his lymph nodes. The following summer, a large, inoperable tumour was found in his lungs.
Williams cast about for treatment options as he updated his will and put his financial house in order for his wife and young daughter, Koralee. That fall, there was more bad news: A scan revealed three small tumours in his brain.
The survival statistics for Stage 4 melanoma patients with brain metastases were grim. Williams worried he might not live to see Christmas.
But a precision dose of radiation, delivered by surgeons at The Ottawa Hospital, eliminated the brain tumours. That made Williams eligible for a last-chance clinical trial featuring a new kind of cancer treatment: immunotherapy.
Immunotherapy seeks to expose tumours to the cancer-killing power of the human immune system. It was declared “Breakthrough of the Year” by the journal Science in December 2013.
In January 2014, Williams entered a clinical trial designed to test two new immunotherapy drugs, known as checkpoint inhibitors. The drugs were designed to inhibit cancer’s curious ability to switch off the body’s immune response to the abnormal cells that form a tumour.
During his first three months of treatment, Williams was in awe as his lung tumour shrank to about one-third its former size.
Today, more than 2 1/2 later, Williams’ cancer remains in check. The shrunken lung tumour is still there, but it hasn’t grown. As part of the ongoing clinical trial, he continues to receive a drug infusion once every two weeks. The side-effects? A bit of fatigue and some mild rashes.
“I feel really lucky,” says Williams. “I’m guardedly optimistic.”
Ed Williams, receiving treatment at the Ottawa Cancer Clinic.
Williams, 53, is among a growing group of late-stage cancer patients whose lives have been saved by immunotherapy during the past five years.
Clinical studies show that, in general, the therapies work remarkably well in a minority — 10 to 30 per cent — of cancer patients, and usually come with far fewer side effects than chemotherapy.
Right now, immunotherapy works best for patients with melanoma, lung and bladder cancer. But there’s frenzied research going on worldwide to unlock the full potential of immunotherapy — and extend its benefits to more patients with different types of cancer.
Some recent studies highlight the extraordinary promise of the fast-moving immunotherapy revolution.
A study released this year at a U.S. cancer conference showed that 34 per cent of patients with advanced melanoma survived five years after starting treatment with the checkpoint inhibitor, Opdivo — double the average survival rate for the same patient group. The clinical trial involved 107 patients who had no other treatment options.
Another kind of immunotherapy — one that involves engineering a patient’s own T-cells to recognize and attack their tumours — achieved equally encouraging results.
In findings published in the October 2014 edition of the New England Journal of Medicine, researchers reported that 27 out of 30 patients with advanced leukemia went into remission after undergoing immune cell therapy. Six months after being treated, 19 of the patients remained in complete remission.
The results are significant not least because of the kind of patients involved: people once regarded as incurable.
Explains Dr. John Bell, a senior scientist at The Ottawa Hospital and one of Canada’s leading immunotherapy researchers: “It’s remarkable because these people normally would not have survived. And not only are they living a long time, but as far as we can tell, they’re going to keep living.”
In recent months, medical and scientific journals have reported more success stories for early stage immunotherapy trials related to kidney cancer, Merkel cell carcinoma (a rare type of skin cancer), as well as head and neck cancer.
Still, cancer patients have been promised breakthroughs in the past only to be disappointed.
When the human genome was sequenced, for instance, researchers believed they’d be able to identify the genes that caused cancer and design drugs to shut them down. The research produced a few success stories, including the drugs Gleevec and Herceptin. But therapies that target genetic mutations in cancer cells have not produced the widespread benefits once predicted.
There’s no doubt that cancer is fiendishly complicated. It involves hundreds of genes and biochemical mechanisms, all of which can evolve during the course of the disease. Genetic mutations found in metastatic tumours, for instance, are often not the same as those that caused the disease in the first place.
So what’s different this time? Why should people pay attention to the immunotherapy revolution?
“I think that’s what’s different about it is that, in the clinic, we’re seeing results that have never been seen before,” offers Bell.
Dr. John Bell in his lab at the Ottawa Hospital Research Institute.
What’s also different, researchers say, is the nature of the immune system — and its adaptability as an anti-cancer agent. The immune system, once it’s engaged in the cancer fight, can evolve alongside a malignant tumour. No drug has the power to do the same thing.
“It’s beautiful,” says Dr. David Stojdl, senior scientist at the Children’s Hospital of Eastern Ontario Research Institute and a professor at the University of Ottawa. “It’s like a drug factory inside your body that’s able to adapt as fast as the biology that you’re chasing. That’s why we’re really keen on this as a tool.”
Immunotherapy is based on some hard-won science.
For generations, researchers had been confounded by cancer’s ability to hide from the body’s immune system.
A healthy immune system takes a firewagon approach to trouble: It rushes white blood cells to the scene and co-ordinates an attack. The body’s first responders regularly halt the spread of bacteria, viruses and mutant cells.
Yet cancer often fails to set off the body’s alarm bells. As a result, the immune system’s best cancer fighters, its T-cells, can be left in the station while tumours slowly grow unchecked.
Scientists, however, have started to decipher cancer’s complex cloaking device. Among other things, they’ve discovered that tumours not only hide, but also commit acts of sabotage: They secrete proteins and other substances that cancel the immune system’s initial response.
“The immune system rushes in and stalls: It just sits there,” explains Bell, a professor at the University of Ottawa. “So the breakthroughs involve reawakening that response, reversing that condition.”
Four immunotherapy drugs, known as checkpoint inhibitors, are now on the market, and the first virus-based immunotherapy, T-Vec, was approved last year by the U.S. Food and Drug Administration.
Together, they offer oncologists important new treatment options for a widening number of cancers.
Former U.S. president Jimmy Carter’s advanced melanoma was successfully treated with one of the new drugs, Merck’s Keytruda, used in combination with surgery and radiation. Another drug, Tecentriq, has been approved by the F.D.A. to treat bladder cancer. Bristol-Myers Squibb’s Opdivo has been approved to treat melanoma, Hodgkin lymphoma, lung and kidney cancer.
Scientists now know that cancer hijacks the biological mechanisms that tell the body’s immune system its job is done and is no longer needed. The shut-off mechanisms usually ensure that T-cells don’t attack healthy tissue.
Checkpoint inhibitors such as Yervoy and Opdivo target cancer’s mischief-making by closing down the communication pathways between tumours and T-cells. They target key proteins with names such as PD-1 and PD-L1.
Gordon Freeman is the Harvard Medical School professor whose groundbreaking research in the 1990s helped pave the way for the development of checkpoint inhibitors. “What’s remarkable about a PD-1 inhibitor is that, if anything, it works better in people than it does in mice,” says Freeman, a scientist at the Dana-Farber Cancer Institute.
Equally remarkable, he says, is the fact that checkpoint inhibitors work well even though they block just one of the chemical pathways that tumours use to misinform the immune system.
“Blocking one is good enough? That was a surprise,” Freeman says.
Since scientists have already identified other chemical pathways used by tumours, they have ready targets for new therapies as they seek to advance the immunotherapy revolution.
The audacious goal of that revolution? Nothing less than to overturn the established order of cancer treatment: surgery, chemotherapy and radiation.
Money is pouring into the field, primarily in the United States, where the federal government has launched a $1-billion “moonshot” to accelerate cancer research. Billionaire entrepreneurs, such as former Facebook president Sean Parker and former New York City mayor Michael Bloomberg, are also spending heavily to spur innovation in the field.
Sean Parker has invested in immunotherapy.
So too has former New York Mayor Michael Bloomberg, centre.
In Canada, immunotherapy and biotherapy researchers held their first national summit in June at a conference in Halifax co-hosted by BioCanRx, a network established last year to accelerate the development of Canadian-made therapies. The federal government has invested $25 million in BioCanRx.
All of the activity comes as the revolution reaches a critical moment: the end of the beginning.
“The revolution is still at the beginning, but the end is coming clearer,” says Dr. Ira Mellman, vice-president of cancer immunology at the biotech firm, Genentech, and the former director of the Yale Cancer Centre.
“It’s beyond the proof-of-concept phase — unlike the other flashes in the pan that have occurred throughout the past 20 years in oncology research.”
“We have got the low hanging fruit,” declares Dr. Elizabeth Jaffee, deputy director of the Sidney Kimmel Comprehensive Cancer Centre at Johns Hopkins University.
Says Dr. Brad Nelson, director and distinguished scientist at the BC Cancer Agency’s Deeley Research Centre: “We can all envision decades now ahead of us building on these successes.”
Some big questions remain unanswered, the most pressing of which is this: Why do only a minority of patients respond to immunotherapy? In labs around the world, including several in Ottawa, researchers are looking for ways to trigger a positive response in the majority of cancer patients.
To do so, they’ll require a more detailed understanding of the intensely complex tumour “microenvironment,” where all kinds of cells, molecules and blood vessels are co-opted to support the growth of malignant cells, and to inhibit an immune response.
One area of investigation involves the mystery of “hot” and “cold” tumours. Researchers know that most tumours are “cold” — they trigger no immune response at all — while others are filled with killer T-cells just waiting to be activated. These “hot” tumours are the ones that generally respond well to immunotherapy.
Researchers are trying to understand the biochemical mechanisms that determine such tumour responses.
“We need more science,” Elizabeth Jaffee says.
Meanwhile, the race is on to find the optimal immunotherapy cocktail.
Hundreds of clinical trials are now in the field to test existing checkpoint inhibitors together or in combination with other immunotherapies: oncolytic viruses and cell therapies. Each of them uses a different mechanism to boost the body’s immune response to a tumour.
Most researchers now believe the full benefit of immunotherapy will only be realized when the treatments are used together, and in combination with chemotherapy and radiation.
There’s already evidence that the cocktail approach can amplify that immune response.
One study, reported recently in the Journal of Clinical Oncology, found that Yervoy and T-Vec, a virus-based therapy, demonstrated a beneficial response in 50 per cent of patients with advanced melanoma. A significant number of patients (22 per cent) remained in full remission after one year on the drug combination therapy.
Most immunotherapy clinical trials still involve weakened patients with advanced cancers. But as more is known about the drugs and their side effects, researchers will be able to deploy them earlier in the disease process when the tumour burden is lower and patients are healthier. Many believe the real power of immunotherapy will only then be revealed.
“I think over the next five years,” predicts John Bell, “you’ll see even more tremendous outcomes because we’re going to learn how to do it better and how to optimize these approaches.”
Bell and David Stojdl are now involved in a unique clinical trial that deploys two engineered oncolytic viruses against advanced tumours. That trial is expected to report its findings next year.
CHEO’s Dr. David Stojdl.
Health Canada has approved three checkpoint inhibitors since 2012: Yervoy, Opdivo and Keytruda. And in some provinces, including Ontario, Yervoy is now being funded as a first line treatment for metastatic melanoma in adults.
Funding for second-generation immunotherapies, Opdivo and Keytruda, is still being examined in Ontario, but pharmaceutical companies have made the drugs available to many patients under special access programs. Bristol Myers-Squibb, for instance, has already provided Opdivo free of charge to 2,000 Canadian patients, including 700 in Ontario, through its access program.
For oncologists, the new therapies are both an opportunity and a challenge since they’ll have to decide when to rely on conventional anti-cancer measures, and how to choose between immunotherapy options.
Dr. Steven Jones, head of bioformatics at the BC Cancer Agency’s Michael Smith Genome Sciences Centre, believes technology can help: He says it’s possible to better target cancer treatments.
British Columbia spends more than $200 million a year on chemotherapy, he says, but much of that money produces only misery. “That (spending) would be just fine if it actually helped all the patients. But it doesn’t. In many cases, all we’re doing is adding more toxicity to these patients that they’ll have to cope with,” Jones says.
Understanding the best therapy for a cancer patient means that doctors have to know more about the individual — and their tumours.
Malignant tumours are hugely complex, often with more than a billion interacting cells; sometimes, the tumours have hundreds of genetic mutations. To complicate matters still further, tumours produced by the same kind of cancer have enormous variability: even within the same patient, tumours can have different genetic mutations.
As part of a government-funded research project, Jones and his team sequenced the genomes of 388 cancer patients and their tumours to better inform clinical decisions about how to treat them.
They compared the genetics of individual tumours against a database of other sequenced tumours to understand what chemotherapy or immunotherapy treatments produced the best results. (In general, research suggests tumours with hundreds of genetic mutations are the ones most likely to respond to immunotherapy.)
The approach represents a form of personalized medicine that Jones believes will one day become the standard of care as sequencing costs come down. The work is expensive, but Jones believes it will ultimately prove cost-effective.
“I think the economics are there,” he said.
The economics of immunotherapy are still evolving. There’s no doubt the new therapies will be expensive, particularly if they have to be used in combination with each other, or for extended periods of time.
The new checkpoint inhibitor drugs typically cost more than $8,000 a month, and it remains unclear how long patients will have to take them to keep cancer in check.
Affordability is just one of the hurdles to be overcome. There will almost certainly be more setbacks during advanced clinical trials since researchers are still learning how to use the powerful new agents, which can trigger dangerous side effects, including lung inflammation, colitis and rheumatoid arthritis — unhappy byproducts of a supercharged immune system.
In July, the F.D.A. ordered a halt to one high-profile immunotherapy trial after three leukemia patients died from brain swelling. The trial, which has since restarted, involves a promising cell-based therapy in which clinicians remove T-cells from a patient, engineer them in a lab to better target cancer, and infuse them back into the person’s bloodstream.
“It’s going to be a long road,” predicts CHEO’s Stojdl. “These are incredibly complex things.”
Some scientists worry the revolution is moving too fast. Genentech’s Ira Mellman argues that clinical trials are now outrunning the science. He wants a pause of sorts in the revolution so that researchers can answer more basic scientific questions.
“I think we have to take a step back,” he says, “and try to understand the mechanisms of the things that do work — so that we can understand which of those mechanisms is not working when it doesn’t work.”
John Bell says it’s hard to put into words how far immunotherapy has advanced during his three decades in the field.
“Someone getting into the field now can’t appreciate how challenging it has been to get to this point, and how much potential there is in front of us,” he says.
In the near future, Bell believes, cancer treatment will not be determined a tumour’s location in the body — breast, liver, skin, bladder etc. — but by its chemical signature. Oncologists will study the tumour’s defence system and select therapies to unleash a targeted immune response.
“It’s incredibly exciting,” he says.
Dr. Esteban Celis, professor of biochemistry and molecular biology at the Augusta University in Georgia, is another scientist who has spent three decades in the field of immunotherapy.
“There’s still a lot of potential that’s unexplored,” he says. “We’re at the tip of the iceberg.”
查看原文...
It was square in the middle of his back, and no matter how he twisted and turned, he couldn’t find it in the mirror. His wife, Isabelle, discovered it in the summer of 2011.
“It didn’t worry me at first,” says Williams, a middle school teacher from Russell with a keen interest in science.
During his annual physical, he raised the issue with his doctor, who ordered tests, and in January, Williams was diagnosed with Stage 3 melanoma: The cancer had already spread to his lymph nodes. The following summer, a large, inoperable tumour was found in his lungs.
Williams cast about for treatment options as he updated his will and put his financial house in order for his wife and young daughter, Koralee. That fall, there was more bad news: A scan revealed three small tumours in his brain.
The survival statistics for Stage 4 melanoma patients with brain metastases were grim. Williams worried he might not live to see Christmas.
But a precision dose of radiation, delivered by surgeons at The Ottawa Hospital, eliminated the brain tumours. That made Williams eligible for a last-chance clinical trial featuring a new kind of cancer treatment: immunotherapy.
Immunotherapy seeks to expose tumours to the cancer-killing power of the human immune system. It was declared “Breakthrough of the Year” by the journal Science in December 2013.
In January 2014, Williams entered a clinical trial designed to test two new immunotherapy drugs, known as checkpoint inhibitors. The drugs were designed to inhibit cancer’s curious ability to switch off the body’s immune response to the abnormal cells that form a tumour.
During his first three months of treatment, Williams was in awe as his lung tumour shrank to about one-third its former size.
Today, more than 2 1/2 later, Williams’ cancer remains in check. The shrunken lung tumour is still there, but it hasn’t grown. As part of the ongoing clinical trial, he continues to receive a drug infusion once every two weeks. The side-effects? A bit of fatigue and some mild rashes.
“I feel really lucky,” says Williams. “I’m guardedly optimistic.”
Ed Williams, receiving treatment at the Ottawa Cancer Clinic.
Williams, 53, is among a growing group of late-stage cancer patients whose lives have been saved by immunotherapy during the past five years.
Clinical studies show that, in general, the therapies work remarkably well in a minority — 10 to 30 per cent — of cancer patients, and usually come with far fewer side effects than chemotherapy.
Right now, immunotherapy works best for patients with melanoma, lung and bladder cancer. But there’s frenzied research going on worldwide to unlock the full potential of immunotherapy — and extend its benefits to more patients with different types of cancer.
Some recent studies highlight the extraordinary promise of the fast-moving immunotherapy revolution.
A study released this year at a U.S. cancer conference showed that 34 per cent of patients with advanced melanoma survived five years after starting treatment with the checkpoint inhibitor, Opdivo — double the average survival rate for the same patient group. The clinical trial involved 107 patients who had no other treatment options.
Another kind of immunotherapy — one that involves engineering a patient’s own T-cells to recognize and attack their tumours — achieved equally encouraging results.
In findings published in the October 2014 edition of the New England Journal of Medicine, researchers reported that 27 out of 30 patients with advanced leukemia went into remission after undergoing immune cell therapy. Six months after being treated, 19 of the patients remained in complete remission.
The results are significant not least because of the kind of patients involved: people once regarded as incurable.
Explains Dr. John Bell, a senior scientist at The Ottawa Hospital and one of Canada’s leading immunotherapy researchers: “It’s remarkable because these people normally would not have survived. And not only are they living a long time, but as far as we can tell, they’re going to keep living.”
Hopes raised … again
In recent months, medical and scientific journals have reported more success stories for early stage immunotherapy trials related to kidney cancer, Merkel cell carcinoma (a rare type of skin cancer), as well as head and neck cancer.
Still, cancer patients have been promised breakthroughs in the past only to be disappointed.
When the human genome was sequenced, for instance, researchers believed they’d be able to identify the genes that caused cancer and design drugs to shut them down. The research produced a few success stories, including the drugs Gleevec and Herceptin. But therapies that target genetic mutations in cancer cells have not produced the widespread benefits once predicted.
There’s no doubt that cancer is fiendishly complicated. It involves hundreds of genes and biochemical mechanisms, all of which can evolve during the course of the disease. Genetic mutations found in metastatic tumours, for instance, are often not the same as those that caused the disease in the first place.
So what’s different this time? Why should people pay attention to the immunotherapy revolution?
“I think that’s what’s different about it is that, in the clinic, we’re seeing results that have never been seen before,” offers Bell.
Dr. John Bell in his lab at the Ottawa Hospital Research Institute.
What’s also different, researchers say, is the nature of the immune system — and its adaptability as an anti-cancer agent. The immune system, once it’s engaged in the cancer fight, can evolve alongside a malignant tumour. No drug has the power to do the same thing.
“It’s beautiful,” says Dr. David Stojdl, senior scientist at the Children’s Hospital of Eastern Ontario Research Institute and a professor at the University of Ottawa. “It’s like a drug factory inside your body that’s able to adapt as fast as the biology that you’re chasing. That’s why we’re really keen on this as a tool.”
A long time coming
Immunotherapy is based on some hard-won science.
For generations, researchers had been confounded by cancer’s ability to hide from the body’s immune system.
A healthy immune system takes a firewagon approach to trouble: It rushes white blood cells to the scene and co-ordinates an attack. The body’s first responders regularly halt the spread of bacteria, viruses and mutant cells.
Yet cancer often fails to set off the body’s alarm bells. As a result, the immune system’s best cancer fighters, its T-cells, can be left in the station while tumours slowly grow unchecked.
Scientists, however, have started to decipher cancer’s complex cloaking device. Among other things, they’ve discovered that tumours not only hide, but also commit acts of sabotage: They secrete proteins and other substances that cancel the immune system’s initial response.
“The immune system rushes in and stalls: It just sits there,” explains Bell, a professor at the University of Ottawa. “So the breakthroughs involve reawakening that response, reversing that condition.”
Four immunotherapy drugs, known as checkpoint inhibitors, are now on the market, and the first virus-based immunotherapy, T-Vec, was approved last year by the U.S. Food and Drug Administration.
Together, they offer oncologists important new treatment options for a widening number of cancers.
Former U.S. president Jimmy Carter’s advanced melanoma was successfully treated with one of the new drugs, Merck’s Keytruda, used in combination with surgery and radiation. Another drug, Tecentriq, has been approved by the F.D.A. to treat bladder cancer. Bristol-Myers Squibb’s Opdivo has been approved to treat melanoma, Hodgkin lymphoma, lung and kidney cancer.
Scientists now know that cancer hijacks the biological mechanisms that tell the body’s immune system its job is done and is no longer needed. The shut-off mechanisms usually ensure that T-cells don’t attack healthy tissue.
Checkpoint inhibitors such as Yervoy and Opdivo target cancer’s mischief-making by closing down the communication pathways between tumours and T-cells. They target key proteins with names such as PD-1 and PD-L1.
Gordon Freeman is the Harvard Medical School professor whose groundbreaking research in the 1990s helped pave the way for the development of checkpoint inhibitors. “What’s remarkable about a PD-1 inhibitor is that, if anything, it works better in people than it does in mice,” says Freeman, a scientist at the Dana-Farber Cancer Institute.
Equally remarkable, he says, is the fact that checkpoint inhibitors work well even though they block just one of the chemical pathways that tumours use to misinform the immune system.
“Blocking one is good enough? That was a surprise,” Freeman says.
Since scientists have already identified other chemical pathways used by tumours, they have ready targets for new therapies as they seek to advance the immunotherapy revolution.
The audacious goal of that revolution? Nothing less than to overturn the established order of cancer treatment: surgery, chemotherapy and radiation.
Here comes the money …
Money is pouring into the field, primarily in the United States, where the federal government has launched a $1-billion “moonshot” to accelerate cancer research. Billionaire entrepreneurs, such as former Facebook president Sean Parker and former New York City mayor Michael Bloomberg, are also spending heavily to spur innovation in the field.
Sean Parker has invested in immunotherapy.
So too has former New York Mayor Michael Bloomberg, centre.
In Canada, immunotherapy and biotherapy researchers held their first national summit in June at a conference in Halifax co-hosted by BioCanRx, a network established last year to accelerate the development of Canadian-made therapies. The federal government has invested $25 million in BioCanRx.
All of the activity comes as the revolution reaches a critical moment: the end of the beginning.
“The revolution is still at the beginning, but the end is coming clearer,” says Dr. Ira Mellman, vice-president of cancer immunology at the biotech firm, Genentech, and the former director of the Yale Cancer Centre.
“It’s beyond the proof-of-concept phase — unlike the other flashes in the pan that have occurred throughout the past 20 years in oncology research.”
“We have got the low hanging fruit,” declares Dr. Elizabeth Jaffee, deputy director of the Sidney Kimmel Comprehensive Cancer Centre at Johns Hopkins University.
Says Dr. Brad Nelson, director and distinguished scientist at the BC Cancer Agency’s Deeley Research Centre: “We can all envision decades now ahead of us building on these successes.”
Some big questions remain unanswered, the most pressing of which is this: Why do only a minority of patients respond to immunotherapy? In labs around the world, including several in Ottawa, researchers are looking for ways to trigger a positive response in the majority of cancer patients.
To do so, they’ll require a more detailed understanding of the intensely complex tumour “microenvironment,” where all kinds of cells, molecules and blood vessels are co-opted to support the growth of malignant cells, and to inhibit an immune response.
One area of investigation involves the mystery of “hot” and “cold” tumours. Researchers know that most tumours are “cold” — they trigger no immune response at all — while others are filled with killer T-cells just waiting to be activated. These “hot” tumours are the ones that generally respond well to immunotherapy.
Researchers are trying to understand the biochemical mechanisms that determine such tumour responses.
“We need more science,” Elizabeth Jaffee says.
Meanwhile, the race is on to find the optimal immunotherapy cocktail.
Hundreds of clinical trials are now in the field to test existing checkpoint inhibitors together or in combination with other immunotherapies: oncolytic viruses and cell therapies. Each of them uses a different mechanism to boost the body’s immune response to a tumour.
Most researchers now believe the full benefit of immunotherapy will only be realized when the treatments are used together, and in combination with chemotherapy and radiation.
There’s already evidence that the cocktail approach can amplify that immune response.
One study, reported recently in the Journal of Clinical Oncology, found that Yervoy and T-Vec, a virus-based therapy, demonstrated a beneficial response in 50 per cent of patients with advanced melanoma. A significant number of patients (22 per cent) remained in full remission after one year on the drug combination therapy.
Most immunotherapy clinical trials still involve weakened patients with advanced cancers. But as more is known about the drugs and their side effects, researchers will be able to deploy them earlier in the disease process when the tumour burden is lower and patients are healthier. Many believe the real power of immunotherapy will only then be revealed.
“I think over the next five years,” predicts John Bell, “you’ll see even more tremendous outcomes because we’re going to learn how to do it better and how to optimize these approaches.”
Bell and David Stojdl are now involved in a unique clinical trial that deploys two engineered oncolytic viruses against advanced tumours. That trial is expected to report its findings next year.
CHEO’s Dr. David Stojdl.
Health Canada has approved three checkpoint inhibitors since 2012: Yervoy, Opdivo and Keytruda. And in some provinces, including Ontario, Yervoy is now being funded as a first line treatment for metastatic melanoma in adults.
Funding for second-generation immunotherapies, Opdivo and Keytruda, is still being examined in Ontario, but pharmaceutical companies have made the drugs available to many patients under special access programs. Bristol Myers-Squibb, for instance, has already provided Opdivo free of charge to 2,000 Canadian patients, including 700 in Ontario, through its access program.
For oncologists, the new therapies are both an opportunity and a challenge since they’ll have to decide when to rely on conventional anti-cancer measures, and how to choose between immunotherapy options.
Dr. Steven Jones, head of bioformatics at the BC Cancer Agency’s Michael Smith Genome Sciences Centre, believes technology can help: He says it’s possible to better target cancer treatments.
British Columbia spends more than $200 million a year on chemotherapy, he says, but much of that money produces only misery. “That (spending) would be just fine if it actually helped all the patients. But it doesn’t. In many cases, all we’re doing is adding more toxicity to these patients that they’ll have to cope with,” Jones says.
Personalized medicine
Understanding the best therapy for a cancer patient means that doctors have to know more about the individual — and their tumours.
Malignant tumours are hugely complex, often with more than a billion interacting cells; sometimes, the tumours have hundreds of genetic mutations. To complicate matters still further, tumours produced by the same kind of cancer have enormous variability: even within the same patient, tumours can have different genetic mutations.
As part of a government-funded research project, Jones and his team sequenced the genomes of 388 cancer patients and their tumours to better inform clinical decisions about how to treat them.
They compared the genetics of individual tumours against a database of other sequenced tumours to understand what chemotherapy or immunotherapy treatments produced the best results. (In general, research suggests tumours with hundreds of genetic mutations are the ones most likely to respond to immunotherapy.)
The approach represents a form of personalized medicine that Jones believes will one day become the standard of care as sequencing costs come down. The work is expensive, but Jones believes it will ultimately prove cost-effective.
“I think the economics are there,” he said.
The economics of immunotherapy are still evolving. There’s no doubt the new therapies will be expensive, particularly if they have to be used in combination with each other, or for extended periods of time.
The new checkpoint inhibitor drugs typically cost more than $8,000 a month, and it remains unclear how long patients will have to take them to keep cancer in check.
Affordability is just one of the hurdles to be overcome. There will almost certainly be more setbacks during advanced clinical trials since researchers are still learning how to use the powerful new agents, which can trigger dangerous side effects, including lung inflammation, colitis and rheumatoid arthritis — unhappy byproducts of a supercharged immune system.
In July, the F.D.A. ordered a halt to one high-profile immunotherapy trial after three leukemia patients died from brain swelling. The trial, which has since restarted, involves a promising cell-based therapy in which clinicians remove T-cells from a patient, engineer them in a lab to better target cancer, and infuse them back into the person’s bloodstream.
“It’s going to be a long road,” predicts CHEO’s Stojdl. “These are incredibly complex things.”
Too much, too fast?
Some scientists worry the revolution is moving too fast. Genentech’s Ira Mellman argues that clinical trials are now outrunning the science. He wants a pause of sorts in the revolution so that researchers can answer more basic scientific questions.
“I think we have to take a step back,” he says, “and try to understand the mechanisms of the things that do work — so that we can understand which of those mechanisms is not working when it doesn’t work.”
John Bell says it’s hard to put into words how far immunotherapy has advanced during his three decades in the field.
“Someone getting into the field now can’t appreciate how challenging it has been to get to this point, and how much potential there is in front of us,” he says.
In the near future, Bell believes, cancer treatment will not be determined a tumour’s location in the body — breast, liver, skin, bladder etc. — but by its chemical signature. Oncologists will study the tumour’s defence system and select therapies to unleash a targeted immune response.
“It’s incredibly exciting,” he says.
Dr. Esteban Celis, professor of biochemistry and molecular biology at the Augusta University in Georgia, is another scientist who has spent three decades in the field of immunotherapy.
“There’s still a lot of potential that’s unexplored,” he says. “We’re at the tip of the iceberg.”
- The interviews on which this story is based were conducted at the Summit for Cancer Immunotherapy in Halifax. Andrew Duffy’s attendance at the summit was financed by a journalism fellowship awarded by BioCanRx, a federally funded, not-for-profit organization dedicated to building capacity in cancer biotherapeutics in Canada through research and funding support.
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