Miraculous: Michael English is living evidence that we may finally have discovered a powerful secret to beating cancer
Michael English is living evidence that we may finally have discovered a powerful secret to beating cancer. Astonishingly, this long-sought answer lies hidden inside our own bodies.
Michael, a 72-year-old retired electrical engineer from Surbiton in Surrey, was first diagnosed with advanced and aggressive stage 3/4 prostate cancer 13 years ago.
Each time doctors tried the latest treatment on him, be it hormones, drugs, radiotherapy or chemotherapy, his tumour was beaten back until it had apparently disappeared.
But four times since 2005 the cancer returned, as each time a few of his tumour cells managed to evade medicine’s best weapons.
They did this by mutating their DNA — adopting a new genetic guise that was resistant to all the therapies that had been tried.
Michael was allocated palliative care nurses, to make his seemingly inevitable death as painless as possible. Conventional medicine had waved the white flag.
For millions of cancer patients and their families, this is a familiar and tragic story.
But now the tables are being turned. For British scientists are discovering that the very thing that can make cancer cells so relentlessly lethal — their ability to mutate and evade our best treatments — may also be their Achilles heel.
Researchers are discovering that each time the cancer mutates its DNA, it creates a tell-tale biological fingerprint. What’s more, our own immune systems can be taught to recognise these fingerprints, and then to attack and destroy these enemies within, so that they never come back.
This new avenue is called cancer immunotherapy. There are several types of immunotherapy treatments, which either help the immune system attack cancer directly or boost it more generally.
Last year Michael was inducted into a medical trial of a new immunotherapy drug by Professor Johann de Bono, the head of clinical studies at the Institute of Cancer Research in London.
Not giving up: Michael was allocated palliative care nurses, to make his seemingly inevitable death as painless as possible. Conventional medicine had waved the white flag
This may have seemed beyond optimistic. Not only was Michael past last chances in terms of conventional therapy, his intestines had been left so ravaged by previous doses of radiotherapy to kill tumours there that his gut was perforated, causing him crippling stomach infections. He was so ill there was little point subjecting him to abdominal surgery to repair this.
Indeed, Michael was so ill that after only ten intravenous doses of the experimental drug pembrolizumab (branded as Keytruda), administered once every three weeks, he was taken off the trial. To complete the therapy he should have received a further 29 doses.
Nevertheless, Professor de Bono’s team gave him MRI scans to check his progress — and found his tumour had disappeared.
That was in April last year. Destroying the cancer rendered Michael strong enough to receive the stomach surgery he needed. He had another cancer scan last week and he’s still clear. ‘It is absolutely incredible,’ he says.
Professor de Bono describes Michael’s result as ‘profound and spectacular’.
What’s more, this science could be repeated in future for millions of patients, experts believe.
What made Michael, despite his frailty, such a good candidate for the trial is the fact that his cancer had aggressively mutated its DNA several times to evade conventional treatment — making it a good test for pembrolizumab’s mutation-targeting powers.
Pain: Not only was Michael past last chances in terms of conventional therapy, his intestines had been left ravaged by previous doses of radiotherapy
‘Patients like Michael have a defect in a gene called CDK12, which controls how a cell can repair faults in its DNA,’ explains Professor de Bono.
This defect causes one in ten cases of prostate cancer. When the gene goes awry, DNA faults run rampant, causing cells to turn cancerous and replicate. The gene also gives tumours a deadly advantage — they change their DNA so quickly that they evade being wiped out by conventional drugs.
‘However, this could be an Achilles heel, because it also causes an increase in jumbled-up DNA that the immune system can more easily recognise as a threat,’ adds Professor de Bono.
To target the cancer cells, first you have to stop them from evading detection by the immune system by ‘cloaking’ themselves in proteins that identify them as healthy tissues. A new class of drugs rolled out over the past seven years, called ‘checkpoint inhibitors’, which include pembrolizumab, ‘unmask’ the cancer cells by blocking their fake cloaks.
Our immune cells can then identify them as dangerous and destroy them. The idea behind cancer immunotherapy is not new. Yet it’s taken more than a century to prove its worth.
New York surgeon William Coley first explored the theory of using a patient’s immune system to fight cancer in the 1890s, after hearing of a man who recovered unexpectedly from cancer following a serious skin infection. Mr Coley believed the infection provoked the patient’s immune system to attack anything that looked alien, including the cancer cells.
He vaccinated ten other cancer patients with cocktails of bacteria and claimed that, in several cases, this spurred their immune systems to destroy tumours. But the medical establishment refused to believe his patients had even had cancer.
Man-power: New York surgeon William Coley first explored the theory of using a patient’s immune system to fight cancer in the 1890s
Instead, cancer surgeons backed the new — and then highly dangerous — radiation therapy as their best hope of a cancer cure-all (the precursor to what we now know as radiotherapy).
Mr Coley’s ideas languished for a century until an immunologist, Charles Janeway of Yale University, challenged a longstanding basic assumption — that our immune defences work simply by recognising things that haven’t been in the body before and attacking them.
But if that were true, Dr Janeway wondered, how could we ever eat a new food without suffering an allergic response? In the late Eighties, he realised that we must have two systems operating: one for detecting alien substances in our bodies; and another that learns to recognise which aliens are threats and flags them for attack.
The implications were revolutionary. If our immune system could learn in this way, then it may also be taught to destroy a another threat: cancer cells.
TEACHING IMMUNE SYSTEM TO ATTACK
But no one believed Dr Janeway. His idea was shunned until the early 2000s, when international scientists finally began to appreciate its potential. For this, others were awarded the Nobel Prize in 2011. The accolade should arguably have been Dr Janeway’s but he had died in 2003 of lymphoma.
A similar fate befell Ralph Steinman, who discovered the key biological mechanism behind Dr Janeway’s ideas — a spiky-looking cell that switches on our immune systems by identifying dangerous invaders.
Dr Steinman, an immunologist at Rockefeller University in New York, christened his discovery the dendritic cell. But when he revealed his theories about the cells’ curative potential at medical conferences in the early 2000s, he was considered outlandish.
Nevertheless, Dr Steinman worked doggedly on using the cells to create cancer-killing vaccines. His colleague, Antony Rosen, now a professor of medicine at Johns Hopkins University, recalls: ‘He was confident enough that it didn’t matter to him that nobody had seen it before and everybody rejected what he said’.
Dr Steinman’s investigations involved extracting dendritic cells from a patient, exposing them in the lab to the patient’s cancer cells — ‘teaching’ them to recognise them as threats — then injecting the dendritic cells back into the patient’s body in order to prime their immune system.
Dr Steinman pursued his goal with deadly urgency. In 2007, with his work still at an early point, he was diagnosed with aggressive pancreatic cancer and told he had only months to live.
He experimented on himself — trying three previously untested vaccines based on dendritic cells exposed to cells from his tumour.
He survived four years longer than doctors predicted, though it is impossible to know if his discovery extended his life, or if was just chance.
Dr Steinman was among the pioneering immunotherapy scientists awarded the Nobel Prize in 2011. The announcement came three days after his death.
Since then, one dendritic cell-based vaccine, Provenge, has been shown to increase the survival of prostate cancer patients by about four months. It is approved for use in the U.S.
Meanwhile in Britain, pioneering immunotherapy researchers also suffered derision and disbelief.
Professor Charles Swanton, now the chief clinician at Cancer Research UK, recalls how in 1995, he was planning to do a PhD in using dendritic cells as a therapy for cancer.
‘I was very strongly discouraged from going into this field,’ he says. ‘In the Nineties it was unclear how this research would have any practical value. Research funders were sceptical.’
Peter Johnson, a professor of medical oncology at Southampton General Hospital, has been working since 1998 to get the human immune system to attack cancers.
‘For a long time immunology was regarded as interesting, but did not deliver much,’ he says. ‘It was a difficult field, because sadly the clinical trials of vaccines were mostly unsuccessful.’
DRUGS THAT LEND A HELPING HAND
All of this is changing, however, with the advent of checkpoint inhibitor drugs — and their ability to unmask cancer cells to our immune defences.
With unabashed satisfaction, Professor Johnson describes as ‘striking’ the cure rates these drugs have achieved in melanoma and tumours such as cancers of the kidney and cervix.
Checkpoint drug therapy works in clinical trials for between a quarter and a third of people with melanoma and lung cancer.
Beyond this, though, is the hope that these therapies may defeat cancer’s ability to return again, after seemingly lying dormant for months or years.
A third of patients with advanced melanoma who received the checkpoint-inhibitor drug nivolumab in a clinical trial at Boston’s Dana-Farber Cancer Institute are still alive five years later. Previously the average survival time for advanced melanoma patients was 11 months.
PROTECTION THAT MAY LAST A LIFETIME
Professor Johnson believes that the immune system, once alerted to tumour cells, not only kills them but continues to search for them — and anything which looks like them that may be a surviving mutant strain.
He explains: ‘If you can get the immune system to lock on to a cancer then, like a vaccination, the benefits may last for life.’
However, there is work to be done if cancer immunotherapy is finally to achieve its promise.
The drug that saved Michael English’s life, pembrolizumab, helps only one in ten men with prostate cancer, says Professor de Bono. Last month he published a study in the journal Cell which indicates that it may only save men with defects in the CDK12 gene.
The huge challenge is to discover why the drug only works for certain genetic types of tumour, and how to make immunotherapy work for the other nine in ten men with prostate cancer.
Professor Swanton, part of a British commercial collaboration of clinical experts, is pinning his hopes on developing a specific type of checkpoint inhibitor drug in the hope that it will be a ‘one-size-fits-all’ cure.
This targets something that he calls a ‘truncal mutation’, the very first gene change that occurs in a cell before it turns cancerous.
Professor Swanton believes this single DNA mutation must be common to all cancers — unlike subsequent DNA changes which may all differ.
The team plans soon to start trials with lung cancer and melanoma patients to see if they can identify this single change and target it for attack by the patient’s own immune system.
If it works, it could be an astonishing breakthrough. The collaboration’s name is well chosen to explain its mission: Achilles Therapeutics. Cancer could finally be brought to heel.
Tumours had spread to Judy’s liver. Now she’s cancer-free
Fighting: Judy Perkins, 51, an engineer from Florida, also overcame aggressive cancer
Judy Perkins, 51, an engineer from Florida, amazed the world when her doctors revealed that her breast cancer, which had spread lethally to her liver, had been eradicated.
Two years ago she had been given only three years to live. But then she was given an intricate — and expensive — new cancer therapy.
‘I had given up fighting,’ Judy told reporters. ‘After the treatment dissolved most of my tumours, I was able to go for a 40-mile hike.’
Judy is living proof of the promise of immunotherapy. There is one massive problem: the expense. Judy’s treatment is estimated to have cost £400,000.
U.S. doctors treated Judy with an advanced form of immunotherapy called CAR-T cell therapy. This genetically alters a patient’s T-cells — the ‘troops’ in the immune system — so that they recognise and attack specific proteins found on cancer cells. This treatment is already being used to treat a small number of patients with blood cancers such as leukaemia.
Doctors took tissue from Judy’s tumours and studied its DNA for mutations specific to her cancer and extracted immune cells that had invaded the tumour to try to kill it. After growing billions of these immune cells in the lab, the researchers screened them to find which would attack Judy’s mutated cancer cells.
The doctors reported in the journal Nature Medicine in June how they injected 80 billion of these immune cells into Judy’s body, along with the immunotherapy drug pembrolizumab. As it stands, this procedure is too expensive for the NHS. The drug rationing watchdog the National Institute for Health and Care Excellence is expected to reject Yescarta — the first CAR-T drug to be assessed — due to the high cost.
Professor David Cunningham, a consultant oncologist at the Royal Marsden in London, says: ‘Harvesting and modifying the patient’s T-cells can cost around £500,000 per patient. That is prohibitive.’
However, in June U.S. researchers announced that they may have discovered a cheaper way of creating CAR-T cancer-killing cells. Rather than taking immune cells out of each individual patient, the scientists, from the Universities of California and Minnesota, say they may be able to mass-produce cancer-destroying immune cells from human stem cells.
In the journal Cell Stem Cell, they reported that they can produce a ‘natural killer cell’ to identify and kill all tumours.
Dan Kaufman, a professor of medicine at the University of California, San Diego, who led the study, said: ‘One batch of stem cell-derived natural killer cells can potentially be used to treat thousands of patients.’
Professor Kaufman says that the new drugs have already shown considerable curative promise in experiments in mice.
Further trials will be needed before the worth of this approach is proven — so it is still, at best, several years before it is available to more patients. Even so, it is a tantalising hope.