Professor Rod Dunbar of Auckland University is researching immunotherapy and what it means for the treatment of cancer and infectious diseases. Photo / Jason Oxenham
At some point today, roughly 60 kiwis will find out they have cancer.
They will join a club no one wants to be part of. A club that claims far too many lives.
But, there are medical advances underway that could see the size of that club reduced dramatically in the not too distant future.
"The field hums with stories of lives extended," as Science magazine described a sweeping new generation of cancer treatment.
In 2013, it dubbed cancer immunotherapy its breakthrough of the year.
Dr Chris Jackson isn't overhyping when he called it the biggest revolution of his 20 years in oncology.
"It's going to reverberate for the rest of my practising life," the Cancer Society's medical director said.
"It's going to change the lives of millions of people around the world."
Here is a way to fight cancer and other diseases using the legion of sentinel cells already roaming about our bodies.
Here is a way, finally, to spare sufferers the hell of chemotherapy and radiation.
Because of it, we're living in a Renaissance for cancer research and the opportunities appear endless. Stories of success are being told.
There's a woman who had a grapefruit-size tumour in her lung from melanoma, who ended up alive and healthy 13 years later.
There's a 6-year-old who nearly died from leukemia but was also saved.
And there is also a man with metastatic kidney cancer whose disease continued fading away even after treatment stopped.
For the average New Zealand patient, however, unless they have advanced melanoma, and qualify for one of only two publicly funded drugs, it's a revolution that's still largely out of reach.
That might be about to soon change.
To understand immunotherapy is to understand our immune system, which has evolved over millions of years in step with our environment.
It shields us against a daily onslaught of pathogenic bacteria, viruses and parasites.
It scours our bodies for damaged cells, marking any that it finds for termination.
It's a remarkably clever network of cells, tissues and organs. But it's still not perfect.
Sometimes, it fails to pick up cancerous cells as they proliferate unchecked.
Many chronic diseases also often get around its defences.
Immunotherapy works by making it do its job properly.
Scientists have even figured out how insert a genetic sequence straight into our immune cells, training them to kill cancer they'd been blind to.
It's safer, gentler, and increasingly effective.
It can wipe out cancer cells at every site of metasteses much more efficiently or accurately than any drug, surgery or radiation therapy currently available.
What's changed since 2013?
"A fantastic amount," said Professor Graham Le Gros said.
The world-renowned immunologist, and director of Wellington's Malaghan Institute of Medical Research, has been watching long-standing walls come down.
"We are seeing a progressive 'beating back' on various different kinds of cancer that were thought to be untreatable five years ago," he said.
"Difficult cancers in difficult organs that could never be reached by conventional therapy before are now being precisely targeted with immunotherapies."
Moreover, Le Gros and colleagues here and overseas have been changing the way we understand some of our most notorious chronic inflammatory conditions.
"Asthma, allergy, gut disease – we're now finding that where the immune system is overreactive or oversensitive we can 'de-tune' it very specifically," he said.
"This is far more effective than the shotgun approach of steroid treatments and can even make the disease go away entirely.
"These are fantastic advancements as a result of the breakthrough five years ago."
Cancer is still our biggest killer and rates, currently 335 for every 100,000 Kiwis, are rising each year.
At some point today, an average 60 of us will find out we have it.
It's always been a confounding challenge for scientists to untangle because of the intricate and individualised nature of what it affects: our cells.
The body is made up of millions of them, all of which grow and are renewed in a controlled way that keeps us healthy.
It's when this control is lost that cells begin to multiply unchecked instead of just renewing themselves.
In some patients – especially those with highly mutated cancers like melanoma and lung cancer – it's often that a group of hunter-killer white blood cells, called T-cells, have stopped attacking and simply switched off.
"It's like a battle between the forces of good and evil," explained Professor Rod Dunbar, a leading expert in human cellular immunology, and director of the University of Auckland-based Maurice Wilkins Centre.
"By analogy with The Lord of the Rings, think of the cancer cells as orcs that are constantly being produced by copying themselves, and aggressively invading new territory."
The T-cells are like the elves that are trying to kill off the orcs.
"But wherever they go, the orcs create a really toxic environment, so whenever the elves get in close they start to tire and eventually stop killing the orcs.
"As more and more orcs are produced, eventually they outpace the tiring elves – and they continue to spread.
"But maybe if the elves could somehow resist that toxic environment created by the orcs… they might win."
Enter a new generation of immune drugs called checkpoint inhibitors.
They stop the cancer cells turning off the T-cells - the elves - and allow them to keep on killing.
In a small proportion of patients, they can continue the job until they wipe out the cancer cells completely.
"This is the amazing thing - the immune system has the power to cure even the most severe cancer," Dunbar said.
"And this is not just a result in a test-tube or an animal model – this is happening in cancer patients all around the world right now."
Two of the most successful checkpoint blocker drugs are pembrolizumab and nivolumab.
We know them better as Keytruda and Opdivo.
Keytruda itself has been shown to be twice as effective as chemotherapy, halting, and even shrinking, tumour growth for a third of patients with advanced malignant melanomas.
An initial breakthrough with one particular mechanism had opened the floodgates for a range of new checkpoint-blocking drugs.
Yet, despite all their promise, they could only work if the patient's immune system had recognised the cancer cells and created plenty of T-cells to attack them.
Sadly for many cancer patients, Dunbar added, this didn't happen.
"For those patients, all these new immune wonder drugs don't work - no T-cells, no cancer killing, no elves, no dead orcs."
Another approach uses vaccines that directly programme cells in the immune system.
The idea of cancer vaccines has been about since a New York bone surgeon named William Coley created a concoction of killed bacteria.
His nasty brew only left his patients worse off, but what he'd perhaps hoped to achieve is being pulled from the horizon by Dunbar and his collaborators.
They've developed a way of effectively tricking a patient's T-cells into recognising the cancer cells they weren't picking up.
First, they found a molecule that these little assassins can go after in the cancer cells.
Next, they've created a mimic of that molecule using chemistry.
And last, they've actually been able to attach that mimic to something that looks like a fragment of a bacterial cell wall.
Having proven this effect in the lab, the researchers are now moving steadily toward the first clinical trials that will test some of the molecules in cancer patients.
Their work is being spun out with a start-up, SapVax LLC, that Dunbar founded with prominent university researchers Distinguished Professor Dame Margaret Brimble and Dr Geoff Williams.
"A really exciting possibility for the future is the use of vaccines that are personalised for each cancer patient," Dunbar said.
Using genome sequencing technology, his team could already identify all the molecules that were altered within a patient's cancer - and predict which ones were likely to be good targets for T-cell attack.
Although producing a vaccine to target these molecules in a single patient would currently take weeks if not months, Dame Margaret's team was already working on a radical new chemistry technique promising to bring this time down to a matter of hours.
Yet another approach was to take blood cells, sift through them to find the T-cells, and grow a new army of them in a lab.
Like most cells, T-cells could make copies of themselves by cell division - but they can also divide particularly quickly in the lab, even around three times a day.
That meant that, once they were found, enough could be generated to infuse into patients within a few weeks.
Already, it's been proven that such T-cell infusions can dramatically shrink tumours, although they are far more likely to work in tandem with checkpoint blockers.
"We've been growing these T-cells in the lab for years, but until now we haven't had the facilities to grow them in the kind of protected lab environment that makes them safe for clinical use," Dunbar said.
At the Malaghan Institute, Le Gros and colleagues have been investigating how a patient's T-cells can be not only extracted and redirected back toward the cancer, but modified to perform better.
Called CAR-T cell therapy, the ground-breaking approach is one he hoped to soon bring to New Zealand for the first time.
"The T-cells can act as living drugs, providing long-term protection against relapse, similar to a vaccine," Le Gros said.
"We are currently preparing for a human clinical trial, including meeting strict regulatory and safety requirements for this type of treatment.
"As a phase I trial, our focus will be on assessing the safety of the treatment in a small group of patients, monitoring closely for side effects, to identify the best dose for larger trials."
Malaghan's Chinese collaborators already had a pipeline of therapies that had undergone initial clinical trials in China, which were now ready to be developed under a Western regulatory environment here.
Other New Zealand-led research has further suggested how immunotherapies might be enhanced the latest chemotherapy drugs.
At Auckland University's Auckland Cancer Society Research Centre, Associate Professors Jeff Smaill and Adam Patterson have designed a series of drugs that become activated in the low-oxygen areas that occur in cancer tumours.
These areas were known to prevent T-cells from killing cancer cells, and recent work had shown that "sterilising" tumours of low oxygen zones using these drugs can help T-cells do their job.
These results were part of a growing wave of combining chemotherapy and immunotherapy - and again held out the promise of ultimately being able to control even advanced cancers in most patients.
The immunotherapy revolution was never going to be solely focused on cancer, such was its unprecedented potential.
While cancer might be New Zealand's biggest threat to life, globally, the number one killer was infectious disease.
No example was more poignant, Le Gros said, than the influenza vaccine.
"We are using 30-year-old flu vaccine technology to treat a disease that evolves annually. It will not last," he said.
"Without some sort of intervention of new technology, the human populace faces a pandemic which holds the potential to completely disrupt the social and economic landscape."
Kiwi researchers are trying to target other nasties.
At Auckland University, scientists have two vaccines under development to fight the streptococcus A bacteria, which can lead to rheumatic fever.
Another team was working toward a vaccine for staphylococcus – the bug most often to blame for potentially fatal post-op infections.
Their vaccine aimed to effectively take down the shield that the bacteria used to evade detection by the immune system.
"We have early evidence from the lab that blood from vaccinated animals can neutralise these factors, and we know that this prevents bacteria from growing," said research fellow Ries, who is working on the study alongside colleagues Fiona Radcliff and Professor John Fraser.
With new funding from the Health Research Council, they planned to trial their vaccinate mice, and then expose them to staph A, which was already becoming resistant to the latest antibiotics.
And a third team was trying to crack the century-old hunt for a vaccine for gonorrehoea, of which New Zealand health authorities are reporting thousands of new cases each year.
Dr Helen Petousis-Harris, a vaccinologist and senior lecturer at Auckland University's Department of General Practice and Primary Healthcare, said fresh hope had come from an unexpected spin-off of the MeNZB vaccine used against meningococcal disease between 2006 and 2008.
When that vaccine also turned out to be linked to falls in gonorrhea cases, researchers suspected there might be a case for cross-protection against closely-related meningococcus and gonococcus.
In fact, later studies suggested the vaccine protected about one in three people against gonorrhea.
"This discovery has opened up many new avenues for research which people all over the world are now pursuing, including here at the University of Auckland," Petousis-Harris said.
This year, the World Health Organisation even held a meeting in Geneva to to discuss strategies for gonorrhoea vaccination, now that it might be a reality.
"Disease modelling has shown that even a vaccine that prevents about one in three to one in four cases could knock the majority of gonorrhoea back – given the emergence of super-bug gonorrhoea this may be our only avenue."
For all of the buzz about it, the immunotherapy revolution hadn't yet translated to life-saving treatments to all who needed them.
"These are very exciting times with huge potential to improve the health outcomes of the general population," Le Gros said.
"But these solutions are not yet cost-effective enough and broad spectrum to be available to everyone."
Dr Chris Jackson pointed out Keytruda: the drug had so far proven extraordinary against advanced melanoma, excellent against lung cancer, and promising with other forms.
Yet, in New Zealand, it and Opdiva were only fully funded for advanced melanoma and not for many of the other many conditions they could combat.
For patients trying to access those agents for other forms of cancer – or using other available drugs that weren't funded – they could be facing paying around $50,000 to $70,000, depending on the product.
And that was over and above the sky-high price of administration and private hospital stays.
As the figures weren't collated, it wasn't possible to say how many patients were being forced to stump up such heavy costs.
But it was obvious that many Kiwis simply couldn't afford it.
"The way in which these treatments become more available is that more of them get government funded – history doesn't tend to show that the prices of these drugs come down over time," Jackson said.
"I think we would use immunotherapy far more widely is they were more widely funded – the limitation here is not the science, it's the funding.
"We spend less than other countries on cancer drugs – and so long as we have a relatively small drugs budget, we are going to have relatively limited access."
Pharmac told the Herald it was considering funding for several immunotherapy treatments, including ipilimumab and atezolizumab, as well as applications to broaden funded access to Keytruda and Opdiva.
"The evidence for immunotherapies is developing quickly and these treatments are often expensive," said the drug-buying agency's director of operations, Lisa Williams.
"While these treatments can look promising, we need to be absolutely sure that these medicines truly deliver the benefits that companies claim they do, and that we spend public money wisely.
"The reality is that funding a treatment with high uncertainty about its results would take away funding from other more proven treatments."
Ricardo Fox could sympathise with Pharmac's situation.
The Hawke's Bay principal was part of the campaign that successfully lobbied for Keytruda to be publicly funded for melanoma.
"There are so many drugs that are coming on to the scene now, and which one do you take over the next? For Pharmac, it's a tough decision," Fox said.
"As an advocate for immunotherapy, the thing that most pisses me off is that drug companies can hold governments and people to ransom because they have the patents for those drugs, and they charge whatever they want for them."
Fox, who still administrates the Fund Immunotherapy NZ Facebook page, said all he could do for patients who couldn't afford treatment to start their own Givealittle campaigns.
"Every week I'm hearing of someone different – and it's horrible all seeing these stories."
But Dunbar remained positive that the dramatic advances in immunotherapy coming out of his colleagues' labs would indeed become a mainstay in tomorrow's clinical landscape.
"These kinds of breakthroughs are the reason why the team confidently predicts that immune therapy for cancer will be commonplace for the next generation, and will help make cancer a manageable disease for the vast majority of patients."
Auckland's Delina Mihaere knows all about immunotherapy - and probably more than any average Kiwi should have to.
To the 39-year-old nanny, it's a desperate last hope.
Last year, she was diagnosed last year with cervical carcinosarcoma – an extremely aggressive form of cancer so rare that only two cases of it have been reported in New Zealand.
Six weeks of radiotherapy and chemotherapy failed to stop the tumour progressing to stage 4 metastatic cancer.
Now she's pinning her hopes on accessing six to eight lots of an unfunded immunotherapy treatment - each expected to cost $10,000.
Speaking from her hospice bed, Mihaere said she was worried she'd wasted months on conventional treatments that had appeared only to have worsened her condition.
If she'd known about Keytruda's potential – the US Food and Drug Administration (FDA) approved it for cervical cancer last year following promising clinical trials – she would have asked about it at the point she was diagnosed.
"Let's face it, I was green – and like everybody, when you are still in shock and not too sure what to do, you're kind of relying on doctors to give you the best options available."
Her brother, Diamond Mihaere, who is now organising a Givealittle campaign, also questioned why immunotherapy wasn't being recommended by more doctors, despite the fact it wasn't funded for most cancers.
"And I'm surprised that's the case here in New Zealand. We are supposed to be this leading country in so many ways – I mean, we've got RocketLab here, and we've even got a research institute in Wellington that's about to start doing CAR-T cell therapy trials," he said.
"It's just crazy to think that there are these treatments out there for her that could potentially save her life – but the Government doesn't want any bar of it because her's is classified as a rare cancer."
WHAT IS IMMUNOTHERAPY?
Immunotherapy is a frontier treatment that uses our immune system to fight disease. In cancer, it works by helping the immune system recognise and attack cancer cells. Some types of immunotherapy are also called targeted treatments or biological therapies.
HOW DOES IT HELP THE IMMUNE SYSTEM?
Our immune system works to protect the body against infection, illness and disease. It can also protect us from the development of cancer. The immune system includes the lymph glands, spleen and white blood cells. Normally, it can spot and destroy faulty cells in the body, stopping cancer developing. But a cancer might develop when the immune system recognises cancer cells but it is not strong enough to kill the cancer cells, or the cells produce clever signals that stop the immune system from attacking it. Immunotherapy can be used to either switch off these signals, or to programme hunter-killer T-cells to go after cancer.
HOW IS IT USED IN NEW ZEALAND?
Currently, immunotherapy is mostly used with people who have advanced cancer. It is not yet as widely used as surgery, chemotherapy and radiation treatment. In New Zealand, checkpoint inhibitor immunotherapies pembrolizumab (Keytruda) and nivolumab (Opdivo) are now available and subsidised for use in advanced melanoma. Immunotherapy is being studied for use in many other types of cancer. Pharmac is considering funding for several immunotherapy treatments, including ipilimumab and atezolizumab, as well as applications to broaden funded access to Keytruda and Opdiva.
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