Cancer frontiers: What to watch
From immunotherapy to genomics, the 2020s are set to bring more big breakthroughs, writes Jamie Morton
It’s New Zealand’s number one killer, claiming nearly 10,000 Kiwis each year. Every day, 60 of us find out we have it. But cancer is being met head-on by a rapidly expanding range of new treatments and interventions, with many more exciting gains to come in the next decade.
“There are lots of reasons to be optimistic about the future of biotech medicine,” said the Cancer Society’s medical director, oncologist Dr Chris Jackson.
“There’s no doubt today that cancer is more treatable, with more options than ever before.”
Immunotherapy
The 2010s saw the rise of immunotherapy, bringing us gamechanging drugs like Keytruda.
But scientists have only just begun to unleash the potential of harnessing the body’s own natural defences and turning them against cancer.
By using substances created either in a lab or within the body itself, immunotherapy can halt or slow the growth of cancer cells — or help the immune system better destroy them.
Researchers have been particularly excited by two forms of drugs: immune system stimulants, which re-engage the body’s defence system, and what are called checkpoint inhibitors.
These inhibitors work off our understanding that cancer cells use certain enzymes to block the body’s immune response.
They do this by binding to — and then turning off — “T cells”, which patrol the body and are normally primed to kill cancer cells.
The new compounds, among them Keytruda and Opdivo, effectively work by inhibiting the ability for cancer to block the immune system.
So far, they’ve proven incredibly promising at combating Hodgkin lymphoma and metastatic melanoma.
It was the latter cancer at which Keytruda, or Pembrolizumab as the drug is named, was first targeted.
It’s since been pitted against lung cancer, triplenegative breast cancer, gastric cancer and head and neck cancer.
In trials, it’s been shown to be twice as effective as chemotherapy, halting and even shrinking tumour growth for 34 per cent of patients with advanced malignant melanomas.
Pharmac now funds Keytruda and Opdivo for use in advanced melanoma.
Jackson said checkpoint inhibitors had been “an absolute revolution”.
“When I started out, stage 4 melanoma was basically incurable — we had a very small number of patients who responded and the fiveyear survival rate was 10 per cent or less,” he said.
“Now, with these two combined checkpoint inhibitors, we are seeing five-year survival rates of 50 per cent, and some people being cured. It’s absolutely unbelievable.”
Cancer vaccines, too, were having something of a resurgence as clinicians teamed them up with checkpoint inhibitors — often with devastating effects.
These vaccines boost the immune system’s ability to recognise and destroy antigens — those substances on the surface of cells that are not normally part of the body.
Most cancer vaccines also contain adjuvants, which are substances that may help strengthen the immune response.
But these interventions were largely still inaccessible to patients, with most still at trial stage overseas.
“I think we’re still talking more about promise than reality,” Jackson said.
In the next decade, he expected a big focus would be working out why some people responded to immunotherapy, while others didn’t.
“We also need to understand whether checkpoint inhibitor therapy should be used alone, or in combination with other therapies — and that’s going to take a lot of work.”
“But regardless, the rate of change in immunotherapy-based research is eye-watering and I’m excited about what the future holds for it.”
CAR T-cell therapy
Elsewhere in the immunotherapy space, New Zealand and Chinese researchers have joined forces on a new intervention called Chimeric Antigen Receptor T-cell, or CAR T-cell, therapy.
This works by redirecting a patient’s own T-cells in the lab, to directly identify and attack cancer cells. The modified T-cells are then returned to the patient where they can attack and destroy cancer cells. The T-cells can act as “living drugs”, providing long-term protection against relapse, similar to a vaccine.
The therapy can attack a range of cancers, but to date has proven most effective with B-cell cancers, such as certain types of leukaemia, lymphoma and myelomas.
Here in New Zealand, Wellington’s Malaghan Institute has been helping run the first clinical trials, with hopes the therapy will prove successful and become more widely available. Jackson said CAR T-cell therapy had worked “beautifully” in some types of blood cancer that had a single surface marker that could be targeted. “Unfortunately, most cancers don’t have just one antigen that you can target, so it’s less useful in other cancers like breast, bowel, prostate and melanoma,” he said “Unless they can find singletumour antigens in these cancers that can be targeted, then maybe CAR T-cell therapy might be limited in its application.”
Biomarkers and circulating tumour DNA
With a plethora of cancer drugs now on the market, special “biomarkers” are crucial to ensuring the right drugs are targeted at the right patients.
They work by detecting whether a tumour secretes the molecule the drug is aimed at, and thus acts as an indicator of the body’s specific response to the cancer.
For new drugs submitted to the US Food and Drug Administration (FDA) for approval, it is now almost mandatory that they come accompanied with biomarker tests.
The advent of biomarkers has helped stem what has been a high attrition rate of potentially effective drugs forced to undergo conventional assessments, while also providing a relatively clear picture as to how drugs might perform.
As so-called “surrogate endpoints”, they indicate the effects of a certain drug on cancer progression and survival — a time and money saving approach being increasingly relied upon for drug development.
Though developing biomarkers for drugs is still relatively timeconsuming, using it to screen potential patients is relatively straight forward. In New Zealand, the use of biomarkers is growing as clinicians use new agents that come with them.
Jackson said biomarkers used in breast cancer — notably the her2 protein and oestrogen receptor biomarkers — have long been used.
More recently many others, such as the ALK, ROS, BRAF and EGRF biomarkers, have hit the market.
“It’s been really fantastic to see that happening,” he said.
“But there’s much more we have to understand: for example, we know that the BRAF biomarker in melanoma is strongly predictive of response to therapy, but in bowel cancer, it’s not nearly as much, because there are alternative pathways for it to evolve in.”
Jackson also expected what’s called circulating tumour DNA to become an increasingly important technology over coming years.
Because tumours are invariably solid, extracting DNA from them requires a biopsy — which can be a very painful and expensive process.
It only gets more inconvenient when the monitoring of treatment demands further biopsies.
But scientists have now found an intriguing way around the problem and point to a way that could allow cancers to be detected much earlier.
While most solid tumours shed tumour cells into the blood at levels that have traditionally been below detection levels, technology had advanced to the point where they could be picked up.
These shed cells hold all the genetic information about the part of the tumour they came from and can be a valuable tool for tracking tumour development and responsiveness to treatment.
It takes just a quick blood test to capture circulating tumour DNA — or ctDNA — and testing can be done as often as desired, enabling more intense patient monitoring and faster clinical responses to any changes detected.
“If your tumour DNA levels go down very quickly after you’ve started therapy — and sometimes this happens within a few days — it tells you that your treatment is working.”
Patients can also have any ineffective treatment stopped and quickly have their treatment plan adapted, potentially giving them a longer life.
Jackson and his Otago University colleague, Professor Parry Guilford, have been collaborating on ctDNA projects targeting breast and bowel cancer.
Genomics and gene editing
It’s been nearly two decades since scientists published the draft of the entire DNA sequence of a human genome — effectively unfurling the blueprint of our genetic make-up.
Over that time, the cost of sequencing the genome has plummeted from millions of dollars to just about $1000.
Countries have been running 100,000 cancer patient genomes through their systems every year, with goals of refining these down to the relatively small number of driver mutations behind most tumours.
Though a tumour, when diagnosed, typically contains many thousands of mutations, most are not important.
This technology is allowing researchers to construct vast databases, from which the critical ones that still elude us will, hopefully, emerge.
Kiwi researchers have been exploring the concept of plasma genomics, which can boost our ability to diagnose and treat cancer.
Cell-free plasma samples are easily accessible from patients, and there may be effective ways to use such samples to monitor patient responses to cancer therapy — and eventually even screen for multiple types of cancer.
A much more contentious area is actually editing our genes using technology like CRSPR/Cas9, which might be described as a pair of molecular scissors capable of removing unwanted genes and inserting new ones.
With it comes the obvious potential of splicing out a gene carrying a cancer-causing mutation.
A scientific panel convened by Royal Society Te Apa¯rangi considered a hypothetical scenario in which gene editing was used to stop the BRCA1 gene — linked to a higher risk of breast and ovarian cancer — being passed down to future generations.
While promising, this also posed some tricky ethical issues: namely that any unintended side-effects would also be inherited.
Studies have suggested how gene editing might also complement other treatments.
This year, Korean scientists announced that they’d developed a new gene editing system which was capable of suppressing proteins that interfered with the immune system — effectively working as a form of immunotherapy.
Whether gene editing will ever become part of cancer therapy in New Zealand is far from clear, as the technology remains strictly controlled under current laws.
Theranostics
Jackson said there’s also been much buzz about molecular “theranostics”.
It involved combining drugs and techniques to simultaneously diagnose and treat medical conditions — hence the name — while also monitoring the patient’s response.
Many theranostics approaches use special nanoparticles that bring together diagnostic molecules and drugs in a single agent.
They act as carriers for molecular “cargo” — like a drug or a radioisotope to cancer patients undergoing radiotherapy — targeting specific biological pathways in the patient’s body, while avoiding damage to healthy tissues.
Once at their target tissue, they produce diagnostic images, while also delivering their cargo.
“One example of theranostics is radio-labelled lutetium, used for things like prostate cancer neuroendocrine tumours,” Jackson said.
“So, if you can get an antibody that targets a particular protein in the cell, you can attach a radio-labelled molecule and draw radiation directly toward the tumour.
“We’ve got this working in a couple of tumour types now, and I think we’ll see this become part of mainstream therapy in years to come.”
The rate of change in immunotherapy-based research is eye-watering and I’m excited about what the future holds for it.
Chris Jackson, Cancer Society