A Malaghan Institute team - including PhD researcher Danielle Sword - has been pushing toward a new CAR-T cell therapy to treat a common type of cancer.
A Malaghan Institute team - including PhD researcher Danielle Sword - has been pushing toward a new CAR-T cell therapy to treat a common type of cancer.
Around 25,000 Kiwis are diagnosed with some form of cancer each year, while 9500 die from it, making it our most lethal disease.
Across New Zealand, teams of researchers are pushing toward new treatments with globally-leading new studies.
They range from 3D “mini-tumours” constructed in the lab using donated samples to a groundbreaking new therapy that’s already saved lives.
In the global fight against cancer, New Zealand researchers are quietly pushing beyond the frontiers of what’s possible. Science reporter Jamie Morton meets some of them.
Releasing cancer’s ‘handbrake’
We know cancer as a disease caused by cells splitting up in an uncontrolled way.
Typically, that process is tightly policedby a balance of signals that keep cell growth in check – but it can be quickly up-ended when there are disrupting factors like genetic mutations at play.
Three decades ago, scientists discovered a certain family of proteins, called p16, that play a crucial role in stopping cells dividing uncontrollably – earning them the label tumour suppressors.
“We currently think of these proteins as analogous to a car’s handbrake: they’re always on when the car isn’t moving, keeping things under control,” explained Dr Christoph Goebl, a principal investigator at the University of Otago’s Mātai Hāora – the Centre for Redox Biology and Medicine.
“Similarly, p16 proteins are present when cells don’t need to divide, acting like tiny blockers that fit between other proteins to stop cell growth and division.”
Ever since that discovery, researchers have been eager to learn more about these enigmatic proteins.
The University of Otago's Dr Christoph Goebl. Photo / University of Otago
In a global breakthrough last year, a team including Goebl, his University of Otago colleague Sarah Heath and Dr Vanessa Morris revealed they had the ability to alter both the proteins' structure and function.
Essentially, they found they could exist in two different forms – including one in which they lost that crucial tumour-suppressing function – and that some cancers could manipulate and release the handbrake to allow cells to keep dividing.
Why was that important?
Because it offered a potential new switch with which to stop tumour growth, if only scientists could understand how to keep it turned on.
Cracking that puzzle could lead to improved diagnostic procedures – and even new treatments that stabilised the protein in its healthy, blocking state.
Now, in a new study supported by the Marsden Fund, Goebl and University of Otago colleagues including Professor Julia Horsfield and Dr Hannah Darroch are taking the work further by studying the changes in living systems.
They include zebrafish, known to develop tumours that are similar to those in humans.
“Our goal is to understand how and why p16 proteins switch between their two states, we wouldn’t have thought this would be possible just a few years ago,” Goebl said.
“This is particularly exciting because p16 is crucial in preventing many cancers, including melanoma, breast, lung and pancreatic cancers.
“By exploring how these structural changes happen, we hope to understand how cancers hijack this process to develop and spread.”
Retraining our cells to kill cancer
Imagine being able to reprogramme a patient’s immune cells to recognise and kill the cancer attacking them.
That’s just the promise that a Kiwi-developed therapy holds – with hopes of it eventually becoming a standard care in New Zealand.
The Enable trial, being run by Wellington’s Malaghan Institute of Medical Research, represents first-of-its-kind technology for New Zealand and a potential game-changer for certain cancers.
Malaghan Institute researchers are trying to find a CAR-T cell therapy more effective than current ones – but also safer and affordable – that can be introduced to our healthcare system. Photo / Malaghan Institute of Medical Research
It involves CAR-T cell therapy, in which a patient’s immune cells are collected, genetically modified to recognise and kill their cancer, then given back to them as treatment.
Used overseas for types of blood cancers including relapsed lymphoma, leukaemia and myeloma, CAR-T therapy isn’t yet available as a funded treatment here.
Some desperate Kiwis, including businessman and comedian David Downs, have been forced to go offshore to access it.
But the researchers behind the trial hope to see that change.
Their locally-developed therapy has been found highly effective against its target cancers – B-cell non-Hodgkin lymphomas – while also being safer than leading international therapies.
Of 30 patients who took part in the trial’s first phase, after exhausting all other treatment options, more than half were shown to be cleared of cancer just three months later.
Researchers began recruiting patients for the second phase of the trial last year, and preparations were well under way to expand it from Wellington to Auckland and Christchurch.
The Malaghan Institute clinical director Dr Robert Weinkove said CAR-T cell therapy could prove a “potential game changer” for the treatment of some cancers.
“At the Malaghan Institute we continue to explore ways to target this treatment to other malignancies such as myeloma, as well as working on manufacturing improvements to shorten and simplify delivery of CAR T-cells.”
Collectively, the type of cancers targeted by the new therapy accounted for about 1600 diagnoses here each year, and it was estimated around 200 of those might benefit from the therapy.
While there was potential to push its reach to other subtypes of lymphoma and myeloma, its prospects for treating “solid” cancers – like lung, breast and prostate – weren’t yet as promising.
Making 3D ‘mini-tumours’
For researchers investigating smarter treatments for what’s the most common cancer among women in New Zealand – and the leading cause of death in those under 65 – lab-made “mini-tumours” could spell a major step-change.
Within each breast tumour is a complex interplay between cancer cells and healthy ones, all of which occurs within a natural scaffold made of proteins.
“This complex environment surrounding cancer cells strongly influences how quickly they grow - and how they respond to drugs such as chemotherapy,” said Dr Emma Nolan, a senior research fellow at the University of Auckland.
Within her lab, Nolan and colleagues have been constructing 3D tumours using tissue donated by breast cancer patients, to study how they’d grow and behave within a body.
These mini-tumours were far superior to and more realistic than long-used 2D models, in which cancer cells were grown on a plastic surface.
“Now, we are taking things to the next level by making them more complex so that they are an even better mimic of human cancer,” said Nolan, who was recently awarded a Rutherford Discovery Fellowship for the work.
“This makes them powerful tools to develop and test new cancer drugs, so one of my goals is to accelerate new drugs made in NZ into clinical trial.”
University of Auckland senior research fellow Dr Emma Nolan. Photo / Walter and Eliza Hall Institute
“I’ll also be using them to understand how healthy cells within a tumour’s environment influence how it responds to chemotherapy or targeted therapy, like Herceptin.
“This could uncover new ways in which cancer cells develop resistance to therapies.”
Nolan added that because the samples had been donated by women from Aotearoa, they represented traits of our own unique population.
“This is an important step towards ensuring patients in New Zealand can access the benefits of new discoveries, rather than relying on research done overseas with less relevance to us.”
Each year, around 3500 new cases of breast cancer are diagnosed in New Zealand, and rates have been climbing.
“There is no other cancer that has had such a huge impact on women in this country as breast cancer,” Nolan said.
“My hope is that my research could ultimately lead to better treatments and therefore have a positive impact on the lives of future patients and their families.”
How ‘smart linkers’ could guide toxic drugs into tumours
For decades, cancer treatments have struggled with a fundamental challenge: how to get toxic drugs into tumours without hurting the healthy cells surrounding them.
As anyone who’s endured chemotherapy would understand, patients have meanwhile had to deal with sometimes debilitating and dangerous side effects.
Ideally, drugs would be able to bypass healthy cells and be guided directly to the tumour.
That’s precisely the aim of what are called antibody drug conjugates, or ADCs, which have been at the forefront of targeted cancer therapy research for 25 years.
They work by carrying a small, toxic drug directly to receptors found in high levels on a tumour cell surface.
“Once inside the cell, the drug is released and actively kills the tumour,” the University of Otago’s Associate Professor Allan Gamble explained.
“In this way you get a higher concentration of drug around the tumour, and less in healthy, non-cancerous, cells and organs, providing an advantage over traditional chemotherapies that are non-targeted.”
Yet even with all the effort, just a dozen ADCs have been approved for use in patients.
To make an effective ADC, two pieces – the antibody and drug – needed to be held together by a chemical “linker” and it was this that remained a major challenge for scientists.
The University of Otago's Associate Professor Allan Gamble. Photo / University of Otago
“It needs to be stable while circulating in blood and healthy tissues but release the toxic drug when inside the tumour cells,” said Dr Jessica Fairhall, a research fellow in medicinal chemistry and drug delivery at the University of Otago.
“However, most of the linkers currently used are unstable, causing side effects and potentially life-threatening toxicity.”
In a new project supported by the Marsden Fund, Gamble, Fairhall and colleagues aim to develop a new type of linkers that connect the two vital pieces, while reducing side effects seen in other ADCs.
“We propose a new strategy, which we have named the bio-orthogonal click-to-trap reaction, to synthesise stable linkers for connecting the antibody to a drug,” Fairhall said.
“It will provide a ‘smart linker’ that’s stable in blood and healthy tissue – but can be rapidly cleaved after binding to the tumour.”
Gamble said a first step would be developing the chemistry involved, and then demonstrating the strategy in colorectal, or bowel cancer cell lines.
“Compared to other cancers, there are limited targeted therapies for colorectal cancer, and there are no approved ADCs for this cancer,” he said.
“We urgently need new, more effective and better tolerated therapies to treat it.”
The mysteries of MAIT cells
They’re called MAIT cells – and they could prove a powerful new cancer-fighting tool.
In a just-funded project, researchers are pushing toward something that has long eluded scientists: how to unlock the cells’ full potential.
MAIT cells – or mucosal-associated invariant T cells - are a unique subset of immune cells found in high numbers in areas including the blood and liver.
First discovered in the early 1990s, they’ve been implicated in many diseases or conditions, from mucosal cancers like colorectal cancer – which causes more than 1200 deaths in New Zealand each year – to immune responses against bacteria and viruses.
Unlike conventional and better-known T cells, which have different receptors to recognise different molecules, MAIT cells all have what’s called an “invariant” receptor to identify them.
“This means that the MAIT cells in one person should respond to a treatment in the same way as the next person,” said the new project’s principal investigator, Associate Professor Bridget Stocker.
Despite that exciting promise, their therapeutic potential has long been hampered by a lack of reliable ways to kick-start them.
Victoria University researchers Associate Professor Mattie Timmer and Associate Professor Bridget Stocker. Photo / Robert Cross, Image Services, Victoria University of Wellington
“We aim to address this and to develop an alternative and complementary approach to cancer treatment,” said Stocker, of Victoria University’s School of Chemical and Physical Sciences.
“It goes without saying that colorectal cancer is on the increase and more aggressive forms of the disease are hard to cure.”
For scientists, a major challenge has been finding compounds that could activate MAIT cells without losing their stability, as can happen when they’re exposed to water or air.
But Stocker and her team – including Victoria University’s Associate Professor Mattie Timmer and Dr Kensuke Shibata, of Japan’s Yamaguchi University – suspect they’ve found a solution in a new class of compounds called RUAs.
They’ve already shown them to be stable, easily prepared and a potent agonist to trigger MAIT cells, she said.
“Now we need to optimise this class of compound and determine its exact mechanism of action.”
That includes carrying out a series of rigorous studies to understand how that triggering occurred – and whether the RUAs could shrink colorectal cancer tumors in experimental models.
If successful, the research, which has received a $941,000 Marsden Fund grant, could pave the way for a new and effective type of immunotherapy.
“We need more cancer treatments and therapies that are significantly different to the ones that already exist,” she said.
“Complementary new therapies that can be used in combination with existing therapies may also lead to better patient outcomes.”
Jamie Morton is a specialist in science and environmental reporting. He joined the Herald in 2011 and writes about everything from conservation and climate change to natural hazards and new technology.
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