A Malaghan Institute team - including PhD researcher Danielle Sword - is pushing toward a new CAR-T cell therapy to treat a common type of cancer. Photo / Supplied
A Malaghan Institute team - including PhD researcher Danielle Sword - is pushing toward a new CAR-T cell therapy to treat a common type of cancer. Photo / Supplied
Scientists have moved a step closer to bringing a ground-breaking cancer therapy to Kiwis, after treating the final patient in a first-of-its-kind medical trial.
The Malaghan Institute’s ENABLE trial is working toward a new treatment for certain types of lymphoma – a blood cancer and the sixth-most common type of cancer diagnosed in New Zealand.
It marks our first clinical trial using CAR-T therapy, in which a patient’s own immune or T-cells are genetically modified to recognise and destroy their cancer.
While now a standard therapy overseas for types of relapsed lymphoma, leukaemia, and for myeloma, it’s not yet available as a funded treatment here.
As it works in a very different way to conventional chemotherapies and radiotherapies, it can be could often prove much more successful for patients whose blood cancer hadn’t responded well to other treatments.
For Kiwi businessman David Downs – once given mere months to live after 12 rounds of chemotherapy failed to subdue his non-Hodgkin lymphoma – travelling to the US to receive CAR-T cell therapy proved a life-saving decision.
Downs has since told his story in the award-winning 2021 documentary film A Mild Touch of Cancer, while signing up as one of the trial’s key supporters.
“For certain blood cancers, more than half of people respond to CAR T-cell therapy, and the responses can last for years,” Malaghan Institute clinical director Dr Robert Weinkove said.
Yet, current CAR-T cell therapies also came with limitations.
These include cases of severe side effects – such as fever, low blood pressure and sometimes seizures – brought on by over-activation of the immune system.
In the trial, researchers were ultimately trying to find a CAR-T cell therapy more effective than current ones – but also safer and affordable – that could be introduced to our healthcare system.
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 / Supplied
Building on second-generation therapies used overseas, their treatment added a new gene segment called TLR2, which has been shown to alter the effect of the CAR-T cells.
Since the trial began in late 2019, the team had been enrolling patients with specific types of lymphoma from across the country, manufacturing CAR T-cells at the Malaghan Institute, and treating them in Wellington.
At this point, Enable is still a phase one trial – which meant it is the first time this type of CAR T-cell has been given to people.
“For this reason, we have only been enrolling people whose lymphoma has not responded to conventional treatments, and who do not have other curative options,” Weinkove said.
“We started at a low CAR T-cell dose, and have been giving increasing doses of CAR T-cells to small groups of patients, with close monitoring for side effects.”
Last month, the team treated their 21st and final patient in the dose escalation part of the trial.
“This is a major milestone, as the results from the first 21 people treated will be used to select the CAR T-cell dose that we will use in future trials.”
Today the 21st and final participant received CAR T-cells in our ENABLE phase 1 CAR T trial dose escalation cohort! We'll continue enrolling to provide data critical to phase 2 trial design, including validating automated manufacturing and outpatient CAR T-cell delivery. pic.twitter.com/n0df9HUFqE
Reaching this stage had taken a huge amount of effort.
Because CAR T-cell treatment is both a gene and personalised cellular therapy, the team had to work through the complex process of manufacturing CAR-T cells themselves, in what’s one of the world’s tightest regulatory environments for genetic research.
After gaining extensive approvals to make the cells and run the trial, hospital safety protocols needed to be set up to monitor and manage any patient side effects.
Remarkably, the team was able to progress the trial throughout the disruption of the Covid-19 pandemic – even obtaining special exemptions for patients to travel during lockdowns.
While final phase 1 results are not expected until later this year, the researchers are already preparing for a larger, phase 2 trial aimed at providing more data to support the new therapy’s safety and effectiveness.
Malaghan Institute clinical director Dr Robert Weinkove. Photo / Supplied
“We’re now working on a new CAR T-cell manufacturing process that makes use of automation, which is important to allow us to treat a larger number of patients,” Weinkove said.
“We’re also setting up outpatient management, with the goal of treating patients with CAR T-cells without admitting them to hospital.
“This needs new safety and monitoring systems, but will reduce hospital costs, and allow more independence for patients while they receive the treatment.”
It was hoped results from the phase 2 trial – expected to get underway next year – would lead to approval for routine use of the treatment here.
To potentially bring it to market overseas, the programme has helped establish start-up companies BioOra and Wellington Zhaotai Therapies Limited.
Even if the programme doesn’t find compelling advantages for a Kiwi-made CAR T-cell therapy, it would’ve put in place the infrastructure needed to bring overseas options to New Zealand.
“There are many groups working on CAR T-cells globally, particularly in the US and in China,” Weinkove said.
“However, we are the only group working on this specific version of CAR T-cell therapy.”
Others were also trying to target the therapy toward a wider range of cancers, including solid tumours.
“We don’t have a clinical trial in the solid cancer field yet, but we are watching the work of other groups, and we have some scientific collaborations with teams who are working in this area,” Weinkove said.
“We hope that our experience with Enable will allow us to work on CAR T-cell therapies for other malignancies in future.”
