Momentum is everything: advancing CAR T-cell research for future trials and treatments

Rachel is not shy talking about her love of T-cells. They’ve been the common thread in her journey as a researcher. 

“The immune system is our guardian or protector, and for me T-cells are easily the most interesting type of immune cell, as they are the warriors that defend us from attack.”

Rachel was fascinated by science from a very young age. She was especially captivated by the concept of how vaccines can prevent us from getting sick, as she wanted to do a job that helped people when she grew up.

“As a teenager, I was a fan of the TV show ER and decided that I wanted to be a doctor. When I did some work experience in a paediatric ward, I found it very unjust that young kids with cancer had to go through chemo and I really wanted to be able to do something about it.”

Determined, Rachel went on to study Health Sciences at the University of Otago. However, she quickly found the rote-learning element of medicine didn’t appeal nearly as much as the freedom of academic research, so pivoted to Microbiology. 

“I realised that I'd much prefer to be working in a lab than being a physician. I wanted to be at the other end of the chain, building hypotheses and making new discoveries that could be developed into therapies to benefit people.”

It was in her microbiology lectures where she first encountered the enigmatic T-cell.

“I had some really inspiring teachers, including the late Professors Margaret Baird and Glenn Buchann. Their enthusiasm for the wonders of immunology was addictive,” she says.

“The immune system is our guardian or protector, and for me T-cells are easily the most interesting type of immune cell, as they are the warriors that defend us from attack.”

"I learnt that T-cells are the elite warriors of the immune system and can help to fight off infections, but also defend us against cancers that arise from mutations in our own cells. Most intriguingly, I learnt that in some cases our T-cells may lack the strength or direction to defend us against attack, but that through research we can discover how to make T-cells to work more effectively.”

After completing her Honours year, Rachel went on to do her a PhD at the Malaghan Institute with Professor Franca Ronchese.

While Prof Ronchese’s research focused on a different part of the immune system – dendritic cells – Rachel never lost her passion for T-cells.

“Dendritic cells are the activators of T-cells. So, I found a way to focus on T-cells by studying how dendritic cells interacted with them to make them into better cancer-fighting cells.”

PhD wrapped up, Rachel then went on to a postdoctoral fellowship at the Ludwig Institute for Cancer Research in Switzerland and then to the Fred Hutchinson Cancer Research Centre in Seattle, working on the best ways to direct T-cells to fight cancer. But the pull of New Zealand was a constant.

“My time overseas was exciting and taught me a lot, but I was ready to come home. I still kept in regular touch with the Malaghan, and was talking with the team about a programme they were starting to run clinical trials for a new kind of T-cell based immunotherapy – CAR T-cell therapy. 

“This fitted perfectly with my research experience and motivation to work on potentially life-saving T-cell therapies and allowed me to return to the Malaghan in early 2020. New Zealand’s first CAR T-cell trial had just gotten underway, and I was privileged to work with Professor Rob Weinkove to grow the CAR T-cell research programme.”

CAR-T trials and tribulations 

“What many people don’t realise is the challenges you face in the long process from testing a pre-clinical product in a controlled setting to treating patients.”

Before the first ENABLE trial participant received their genetically-modified T-cells back to them, a whole litany of testing, quantifying and re-testing had gone on behind the scenes.

By the time the Malaghan treated its first patient in late 2019, it represented the culmination of years of hard work refining the manufacturing process of creating immune cell therapies. 

“In preparation for the trial, blood donated by ‘healthy’ volunteers was used to refine and improve the manufacturing process,” explains Rachel, who worked closely with the GMP manufacturing team, sharing expertise that helped iron out the kinks during the early days of production. 

However, Rachel explains there is a vast difference between healthy T-cells that have never encountered a lymphoma cell, versus T-cells that have been fighting them for years.

“By the time a patient got accepted to the phase 1 trial, they had been fighting their cancer while undergoing multiple treatments that caused a lot of collateral damage. Their T-cells were exhausted and fragile.”

Despite months of preparation, for those early trial patients, there was no way to fully predict the difference between growing CAR T-cells from healthy vs sick patients. 

“Every patient is different, and the treatment pathways they’ve been on before arriving at the trial are intense. Producing one patient’s CAR T-cells went smoothly, but things were more complicated for the next. We had to make lots of adjustments, tweaking the processes in the research lab and then validating them under GMP conditions to make sure we could deliver the CAR T-cells on time.” 

Rachel also led the introduction of automated CAR T-cell production of CAR T-cells – a step change that enabled the scale-up of manufacturing for the ENABLE-2 trial and beyond. Her team worked closely for months with Cocoon developers at Lonza to ensure the CAR T-cells were produced to the highest safety and quality standards. 

Now, with several years of experience under their belt, the clinical team are well equipped to handle anything that comes their way. In ENABLE-2, patients also come into the trial earlier in their treatment journey, which Rachel says has made the overall manufacturing process easier and more predictable.

“There’s still a lot of variation patient to patient, but overall their T-cells are in better shape and so can be transformed into CAR T-cells more effectively.”

Today, the clinical manufacturing side of the ENABLE trial is well established, so Rachel has her sights set on what’s next for CAR T-cell therapy in New Zealand.

Future CARs

Currently, the CAR T-cells used in the ENABLE trials use a single ‘CAR’ to target one specific protein on blood cancer cells – in this case B-cell lymphomas. If the cancer cell has that protein, the CAR T-cells will be able to find them and destroy them.  

That’s great for cancers like B-cell lymphoma or leukaemia where every cell displays that protein, but less so in the case of cancers where individual cancer cells can display different proteins. Multiple myeloma is one such example. So Rachel and her team are working on developing ‘dual CARs’ that have not one, but two protein targets, giving the cancer fewer opportunities to hide.

“This dual-target approach could make CAR T-cell therapy more effective at completely eradicating cancer and open the door for us to treat additional cancers such as multiple myeloma.”

Another project in the lab is aptly named ‘Faster CARs’. Whether they end up with single or dual CARs, patient T-cells have a pretty rough experience when encountering both cancer cells and chemotherapy drugs in the blood and then going through a long and involved CAR engineering process in the lab. 

Rachel says this can result in them burning out when they're injected back into a patient's blood, impacting their ability to effectively fight the cancer cells.  

“We're aiming to shorten the amount of time that the T-cells spend in the lab, and also to switch off the exhaustion signals, so that we can return fitter CAR T-cells to the patients faster.” 

The team are optimistic that they will be ready to do early clinical testing in the next few years – that is – as long as the team doesn’t lose momentum.

Momentum is everything

Medical research relies on funding; to support the researchers, equipment and laboratories that make life-changing discoveries possible. Traditionally, that funding comes in the form of contestable government grants, with many more researchers applying than there are grants to go around. Rachel says a pivotal moment in her work developing new CAR T-cells was a few years back when they failed to secure such a grant.

“That could have spelled disaster,” she explains. “The whole project could have stalled while we scrabbled to find funding.”

On the surface, a pause in research may not seem all that significant, but to researchers working on the cutting edge like Rachel, any gap can compromise progress towards the clinic.

“Right off the bat, if you can’t afford to keep staff, that’s years of skill and expertise wiped off in an instant, skills that don’t just come back. But it goes deeper. Technology changes and things advance so quickly in cancer research so that by the time you do manage to find funding and get back up to speed, you quickly find the field has moved on and you’re lagging behind. Many programmes never catch up and promising research never makes it to trial. Momentum is everything.”

However, Rachel explains, the Malaghan does things differently. As a charity, the institute is backed by generous supporters who share our ambition to cure disease. Their support does more than sustain our work – it gives us the confidence to think long term, pursue bold ideas and build the capability needed to take discoveries all the way to patients. And when funding landscapes shift, those philanthropic partnerships can provide stability to keep progress moving forward.

“In research, we’re constantly planning for a future that isn’t guaranteed. In this instance, we were incredibly fortunate to have philanthropic support that gave us certainty while we worked to secure further contestable grants.”

Thanks to charitable gifts that support multiple myeloma CAR T-cell research and recently secured government funding to develop Faster CARs, Rachel’s team are in a position to do research that could lead to future clinical trials in as early as a few years. 

Had the programme stalled, that future could be delayed years, if it ever got off the ground at all. To Rachel, that is an unacceptable cost for patients desperate for new treatment options.

“At the end of the day, it’s the patients that suffer most when research momentum is lost. We know that many people are watching the ENABLE-2 trial closely, waiting to hear what’s next – to ensure the possibility of future clinical trials for different types of cancer and other diseases, we need to be able to continue the research that feeds into them.”