Primary central nervous system lymphoma (PCNSL), also known as brain lymphoma, can take a long time to diagnose and is notoriously difficult to treat.  

Access to clinical trials of novel treatments, including immune checkpoint inhibitors and CAR T-cell therapy, could be a game changer for these patients, according to Dr Colm Keane. He is a clinical haematologist at the Princess Alexandra Hospital in Brisbane and a brain lymphoma researcher at the University of Queensland’s Frazer Institute.  

He has helped design a world-first clinical trial for PCNSL, with colleagues from the Australasian Leukaemia & Lymphoma Group (ALLG), which is underway in Australia and has plans for a chimeric antigen receptor T-cell (CAR T-cell) therapy study for this patient group too, to give them more treatment options. 

There have been “very few” clinical trials for PCNS lymphoma and Dr Keane said findings from his research into this rare lymphoma subtype may contribute to new treatment regimens for other lymphomas as well. 

What is primary central nervous system lymphoma? 

This rare form of lymphoma is unusual in that it resides only in the brain, Dr Keane explained.  

Patients can present with seizures, problems with vision, or changes in personality because the tumour cells are pressing on important brain structure. 

“Sometimes it can take a long time to get a diagnosis – three or four months, because the symptoms are unusual and because CNS lymphoma is so rare,” says Dr Keane. 

“Brain lymphoma is not really at the front of people’s minds.” 

Dr Keane said that frequently, when viewing an initial scan, the neurosurgeon might think, “oh, it’s a brain cancer” and it’s only after doing a brain biopsy that they subsequently find out it’s brain lymphoma.  

“Surgical excision is not an effective therapy for brain lymphoma,” says Dr Keane. 

Brain lymphoma comes from immune cells, called B-cells, and Dr Keane said it still isn’t known whether these lymphoma cells start out in the brain or traffic to the brain, which he describes as “a niche environment for the tumour cells to grow”.  

The blood-brain barrier acts as a filter, protecting the brain from a lot of circulating toxins.   

“To get into the brain’s fluid and the brain, this blood brain barrier must be crossed. That’s why regular chemotherapy, which is floating around in the blood, doesn’t get into the brain,” explains Dr Keane. 

The cure rate for CNS lymphoma is “not very high”, said Dr Keane, and “you’ve really got to go through a lot to get to the cure, and unfortunately, a lot of patients can still relapse”. 

The genetics of brain lymphoma 

Systemic diffuse large B-cell lymphomas (DLBCL) can have “all sorts of different genetic changes” and are quite heterogeneous, but comparatively, a lot of brain lymphoma, which is a subtype of DLBCL, possess a small number of similar mutations. 

Dr Keane said at least 70% of brain lymphoma will have one of three mutations. 

“And it also appears to have a lot of mutations that makes it capable of avoiding the immune system, which is quite interesting,” he says.  

“It’s hidden in the brain, but it’s still trying to avoid attack by the immune system.” 

And those “immune pathways which Dr Keane mentioned “are possible targets for therapy”. 

“There are new targeted therapies that could be useful and could have a big impact on patients but they’re not available in Australia through the PBS (Pharmaceutical Benefits Scheme).”  

“Because this is a rare tumour with small groups of patients, it’s not a priority for a lot of the drug companies.” 

“That’s why we have designed some trials to give some of our patients access to some of these agents that we think might work,” says Dr Keane. 

World-first clinical trial for primary central nervous system lymphoma 

The first study, called ALLG NHL32*, is led by Dr Gareth Gregory from Monash Health and is run through the ALLG.  

This Australian Phase II clinical trial opened in June 2022 for patients with newly diagnosed primary central nervous system lymphoma. Currently available at eight centres, a further seven centres are expected to offer the trial across Australia. The aim is to recruit 48 patients over three years. Dr Keane said the study is “recruiting well”, with 13 participants who are “doing quite well”. 

Patients on the NHL32 trial receive standard of care chemotherapy but instead of having a stem cell transplant or toxic radiation to improve responses, they have an immune checkpoint inhibitor – pembrolizumab (Keytruda®), which is also used to treat patients with another DLBCL subtype, primary mediastinal B-cell lymphoma and is also effective in Hodgkin lymphoma.  

Pembrolizumab is a form of immunotherapy that targets and blocks a protein called PD-1. 

“It’s used to try and enhance immune attack against the tumour because we know this tumour uses that pathway to try and avoid detection,” explains Dr Keane. 

“The immune system can become weary and can no longer get rid of these cancer cells because they’ve been floating around for so long that the T-cells are just tired out from attacking it.”  

“Giving these immune checkpoint therapies can reawaken the T-cells to recognise the tumour and kill it off. This has been very successful in melanoma and lung cancer and also Hodgkin lymphoma, but we still don’t fully understand why it works or when is the best time to use them.” 

This Australian study is the first time this immune checkpoint treatment regimen has been used for brain lymphoma at diagnosis.   

Research into the rare lymphomas is a massive need 

Diffuse large B-cell lymphoma is Dr Keane’s main area of interest. 

“Seeing patients in the clinic and seeing the issues they have – the toxicities of therapy and the outcomes from therapy – really informs you as to what you should be looking for in the lab,” Dr Keane explains.    

“DLBCL is called one disorder but already we can split 60% of it into five separate genetic groups as we learn more, and most lymphoma subsets may in the future have a slight variation in how they are treated.” 

“The treatment for Hodgkins is quite different from the treatment for patients with DLBCL. Primary CNS lymphoma has very different treatment from systemic DLBCL even though the malignant cells are very similar.” 

 “A lot of the rare lymphomas, which tend to have poorer outcomes, are under researched.”  

“They are really interesting from an immune point of view and there may be more value in researching them, to improve outcomes for patients with those diseases. It’s a massive need,” he says. 

Of the 100+ different subtypes of lymphoma, brain lymphoma makes up about 2% of all lymphomas, and around 5% of brain tumours.  

“Unfortunately, these patients don’t do very well, and we’ve got some ideas about how we can improve that,” says Dr Keane. 

“We’ve analysed brain biopsies and we can see particular abnormalities that might be targetable for new drugs, and that’s how we come up with the trial designs.” 

“Patient samples from trials where they’ve had immune therapy can be used to investigate what changes happened in that patient’s immune system to contribute to the response, or, if they didn’t respond, why – what was going wrong with their immune system? What was different between them and someone who did respond?”   

A lot of research is based on looking at trial samples and patient samples – at immune changes within the tumour and within the blood and looking at their immune system and T-cells.  

“There are a lot of novel technologies now and you can get levels of complexity of understanding the immune system that we never had before,” says Dr Keane. 

“Before we might have identified two T-cell types in the blood. Now we could probably identify 10 or 12 from one sample, and understand which cell is contributing most to improved response, whether it’s good or bad.” 

“We’ve got to run these clinical trials to see what works and what doesn’t. Whatever works, we take forward, and whatever doesn’t work – we go back to the drawing board, to see why those patients didn’t respond, or are there things we could do to enhance the response rate?” 

“With a lot of these things, until you give them to patients, you don’t know what’s going to happen.” 

CAR T-cell therapy to treat primary CNS lymphoma 

Dr Keane has applied to the Medical Research Future Fund (MRFF) for a second clinical trial that would “utilise CAR T-cells, which have never been given to patients of primary CNS lymphoma” in Australia. 

“But we need to source funding for that, so it’s aspirational at this stage,” explains Dr Keane.  

He believes there is potential for CAR T-cell therapy to be used for brain lymphoma “because the same target that’s been so successful in systemic lymphoma is there in brain lymphoma”. 

“To get a trial underway in Australia would require $4 million which would fund CAR T-cells for 25 patients and some drugs to augment the CAR T-cell response.” 

“If you were to do that trial buying the CARTs from the commercial providers, it would cost multiples of this cost.” 

Dr Keane said he already had a lot of buy-in for this trial.  

“Every city in Australia where CARTs are available – they’re all invested in this. We would make the CAR T-cells ourselves, which is a lot cheaper, but you’ve got to have the money, and the additional advantage of making them locally is you could get them back to the patient much quicker.” 

“The only conduit for us in Australia to fund CAR-T for brain lymphoma is through the Medical Research Future Fund but this scheme is highly competitive with most proposals going unfunded.”  

“This trial would obviously bring a lot of technical and manufacturing knowledge to Australia if our MRFF is successful. It would be great for the patients, a lot cheaper, and provide us with the knowledge to understanding if CAR T-cells work or don’t work,” explains Dr Keane. 

“Unfortunately, at the moment, you can’t get access to CAR T-cells for brain lymphoma in Australia despite emerging evidence that this therapy may well be very useful at relapse.” 

“Primary CNS lymphoma got excluded from the CAR T-cell trials that resulted in registration. 

“The thing with CARTs for brain lymphoma is – we need to learn more about it, because so few patients have received them.”  

“From the small groups in the U.S. and France that have received them, there have been good responses. It’s an area that just needs to be investigated,” emphasises Dr Keane. 

The importance of clinical trials  

“Clinical trials are critical for patients to give them more options and for them to feel like they’ve been given their best shot or given every opportunity to have a good outcome.”  

“And trials are really important for clinicians because you learn an awful lot about your practice and about the standard of care from what you do on a trial, and you get to learn about new drugs.”  

“When we also get to run the science behind them, we get to see what impact the treatment might be having, whether it’s good or bad by looking at the outcomes and then at patient biopsies to understand reasons why the tumour might respond in some patients but not others.” 

“There aren’t enough patients going on clinical trials. That’s the reality of it.” 

“There are huge groups, obviously regional and rural patients, and it’s very difficult for them to access a clinical trial but organisations such as the ALLG try to ensure that these patients can get access to clinical trials. 

Dr Keane said most patients understand the potential benefit of a clinical trial.  

“It’s pretty rare that patients turn down studies when they’re offered them.” 

“Some people will, because they don’t want to be in hospital all the time and there are lots of tests and a trial may not help them, but most people sign up.” 

“I think every single trial has its merits and the trials we run in Australia, and through the ALLG, are particularly important because we get to collect translational samples and to analyse them locally, and we get a lot of value add-on to the studies that supports our research community as well as our patients.” 

“Being able to take what we find in the lab back to the patients and using the patient samples to inform what we do in the lab contributes to designing better studies or better experiments going forward.” 

The flow-on effect of Leukaemia Foundation-funded research 

Dr Keane was awarded research grants from the Leukaemia Foundation in 2009 and 2015 which he says, “made a huge research difference”, and he attributes his pursuit of a research career completely to all the funding he’s had. 

“It’s important to keep you involved,” he says. 

“All my work has been a steady progression. What I did in 2012 is, in some respects, the same as what I’m doing now – we’ve just got new techniques and new ideas. 

“The longer you can keep young researchers in the game, the more likely they are to persist with it. If they don’t have funding at important times, like finishing haematology training, they’re lost to research forever.”  

*To find out more about the ALLG NHL32 trial and how to access it, speak to your haematologist.