Glioblastoma and the legacy of Professor Richard Scolyer’s ‘patient zero’ immunotherapy experiment

“I didn’t know if his brain was going to blow up or not.” 

Dr Helen Wheeler is talking about Professor Richard Scolyer.

He died in June having become a self-declared guinea pig, “patient zero”, in an experiment to discover whether the wonders of immunotherapy could apply in the treatment of grade 4 IDH-wildtype glioblastoma (GBM).

Australia has been riveted by his story, whether some of the country’s top medical researchers could save one of their own, a story offering a rare glimpse behind the professional facade: the very human response of friends and family to a man they loved who was dying.

What you are about to read reflects a truth that doctors more than most are familiar with. Medical breakthroughs are rarities, and even when they do occur, remain grindingly slow strikes of scientific enlightenment.

What is the legacy of Professor Scolyer’s very public N=1 experiment? Is there new hope for GBM patients? Are we close to a treatment that will extend a liveable life for people given a doomed prognosis?

Dr Wheeler is head of medical oncology at Royal North Shore Hospital in Sydney, specialising in primary brain tumours. She was part of Professor Scolyer’s treatment team brought together by him and Professor Georgina Long shortly after his diagnosis in 2023. 

As is now well-known, Professor Scolyer had been in Poland with his wife, Katie, for a conference when he experienced a seizure. 

An initial CT scan in the local hospital cleared him of a brain bleed. But later that evening, he was taken by lights-and-sirens ambulance to a university hospital in Krakow.

Following more investigations and conversations with his medical colleagues back in Sydney, GBM seemed the likely diagnosis. 

He was 56.

As we know, he spoke to Professor Long, his co-medical director at Melanoma Institute Australia and an expert in immuno-oncology, and they began wondering whether they could use immunotherapy.

Professor Long said at the time that, somewhat to her shock, in terms of published research, it was a “barren landscape”.

It was as though the transformations she had witnessed in her own field, where five-year melanoma-specific survival in patients with stage IV disease had increased from less than 5% to 57%, had been distant noise.

Sitting in her office at Royal North Shore Hospital, Dr Wheeler acknowledges that the small number of previous immunotherapy trials for GBM had not been successful.

But there were reasons for the caution within the brain cancer research community.

Adverse effects of immunotherapy used in MS, including encephalitis resulting in autoimmune attack on CNS structures, highlights just how badly these treatments could go should the autoimmune response go into overdrive.

“Richard and Georgina came in with their concept and said to me, ‘Can we do it?’,” she tells AusDoc.

“My response was: ‘You guys know more about successful immunotherapy than I do by far. You’ve obviously got very informed consent about what you think you’re going to do.’

“I said if there was any chance of improving outcomes and collecting scientific data for GBM management, I’d support them in any way I can.

“I would take a role in the background, I said, but would be happy to help if needed, and if they got into big trouble, I could possibly help.

“But I was hesitant, and it was because it hasn’t really been done before. The weekend before they talked to me, one of the melanoma patients on combination immunotherapy needed breathing support in ICU as it had weakened all his muscles.

“These treatments are not a walk in the park. Obviously, at [Royal] North Shore Hospital, a tertiary centre, we often have to admit patients that develop severe complications from immunotherapy.

“I may have a biased view; I know that. There are numerous patients receiving immunotherapy who never need to be admitted with severe side effects. I only see the rare, complicated patients. But picking up the pieces when things go wrong, that can be very hard.”

Professor Scolyer, a pathologist intimately involved in the melanoma revolution, knew what he was getting into.

So was he worried about his brain blowing up, specifically that material risk of a massive cerebral oedema which might prove difficult to control?

“No, never, he didn’t seem to worry,” Dr Wheeler says. “He had seen how harnessing the immune system to attack cancers had such spectacular results.

“Often when people present with glioma, they have significant brain swelling causing them neurological symptoms, and we use dexamethasone, a corticosteroid to try and rapidly reduce the pressure.

“Unfortunately, it suppresses the immune system, so Richard would not take a molecule of dexamethasone under any circumstances, and that included coming home post-seizure with increased cerebral pressure on a long-haul flight.

“It was almost like we were suggesting he take arsenic!”

The treatment

The approach taken by his treatment team was to administer a combination of three immune checkpoint inhibitors (ICIs) — anti-PD-1 (nivolumab), anti-CTLA4 (ipilimumab) and anti-LAG-3 (relatlimab).

It worked like this:

Thirteen days after his first dose of immunotherapy, he underwent safe maximal resection.

Tissue from the resection was then shipped to an international research company tasked with developing a personalised tumour-targeting vaccine, an approach based on the successes with the COVID-19 mRNA vaccines.

He then undertook a six-week course of adjuvant radiotherapy before recommencing ICIs as monotherapy or in combination, adjusted for toxicity.

Three months later, when it became available, he started a monthly injection of the personalised vaccine.

When it comes to the three ICIs, the car number plate nomenclature does not give much insight into what is going on beyond the general principle that they enable the T-cells in the brain to recognise and attack the tumour.

But the details capture something of the grim adaptive wonders of cancer cells in their own struggle to survive the attack of the human immune system, itself the product of 500 million years of evolution.

As anyone who has read about last year’s Nobel prize for medicine and the discovery of Treg cells will know, over the past 30 years, scientists have uncovered the varied ways that the immune system has evolved to inhibit the activity of T-cells, given the diseases which result if they go AWOL.

But cancer cells have in turn evolved to exploit this system for their own protection.

So what is CTLA-4? 

When the immune system is deciding whether to activate a T-cell, it needs both a recognition signal that this is an alien entity as well as a ‘go’ signal.

CTLA-4 means cytotoxic T-lymphocyte-associated protein 4. This molecule competes with that ‘go’ signal and tells the T-cell: slow down, do not overreact.

The idea is that by raising the threshold for T-cell activation, CTLA-4 helps ensure T-cells respond to real danger rather than weak or mistaken signals.

In cancer treatment, the immune checkpoint inhibitor ipilimumab blocks the CTLA-4 receptor allowing lymphocyte activation and an anti-tumour response.

PD-1? That’s another checkpoint receptor on T-cells. When it binds to PD-L1 or PD-L2 proteins on another cell, it sends a signal that suppresses the T-cell. Cancer cells can exploit this pathway by expressing increased PD-L1 receptors, helping them evade immune attack.

Nivolumab and other PD-1/PD-L1 antibodies bind to PD-1/PD-L1 and block this interaction, again helping restore T-cell activity.

LAG-3 stands for lymphocyte activation gene 3. It is an inhibitory receptor often found on exhausted or overstimulated T-cells.

The protein molecule often appears alongside PD-1 when T-cells have been chronically stimulated by cancer and are exhausted.

Blocking PD-1 may release one brake, but LAG-3 can remain another pathway keeping the T-cell subdued.

Again, relatlimab has been designed to block LAG-3.

Before these drugs were first used 15 years ago in the context of metastatic melanoma, a newly diagnosed patient with stage IV melanoma would usually be dead within four months.

There are reasons for their success. Melanomas are ‘hot tumours’.

They have numerous genetic mistakes, expressing a varied range of abnormal tumour signals (antigens) — around 160 varieties — so the immune system can easily recognise them as alien.

The tissues surrounding the cancer cells also vary depending on cancer cell location. In the case of melanoma, the microenvironment will have substantial T-cell infiltration.

And the tumours are also peripherally located, so when ICIs are administered, they get relatively easy access to do their work.

The brain is a foreign country

But this is all very different when tumours emerge in the brain.

They have limited mutations and are regarded as “cold”. The brain microenvironment also contains a different set of protective immune cells.

And importantly, it is (somewhat) protected by the blood-brain barrier.

Again, the evolutionary reasons are obvious given the brain is a space where any infection or overstimulation by an overheated immune response can have catastrophic effects.

“There was obviously a lot of interest in using immunotherapies for brain cancer treatment,” Dr Wheeler says.

“But the initial hesitation was simply because of that question of what happens when you get a bucket full of immune cells running into the brain and suddenly everything is attacked, including normal brain cells.

“A massive immune response is associated with massive brain swelling, which at times can cause seizures and neurological deficits. And if it gets really bad, it causes cerebral death.”

She adds: “Even with immunotherapy and melanoma, some people can have one dose and end up in hospital with their entire immune system activated, attacking their thyroid, their lungs, the colon.

“Yet other people can tolerate six, eight months or even years of therapy without any problems. 

“So, it seems that we were all born with a different genetic program of how our immune system reacts to stimulation and foreign invasion.”

Given this, she says that in her view, when it came to Professor Scolyer, he was something of an outlier.

“He was unique in the fact that he hardly got any side effects from these three ICIs, whereas I’ve seen people get bad side effects from any one of them, let alone when they are put together.”

The first paper on his treatment came out in April 2024 as a preprint, with Professor Long as the lead author.

It was described as the first in the world case study of a newly diagnosed GBM patient treated with triplet neoadjuvant ICIs.

The study indicated that something significant was happening.

The microenvironment seemed to be changing between the biopsy, the administration of immunotherapy and surgical resection of the tumour.

CD8+ T-cells — the main killer T-cells — were found closer to tumour cells, along with CD4+ which help co-ordinate the immune response, suggesting they were reaching the cancer rather than remaining at its edges.

The number of circulating tumour cells (the cancer cells being shed into circulation) also fell from 16 cells per 7.5mL of blood before the treatment to none detected by day 190. 

This result was based on a newly developed, highly specialised blood test — blood tests in the context of brain cancer being an area of huge research interest given the potential benefits if they prove robust.

But Dr Wheeler stresses it was a test, like the others now being developed, yet to be fully validated.

The finding that the treatment seemed to have crossed the blood-brain barrier and possibly stimulated an immune response was not in and of itself totally new.

For instance, a 2019 phase III trial using neoadjuvant anti-PD-1 to treat GBM had demonstrated that already.

But it was the first time a triple therapy had been used which appeared to have succeeded in making the GBM into a more immune-active tumour, with substantially more T-cells infiltrating and interacting with the cancer cells.

It is worth stressing that many of these findings were a product of Professor Scolyer’s willingness, for the purposes of his experiment, to undergo an open craniotomy biopsy rather than a core biopsy. As he told AusDoc at the time: “I wanted to get enough tissue so we can perform really good research.”

And the results were a source of genuine excitement within the brain cancer research community.

So was the fact that Professor Scolyer was still in good health around this time. There had been no recurrence in a cancer that he feared would kill him within months. There was hope.

“Brain cancer has got a moat wall around it, and we saw after Richard’s therapy that that moat was broken down and some immune cells could go in and take a look at the cancer cells [in the tumour],” says Dr Wheeler.

“Blood-brain barrier or not, these immune cells can infiltrate; they can come from the periphery, they can go in there. 

However, there is a significant ‘but’.

“The big issue is, when they get there, do they do anything?”

Dr Wheeler adds: “GBM cells have set up such a protective mechanism partly because the brain is also protecting itself against infection, inflammation and everything else.

“They’ve adapted a system we use to protect our brains to protect cancer.

“And so yes, Richard’s research has shown that they can get stimulation… but we cannot validate cancer destruction.

“Put another way, [the question for me is whether] we arm them with anything else that would make them attack, rather than just let them go and have a look?”

Patient hope?

Much of this was made clear in Professor Long’s preprint paper, which was published following peer review in Nature Medicine in February last year.

But whether the public fully understands, despite the research successes, how far this was not just from making the therapy a real-world option, but even showing it actually works in one patient, is difficult to know.

GBM is a bleak midwinter usually with no spring to come. During the course of Professor Scolyer’s treatment, amid the social media rush, the Instagram posts and YouTube videos, and those moving Australian Story episodes on the ABC about what he was going through, a little light was breaking.

Beneath the media narrative, however, Dr Wheeler says it was also a very difficult time. Patients and families confronted with a death sentence were coming in having seen what was looking like salvation – a miracle cure. 

“You knew these patients,” AusDoc asks. “They were in your clinic being cared for by your staff. How was that managed?”

“With tears,” she says. “It was hard. ‘My three-year-old has got a GBM. Can you please help them? Can you please do this?’ And it was heartbreaking. I mean, it’s just … it was just awful.

“There was very real stress on the staff.”

Dr Wheeler understood from the beginning the risks. When asked to be involved in his treatment, she told Professor Scolyer and Professor Long that she would support them.

“But I said don’t put my name anywhere near it, and keep it quiet, do not put it out to the world, because this is going to be so disappointing for anyone else who’s had a relative, loved one diagnosed.”

But news did get out within weeks, and Dr Wheeler says she was soon dealing with brain cancer patients wanting to know why they could not undergo immunotherapy that seemed to be extending Professor Scolyer’s life with drugs that were off the shelf and in common use.

Conversations explaining why the pathologist should remain an N=1 were tough to have with people who were highly likely to die.

Professor Scolyer himself passed away in June this year. He was brave and brutally honest, and the public mourning has been deep.

Professor Long lost her cherished colleague, someone who, through his teaching, mentorship and research, she said had left an enduring impact on the doctors and scientists he worked with.

Asked about why the treatment ultimately failed, Dr Wheeler says: “Around 30% of a GBM is made up of these horrible [tumour-associated] macrophages and microglia. Some come from monocytes in the peripheral blood, while others are microglia [the brain’s resident immune cells].

“The tumour can reprogram both to dampen the immune response. They also have a lot of Tregs, those immune-suppressing cells, which we need to try and reprogram.

“If you’ve got some lymphocytes in there, [the T-cells that either kill or co-ordinate an immune response], they have obviously recognised it’s a bad guy, but you can get lymphocyte fatigue or lymphocyte burnout.

“If they’ve been stimulated all the time, they just stop working.”

How soon is now?

There has been much talk of future trials based on the interventions used to treat Professor Scolyer. These are important. The one that has been registered but is yet to start is the GIANT phase II trial that will be run both in the US and here in Australia. 

It will involve nivolumab with or without relatlimab in patients with newly diagnosed wildtype GBM — not quite the triple therapy used with Professor Scolyer — and will assess the feasibility of undertaking a peri-operative study.

Medical trials are a high-cost enterprise and money calculations have to generate a viable argument for doing them. They also take time before they deliver on their findings which are not always clear cut.

Drug companies can be cautious too when it comes to brain cancer because of the very real reputational risk involved if the treatments go pear-shaped, if they begin triggering a catastrophic immune response in the brain and start killing the trial subjects.

The fallout would not be good for any drug company’s money-maker products whose emergence in the context of melanoma has been described as a penicillin moment.

Patient selection, as Dr Wheeler puts it, in any future trials will also be complex in terms of ensuring clear answers emerge on the efficacy of the therapies.

GBM remains a rarity. That is some good news, but among this small group, you still need to select for trial patients with the tumour in the right place, where it is not causing any immediate major brain damage.

And would patients joining a trial, like Professor Scolyer, be prepared to wait for the immunotherapy to take effect before undergoing resection. Possibly not.

Added to that are the complications associated with the processes required to assess the results of trial treatment. Again, those craniotomy biopsies that Professor Scolyer underwent?

“That is not an easy ask. Researchers will hope to try and insert a capsule into the brain fluid compartment [of subjects] to sample CSF on a regular basis.”

Progress in medical research is slow for these very reasons.

Dr Wheeler stresses throughout the interview that brain cancer research has shifted a long way and that shift continues because of Professor Scolyer.

“When I started doing brain cancer, there was not much interest from oncologists, and it was just put into the too-hard basket.

“I once went to a big American meeting that now attracts about 3500 people, and there was a total of 167 people in the room. 

“This was back in around 1998. No-one was doing the research because brain cancer outcomes were so dismal.”

She thinks effective treatments will emerge, but from across the disciplines. Treatment for GBM relies on numerous specialists combining to formulate a therapy plan.

A pioneering oncology researcher herself, she mentions the researchers looking at the immune system and the researchers looking at the molecular biology, the researchers looking at gene therapy and epidemiology.

“I get completely bamboozled now because, you know, some wonderful person’s just done their PhD on KRAS or other mutations along the pathway that drive malignancy.

“I guess, they will need AI to try and combine all this research into a package we can use to treat. 

“Clearly we’re going to need a combination of therapy. The complication is when you start combining these things together, the side effect profile usually increases significantly.”

Dr Wheeler points her finger towards the ceiling.

This month, a State Memorial Service was held at the Sydney Opera House in honour of Professor Scolyer.

The prime minister Anthony Albanese was in attendance, along with Peter Garrett, the lead singer of Professor Scolyer’s favourite band, Midnight Oil.

Dr Wheeler says the impact of his very public journey as patient zero has been significant. She hopes it will lead to increased research interest and the required funding resulting in new clinical treatments.

“Primary brain cancer obviously has a devastating effect not only on the patient but the family and carers,” she adds.

“Everyone is terrified of seizures, falls and making sure medications are administered correctly.

“Some patients develop physical disabilities and require 24/7 assistance.

“Whereas major treatment developments in other cancers have been developed in the past few years, we are still waiting for new GBM treatments.

“We are grabbing anything we can from these studies that might be relevant to GBM therapy.” 

Additional reporting by Carmel Sparke