Speaking of Science: New frontiers in brain cancer research with Professor Misty Jenkins AO and Professor Matt Dun

Watch our latest Speaking of Science webinar as both professors talk about their groundbreaking projects, and how their research programs have taken significant strides towards promising new pathways for brain cancer treatment.

• Professor Misty Jenkins AO: 'Novel immunotherapy approaches to treating brain cancer.'
• Professor Matt Dun: 'Running Toward a Cure: Science, Loss, and the Fight Against DIPG.'

Recorded on Tuesday 16 July 2025 from 1:00 pm – 2:15 pm AEST.

Video transcript

0:13 Professor Steve Wesselingh
OK. I think we might start.

I think there's probably still a few people joining us, but it has gone past 1:00 and I think it would be good to get started because we have two fantastic speakers and we want to give them every bit of time for their talks and also for a question and answers.

I'm Steve Wesselingh, I'm the CEO of NHMRC and welcome to another instalment of the NHMRC Speaking of Science series, where we host some of the best Australian researchers and they talk to us about the issues, the breakthroughs and the innovations across the research spectrum. Really pleased that so many of us, so many of you could join us here today.

I'd like to begin by acknowledging the traditional custodians of the land on which I am today, the Ngunnawal people, and pay my respects to elders past, present and emerging. I'd also like to extend acknowledgement to all of the traditional owners of the lands where all of you are working today, and all of the First Nations people present involved in the webinar today.

Really important acknowledgement to make before we get started, bit of housekeeping. We do want to have questions and answers at the end, so please use the Teams chat to put up your questions so we can start the discussion at the end of the presentations.

Just want to emphasise that if you want to watch it again or you can't watch the whole thing or you want to watch past ones, they're all on the website and so you can rewatch them.

Lastly, but very importantly, please keep your microphones off throughout the presentation so we don't get any feedback.

2:11 Professor Steve Wesselingh
Around 2,000 Australians are diagnosed with brain cancer every year and in the past 30 years, brain cancer survival rates have only improved by 1%.

In fact, on average, only 2 in 10 people diagnosed with brain cancer will survive more than 5 years. So, this is clearly an area that needs a lot of work, a lot of innovation and some really smart medical researchers and today I think we're really lucky to hear from 2 Australian health and medical researchers who really have dedicated their careers to this problem, this area of truly unmet need.

We have 2 of the, the most outstanding young, and I think I can use the word young, I hope Matt and Misty, but young medical researchers and you know, obviously I've met both of them and they really are outstanding.

Professor Matt Dunn is Chair in Medical Sciences and Professor of Paediatric Hematology, Oncology Research at the University of Newcastle. A recognised leader in paediatric cancer research, he serves as Director of the Brain Cancer Research within the Hunter Medical Research Institute's Precision Medicine Research Program. That's a long title and leads the Paediatric stream of the Mark Hughes Foundation Centre for Brain Cancer Research.

Matt is also the founder and director of Run DIPGA, a not-for-profit charity dedicated to raising awareness and accelerating research into childhood brain cancer.
Matt leads several major research programs, and his research underpins the international Adaptive clinical trial for TMG, which is driving the development and clinical translation of novel therapeutic strategies for DIPG.

Just moving on to Misty now. Professor Misty Jenkins AO is the Laboratory Head in the Personalised Oncology Division at WEHI. She leads the Immunotherapy Program and serves as a Co-Director of Research Strategy at the Brain Cancer Centre.

Misty's research focus on discovering. Misty's research focuses, sorry on discovering novel immunotherapy targets and developing CAR T cell therapies for adult and paediatric brain cancer. Her team utilises cutting-edge 2 photon microscopy combined with mouse models to investigate the tumour microenvironment, uncovering unique aspects of brain tumour biology.

In 2023, she was appointed an Officer of the Order of Australia for distinguished service to medical science and immunology, the advancement of women in STEMM and contributions to the Indigenous community.

It really is truly a great pleasure to have both of you here today, and I'm going to ask Misty to kick off and then followed by Matt. Misty's presentation is titled 'Novel Immunotherapy Approaches to Treating Brain Cancer'.

Thanks so much Misty.

5:40 Professor Misty Jenkins AO
Thank you so much, Steve, for that really lovely introduction.

And you know, and I agree, you know, talking about brain cancer today that the dial hasn't shifted in decades. And you know, for most patients, the best advice that doctors can still give, unfortunately, is to go home and make memories.

And, you know, we're absolutely united in the fact that this is not good enough. But I think we do have an opportunity to invest in science at the same time, invest in lives and stop brain cancer being the death sentence it currently is.

But I do use the word investment intentionally. I think we can solve this problem like we've seen the dial shift on many other cancer types and end brain cancer is a terminal illness. But it's going to take people and capital.

Are my slides coming through OK, Steve? Fantastic. Ok, yeah.

6:26 Professor Steve Wesselingh
Looks good.

6:27 Professor Misty Jenkins AO
Thank you.

So, I'm a Gunditjmara ex woman from western Victoria, and so I grew up on Wadawurrung country, but now live, work and play on beautiful unseeded Wurundjeri Country here in Naarm.

I want to acknowledge and pay my respects to our elders, past and present, and extend that acknowledgement to all you Mob who might be joining us today.
The problem that the reason, one of the reasons that brain cancer is so challenging is its location. By nature, it infiltrates your brain. You know, unlike other cancers where surgeons can easily go in and take big margins, this is not possible in a place like the brain.

It's also, it's very infiltrative. It's electrically active, it's talking to neurons and so this is a real image of a glioblastoma growing in this mouse brain where you can see all the blood vessels are in yellow and the tumour is in pink.

I hope what you can appreciate here is much like throwing a handful of black sand onto a white beach, it's almost impossible to pick out all those black granules, you know, of sand. It's really challenging for our neurosurgeons and it's also really challenging to design treatments which kill the tumour but leave the healthy cells unharmed.

And so, you know, our brains have also evolved to keep us safe from toxins and disease and it is sort of protected by a blood brain barrier. In fact, a lot of drugs are actually screened not to get into enacting our brains and so consequentially, there's been no new treatments really in decades.

We're still treating patients the same way we did back in the 1990s for adults. In kids, it's actually an even more dire situation. But I think that there is hope. In adults, as Steve said, the average survival is about 14 months.

But actually, in children, it's even worse and I'll leave Matt to introduce this particular devastating tumour because he has a personal experience. But DIPG grows in the brain stem and your brain stem controls your breathing and your swallowing. Therefore, it's impossible to surgically remove and chemo and radiation doesn't work. We can't talk about 5-year survival rates in childhood cancer. We need to talk about going for cure.

This is just really to point out that other survival rates for brain cancer remain low, prognosis has been really stagnant and when you look at, even sort of this in the orange here from the 1970s through to the 2020s, the progress that has been made in other tumours and yet paediatric brain cancer remains stagnant. In fact, Neil Armstrong's daughter died of a DMG in the 60s and we're still treating patients the same way. It's clearly not good enough and new treatments are urgently required.

But I think, you know, there is hope. Imagine this for a moment that you know, your loved one is diagnosed with brain cancer and within a mere couple of weeks, a personalised therapy tailored specifically for your tumour is ready for action and that's the really the future we're envisaging, and I think it is within our grasp and certainly hopefully in my lifetime.

When we think of the immune system, we often think of blood cells rushing to heal or cuts and fight off a cold. Here's a video of them doing just that, where this is an orange T cell, the kind of specialised white blood cell that zooms around your body and your blood and your lymph and your tissue attaching to this blue cancer cell.

When they're doing their job, they're incredibly effective and with laser like precision are able to throw their bullets at the enemy shown here. The bullets shown here in red are this arsenal of toxic packages or grands arms and perforin and thrown at this target to essentially reduce apoptosis or programmed cell death of the target.

This kind of approach has been really instrumental in designing new treatments for brain cancer and because our T cells, unlike a lot of other drugs and molecules, actually can cross the blood brain barrier and can get in there.
We're also now in updated new clinical trials happening around the world, delivering the cells directly into the brain, into the ventricles, enabling us to really deliver the therapy exactly to the site where it's needed.

This is just a little video taken down the microscope of live T cells entering this pink tumour here and really doing their job quite effectively. We know that we can design these T cells to recognise brain tumours actually pretty well. So why doesn't it happen just normally in our body?

Brain cancers have this invisibility cloak on them, if you like, where it's really difficult and challenging for our own endogenous immune system to recognise, seek and destroy these brain tumours. But we can actually engineer them and take off that invisibility cloak and engineer our T cells to recognise these tumours and we do this using CAR T chimeric antigen receptor T cell therapy.

Just a fun little cartoon, but essentially this is what it would look like for the patient. This is a chimeric antigen receptor here in the schematic shown on the right-hand side of the screen, whereby an antibody binder, it's a very modular receptor, takes all the best signalling bits of a T cell receptor and essentially pieces them together to have this immune form and a new immune sensor called a CAR.

After a patient is diagnosed, essentially what this would look like for a patient is that their blood or their T cells are harvested, expanded. They're then given the right CAR to the right key that fits the lock of their particular brain tumour that they have. Those T cells are turned into CAR T cells. Those CAR T cells are then grown up into large amounts in wave reactors in clean rooms at the couple of manufacturing sites we have around the country. They're then able to be infused back into the patient to recognise and destroy the brain cancer.

This kind of approach has been really successful for blood cancers and this is Emily Whitehead, who was the first paediatric patient treated for her refractory acute lymphoblastic leukaemia. She is now, she actually made medical history at the time and she's now completely cancer free and off to university. There've been 7 products now FDA approved mostly for blood cancers, but not solid cancer.

When thinking about taking the success story of patients like Emily and applying it to our kids with paediatric brain cancer, we know that we can make the CAR T cells really potent and they can get in there and do and do their job. But we need to be able to equip them with the right keys to fit the right to fit the lock.

How does this really work in reality? Well actually the recent studies have shown that we have seen some long-term cures for DMG and improvements to quality of life. This is just a recently published clinical trial of a group of patients with that brain stem tumour, diffuse midline glioma.

Actually prior to one CAR T cell infusion, this a teenage patient here, you can see they're really struggling with their gait and 2 weeks after one T cell infusion, he was able to walk very well, and he is now actually more than 3 years completely cancer free. It's really quite remarkable for this really insidious and intractable disease. We're seeing some signs of hope, but of course not all patients on this trial.

I'm struggling with my slides. There's a bit of a delay.

This is just a swimmer plot from that particular trial and this patient, the patient 10 here, second from the bottom is the video that I just showed you. Each of these black little lines is when those patients received their CAR T cell dose and I think that's the other thing that's really changing for brain cancer that's different to other kinds of cancers is that these patients are being dosed at monthly intervals directly into their brain via this little device here called an Ommaya reservoir and there are others similar to it. But essentially this can mean patients aren't having to go through harsh radiation and chemo. They can come in as an outpatient once a month and receive their dose.

But there were clearly patients here that didn't have a remarkable outcome to the treatment. This is the next big challenge in the field is why those patients failed the trial and how the trial failed them, why the trial failed them, I should say, and how we can predict that better and make better treatments.

The tricky thing about brain cancers, like a lot of other solid tumours, is that it's also really heterogeneous, much like a handful of sorts of coloured jellybeans. If we design a therapy just to the red one, the blue ones are going to grow out and so we need to be able to target multiple facets of the cancer simultaneously. Really combination therapies are going to be key here.

You can see really just this has only really just exploded in the last 5 years whereby CAR T cell trials have been run against single protein targets expressed at the surface of the cancer cells.

In more recent times, I think as we seek clinical impact, these CAR T cell therapies going into the clinic increasing in complexity, whereby the field now is targeting more than one antigen, recognising that monotherapies are not going to solve the problem of brain cancer, but also armouring them and giving making the T cells using the fact that it's a personalised living therapy that is also able to then secrete antibodies and drugs into the tumour microenvironment directly. I think this is a really exciting space in terms of genetic engineering.

This is one example of that where this team led by Marcella Mouse and Brian Choi, treated a cohort of patients with a CAR T cell recognising a cell surface truncated protein of EGFR, EGFRvIII. That the T cell also locally secreted a biospecific antibody or a bite or here called a team because Amgen copyrighted it into the microenvironment here and so you can actually then pull other endogenous T cells into direct contact with the tumour cells themselves.

There are still many challenges to overcome in this space. We are seeing patients, some tumours being resistant to these sorts of therapies. Tumours themselves as I said are very heterogeneous. We have a really complex tumour microenvironment with that that is a sort of immunologically cold and immunosuppressive place for these therapies to work and a lot of natural immunosuppression.

To overcome this, we've created this pipeline here whereby in my lab, we are taking brain tumours directly from the operating room through the generous donation from patients and their families and are using cell surface proteomics and mass spectrometry to map the surface of these tumours.

Then this enables us to identify what CAR targets and other drug targets that might be at the cell surface of these tumour cells. We then have really great methods for making the antibodies, engineering them into the right CAR key and all of the in vitro and in vivo models now established to test them and now ready to take our first assets into the clinic.

Essentially this is me in the operating room where this neurosurgeon here is removing a glioblastoma from this young man's brain. Just as a big thank you to the patients, families, neurosurgeons, clinical team and bio banks. It really does take a huge amount of infrastructure and a real village, a team of people to enable these workflows to happen.

This is just a slide to show that the pipeline we've established works really well and is robust. This is our mouse neurosurgeon here, Melinda, who's implanting brain tumours into the brains of these mice. We've developed a CAR T cell. This one example I'm showing you here is recognizing EGFRVIII. We can map the epitope binding domains of the binders and have curative models here now whereby we can cure completely see totally tumour responses in these mice.

As I said, we now have several assets in which this is the case and so this is just another of a therapy targeting a cell surface expressed protein called EphA3. EphA3 is really highly expressed in glioma both in adults and in kids as well and it also actually lines the blood vessels of these brain tumours.

We get a bit of a double bang for our buck here because we're melting the tumours from within these CAR T cells and it's expressed on the tumour cells themselves and so in green here, you've got a cohort of mice that have never seen tumour, just to show you where the baseline luminescence is here. This isn't looking at in vivo, these tumours growing over time and hopefully you can appreciate here in red, we had a complete tumour regression here by about 3 weeks and 100% survival of our mice.

In fact, these mice were running around on the shelf very happy eating their rice bubbles and we asked the question whether or not they could protect against the secondary tumour challenge and I'm not showing the data today, but the answer was yes. Very potent T cells, very potent responses.

In fact, sorry, I am showing it to you. This is the memory response here. We rechallenged the mice with an age match control cohort and those memory CAR T cells. They weren't treated with any other therapy. The memory CAR T cells were also able to clear that secondary tumour.

Now I've told you at the start that these CAR receptors themselves by nature are modular and so they are comprised of a number of different components and each of these different individual components actually plays a really important role in the function of the receptor itself.

As we as we start to appreciate the different binders with different affinities, the different lengths of this linker region here, the different choice of transmembrane domain and how this protein sort of sits in the membrane that can be a monomer, a dimer or a trimer which influences how it signals the choice of cosignalling domain. As you can see, there's a lot of complexity that can be potentially built into these receptors and so it can be really difficult to then be able to test these 1 by 1.

Essentially we've designed, I'm not going to go into too much detail about this in today's talk, but essentially large library screens where we can take all of the complexity of all of the different signalling domains combined with a variety of different antibody binders to the protein target of interest and design large library screens to test them.

Very, very simply, this is how it works. We create a large library pool of plasmids, which we then make virus infect the CAR T cells within co culture the CAR T library with our tumour cells and we can then screen for the CAR T cells that have activated and had functional CAR receptors and then read out through nanopore DNA sequencing.

In fact, we've got this is real data here in this little purple circle showing our library input here and the numbers of clones and the numbers of positive clones we pull out at the other end. This has been a really robust technology for us to be able to screen virtually thousands of CARs simultaneously with the view and the aim here, as I said, that a monotherapy is not going to cure brain cancer. We need to be able to combine them in a rational and really meaningful way.

In the interest of time, I'm just going to skip forward because I think I've made my point on that one. Really just one final piece of data here just to show you that the combination CAR T cells are more potent than monotherapy and we know that when we combine CAR T cells that recognise several protein targets simultaneously, we see much better responses both in vitro and also in vivo.

Now, the data I've just showed you before though, is all in an immunocompromised mouse because we're looking at human CAR T cell responses to human tumours. However, to really recapitulate, and this is why a lot of clinical trials fail because we can see really good responses in mice, but then really not tested in models that recapitulate well the human disease and so this is a real problem not just for the brain cancer field, but for all preclinical scientists working in in cancer.

Efforts are being made to test to test these models in syngeneic, mouse models that really recapitulate the tumour, but also in particularly in the case of paediatric tumours, testing them in age-appropriate models and we know from the work of people like Riley and Andersby and others that this is a really important characteristic of the disease as well. We know that these tumours grow faster in baby mice compared to adult mice, for example. Making sure that we're testing in syngeneic models that that are also age appropriate for the kinds of cancers that we're looking at is really, really important.

Monotherapies are not going to cure brain cancer. We need to combine them in a rational way. But how do we do this in an affordable way without running large scale clinical trials for every single asset that we have, which is going to be long, expensive and very resource intensive.

Really what we're moving to now is to try and build a national framework for agile translation such that we can take our CAR T cell therapy products and in combination with other drugs, checkpoint antibodies, small molecule inhibitors for example, and be able to test them in as CTN enabling clean room environment in Australia. There are some examples of these sort of decentralised model popping up now in Australia and particularly for these rare cancers which haven't seen large commercial and industry investment in Australia, particularly because of the small patient population sizes.

These are really lethal, awful, awful cancers. But because we're still dealing with small numbers of patients, we need to think outside the box and how we translate them in Australia. I would argue really strongly, we need to be taking advantage of our regulatory landscape. We have in Australia here where we can run CTN enabled clinical trials through our TGA network. This is really what we're doing.

Michael Brown's a fabulous example of this in Adelaide where they’re manufacturing CARI, and definitely checkpoint block hide as well and other modulators of the tumour microenvironment. I've mentioned briefly at the start around the advances being made in genetic engineering and synthetic biology. We have this incredible synthetic biology toolbox now that we have access to in terms of souping up and arming our CAR T cells and enabling them to secrete other factors and drugs directly into the environment where they need to act, which I think is really powerful.

I think we're really just scratching the surface on what's possible in this space and particularly in brain cancer now where we are changing that route of delivery and we can deliver these therapies directly into the brain.

Happy to answer any questions about that, but I will leave that there. That's my 25 minutes up.

I just want to acknowledge my incredible team that do all the work. These are really large, large experiments to do these mouse models with 90 mice in a cohort, they're large, expensive experiments. My collaborators are extraordinary. My clinical collaborators, all the primary tissue has enabled us to identify new targets over the years. We couldn't have done that without you and the patients and your families.

I've been very gratefully supported by NHMRC. So, thank you, Steve, and your entire team and your crew over the years. We're very lucky to have you all.

I want to acknowledge my funders here again, I started my lab as an immunologist and I started my lab, did my PhD with Peter Doherty and Steve Turner many years ago and was with Joe Trepani at Peter Mac. Then when I made the move to WEHI, Doug Hilton said, go and do great science and that was a time when I had a girlfriend who was a neurosurgeon who said, Misty, you need to look at brain cancer because I'm sick of telling my patients they're going to die.

It was just the catalyst I needed to start going down that PubMed rabbit hole and realising that we could really make an impact here and make a difference. There was just such a small number of amazing labs in Australia working on brain cancer and I think we've seen that grow in the last 5 years, which is fantastic because we need more of us trying to tackle these complex problems.

I'm really grateful to have the Brain Cancer Centre and these foundations here that have supported that work and supported my lab at a time when I was making a pivot to come and work on brain cancer. Thank you very much.

27:18 Professor Steve Wesselingh
Thanks, Misty. That was absolutely fantastic and so inspiring.

Really, really brilliant.

We’ve got to move from Misty, and we will hold questions until the end, but we're going to move now to Matt.

Hopefully Matt's still there. Good.

I introduced Matt Dun earlier, and Matt's going to give us a talk titled 'Running towards a Cure: Science Loss and the Fight Against DIPG'.

Thanks so much, Matt.

27:51 Professor Matt Dun
Thanks, Steve, and thanks Misty for a fantastic presentation.

My presentation is coming. It's indicating that we're having some difficulty loading. Here we go.

Thanks, and thanks for the invitation to be here. It's indeed an honour to share the stage with Misty and an exciting time, as you can see from Misty's work for the development of new strategies towards these devastating tumours.

I'll start with some disclaimers. Of course, as many would know, I entered the DIPG research world after the diagnosis of my daughter of DIPG on the 17th of February 2018 and prior to that I was an NHMRC and Cancer Institute NSW supported leukemia researcher. When Josie was diagnosed, I kind of had all of the tools needed in my lab. I just needed some cells to grow and some data to start generating and Misty presented some beautiful data from the initial CAR T therapy trials using GD2 from Professor Michelle Monji at Stanford. She was in fact the first DIPG person I spoke to after Josie's diagnosis, and she sent 8 of her DIPG models to my lab within 2 weeks of diagnosis.

We were growing those cells to try and find an option to treat Josie, and you can see Josie here about 6 months prior to diagnosis.

29:15 Professor Misty Jenkins AO
Matt, the last slide just did not come through.

29:17 Professor Matt Dun
Can you not hear me?

29:19 Professor Steve Wesselingh
Yeah, we can hear you, but we can't see the slides.

29:21 Professor Matt Dun
Oh, really? Why is that?

29:24 Professor Steve Wesselingh
Maybe bring them back.

Yeah. Try again.

29:32 Professor Misty Jenkins AO
I think we've lost him now. Hopefully he'll come back.

Michelle Monji was also incredibly generous to me when I started my lab and she shared her the DIPG cells, and it was an extraordinary catalyst.

Here he comes now you're on mute.

29:57 Professor Matt Dun
Thank you.

Can you see my slides?

30:00 Professor Steve Wesselingh
Yep.

All good.

30:01 Professor Matt Dun
I'm not sure why they didn't.

30:02 Professor Steve Wesselingh
Perfect.

Well done.

30:03 Professor Matt Dun
This is Josie just 6 months prior to diagnosis. I hope you can see my video and you can see her scooting around our local netball courts, which are about 2 kms from our house. In fact, all of our children have learned to ride bikes and scoot on that netball court, and you can probably see this beautiful eucalyptus tree at the top of your screen on the video and that's now where she's underneath, where she's buried.

This project has received funding from a pharmaceutical partner known as Kazia Therapeutics and as Steve mentioned in his introduction, I'm the founder and director of the nonprofit charity Run DPIG.
Misty gave a great overview of DIPG. But I thought given that we're focused on the blueprint, I would provide a little bit more detail about what DIPG is.

DIPG is diffuse intrinsic pontine glioma and in 2020 was also given the name diffuse midline glioma, which encompasses tumours that are diagnosed along the midline structures of the central nervous system. DIPG really is a set of diseases that's uniquely restricted to the pontine region, and you can see in these, Josie MRIs throughout her journey that the tumour is located within the brainstem here, which is represented by this cloud of cells that's taking up contrast and enhancement and really progresses throughout her journey.

The median overall survival for kids with DIPG is only less than 12 months and there's no long-term survivors for this disease. Two years survival is less than 10% and less than 1% of patients will live 5 years. It's most typically seen in kids at the age of 6 and 7. But there's also adolescents and young adults that are more frequently being diagnosed than in Australia. Off the top of my head, I can name about 6 or 7, 21- to 24-year-olds with DIPG around Australia. Remarkable young Australians that are also given no treatment options.

Why is it so devastating and lethal? Well, it originates in the brainstem as I mentioned in the brainstem is responsible for much of our autonomic responses. Many things that we don't think about, so things we don't think about a heart rate, swallowing and breathing. When you have a tumour that's rapidly growing throughout this this critical region, you can understand why it has such fatal consequences.

The only treatment that's been developed that's approved for therapy outside of clinical trials and in Australia, we've mandated that we want to have clinical trials as standard of care. Radiotherapy is the only recognised treatment and for the young kids like JoJo, these kids require a general prior to every dose of radiotherapy and at the moment we give 54 grey of radiotherapy spread over 6 weeks. So, you can imagine how difficult that is for a young person to receive 30 consecutive doses of general anaesthetics followed by stereotactic guided radiotherapy.

As Misty mentioned, the DIPG was diagnosed in Captain Neil Armstrong's daughter Karen or also affectionately known as Muffy in 1962 and she passed away just 6 months after diagnosis and was given the same treatment that Josie was received, 54 Gray of palliative radiotherapy.

Josie was diagnosed just prior to her third birthday also too, and I kind of think about my journey in a in a serendipitous light throughout many of the things that happened. I was recently invited to the University of Cincinnati to give a talk and as I was driving into Cincinnati with a great colleague, Tim Phoenix, who makes much of our syngeneic models that Misty spoke about, he pointed it out to the right as we were coming from Ann Harbor in Michigan at another meeting. He said, well, that's where Neil Armstrong grew up and then I Googled this later and found out that Neil actually becomes the Professor of Aerospace Engineering after he retired from NASA in 1971.

Look, it's been something I've reflected on more lately because of, I suppose, so many changes that have been made in paediatric cancer treatment since the 60s when Neil walked on the moon. Neil made a giant leap for mankind, but kind of didn't make any movements towards improved outcomes for kids like his daughter Muffy or like Josie.

If he had used his notoriety and fame to advocate for research into DIPG back in the 60s, then potentially families like mine would have been given the tools that they needed to have long term survival.

It's a bit of perspective, but I suppose since Josie's diagnosis and given the courage of so many Australian families and the advocates that are associated with run DIPG, we've kind of advocated for improved investment from the NHMRC and MRFF and this has been championed by the Health Minister, Mark Butler, and we're finally starting to receive some of the building blocks that we need to build the infrastructures that we need to change the outcomes.

It's delightful to see the pipelines that Misty's generating and I'm really hoping that all of this new investment and continued investment will mean that we will have personalised CAR T therapies for every patient with a high-grade glioma in the not-too-distant future. I'm with you, Misty, I'll backing you 100%.

Let's focus on the challenges just for a moment while we look towards the opportunities. Surgical resection is not an option for these tumours. These tumours grow diffusely, and they infiltrate the brain stem. They hijack the delicate architecture, and they invade the critical structures that are needed for survival. Attempting to remove these tumours would cause catastrophic damage to the very parts of the body that we need for survival.

The tumour is made-up of many different cells, and some of these cells will respond to radiation treatment or targeted therapies and many won't, so it makes it really hard to find a single therapeutic and Misty mentioned combination strategy. Not just combination CAR T, but also combination systemic therapy, radiation therapy, immune therapy. These are all necessary as part of the jigsaw of treatment that we need to develop.

Now studies using patient biopsies, mostly led by Maryla Philbin at the Dana Farber Cancer Centre has shown that these cells are made-up a mix of a cell type. Although most of them are DMG cells and they also have other brain resident immune cells within the tumour, they kind of reside in different states. Some of the tumour will be pro proliferative or migratory and mesenchymal like where others will be dormant and stationary and quiescent. But the major pool of these cells, proliferative oligodendrocyte precursor cells or OPC black cells.

This is really important because we need to understand the cell of origin of these diseases because it gives us critical insights of how this tumour starts, how it spreads, and most importantly how we're going to fight it.

The mutations that give rise DMG occur in oligodendrocyte precursor cells in the brain, and these cells are naturally active and very adaptable. OPC cells are responsible for forming the myelin that protect and coat the neurons that give rise to all of the neurons and nerves of the brain and the central nervous system, and they also respond to brain injury and infection.

When things go wrong in the brain, OPC send out signals that encourage immune cells to migrate to the brain and to help repair the damage that's being caused and so together with their more mature oligodendrocytes, which you can see in the middle of your screen, the OPCs sit at the crossroads of protection, immunity and repair. This explains in some degree the complex immune environment we see in DMG, where more importantly, it gives us a critical opportunity that we can harness the power of these OPC cells to turn against themselves, to turn them into a more beneficial response to treatment for the patient rather than being totally malignant.

I suppose Misty also mentioned this quite beautifully, is that we face this huge challenge of the blood brain barrier as the brain is protected by a coating of cells that is a living network of vessels that stop molecules from getting into the brain. I don't exactly know how T cells get across the BBB and need to have a workshop with Misty of how that happens. But indeed, it does stop things getting into the brain. You know, we don't need infection in the brain, and we don't want large molecules to get in there that it can damage the brain. It's a dynamic layer of protection that we really need to address if we're going to really improve the treatment of DIPG and other high-grade gliomas.

Now if we turn to look at how DMGs interact with the immune system, if you look at untreated tumours, these are what we call immunologically cold. That means that they don't naturally attract cells, immune cells into the brain and they actually somehow avoid detection by the immune system. I'll go into a little bit more detail of how this happened shortly, but we've done a lot of work in this regard in my group and we've kind of identified a number of really important features that we think we can harness and reverse. I hope by doing that we can encourage the therapies that Misty is developing to work even better than they do in her models, but particularly in patients.

If I turn to the genetics, and this is important for the disease because remarkably, DMGs are caused by a change and a mutation in a protein called a histone protein and this is a key part of the machinery that controls how the DNA within the oligodendrocyte precursor cells is packaged and read. These changes were only discovered in 2012 by research teams in North America and we're fortunate in Australia that one of our own clinician scientists at the Royal Children's Hospital, Doctor Dong-Anh Khuong-Quang, was working in the group of Cynthia Hawkins at the time in Toronto at the Hospital for Sick Kids and she was part of the team that also discovered this mutation.

We only discovered the mutation in 2012. We only discovered the cell of origin. We got some indications in 2018 and confirmed in 2022, which I was part of that work at Dana Farber. We've had a long leading time to develop the targeted strategies that we need and to understand the biology of these tumours that will mean we'll be able to change the outcome of these patients.

When the mutation is caused in this histone protein, you lose a key chemical mark that kind of silences the way that this DNA, which is usually involved in silencing how DNA is unravelled from this core nucleosome and is read by the transcription factors leading to gene transcription. It's quite well articulated in this this plot here on the bottom right of your screen, where you can see the loss of these red peaks means that the DNA is now completely unwound and accessible to transcription factors to mean that you can produce genes that are involved in proliferation, growth, and immune system avoidance.

If you look at these scanning electron microscopy marker graphs, you can see all this white within the nucleolus. Here it's unravelled or heterochromatin DNA, meaning that when a patient has DIPG, the DNA is completely unwound and opened to accruing additional mutations. Not only do we lose this methylation of this core histone protein, but we also lose total DNA methylation. This kind of points to emerging evidence that there's a link between the metabolism of these tumours and the way that the genes and the gene expression profiles of these tumours are regulated.

As I mentioned, as these tumours unfold, the DNA, they accrue mutations throughout the life of the patient and these tumours are always diagnosed at grade 4. Many of the audience here will know that patients diagnosed at grade 4 have little hope of long-term survival. The co-occurring mutations that occur with these histone mutations are always seen in proliferative genes and they're listed here in the top.

We see loss of function mutations in the genes that are the stop signals for growth and proliferation, and these are tumour suppressor genes here. These tumours evolved throughout patient's journey, and this is actually Josie's genomic architecture where she accrued this histomutation and acquired PR3 kinase mutation and it evolved throughout her journey of treatment from diagnosis to death.

Now finally, the key limitation and challenge that we face that I'm articulating today, and it was alluded to by Misty as well, but patients at diagnosis are immunologically suppressed in some way, there's some kind of crosstalk between the tumour and the patient's systemic immune system that means that the cancer fighting T cells that Misty uses to treat the tumours are suppressed in patients’ blood and diagnosis. We observed this number of years ago working with researchers from the Princess Maxima Pediatric Hospital in the Netherlands and this was also published last year that also showed that patients with DIPG had lower levels of lymphocytes and CD 4 CD 8 T cells within their bloods of diagnosis.

Because of all of these factors, you know, the tumours are driven by many different mutations. They're diagnosed at very late stages. No immune cells are allowed into the tumour. They're diagnosed and delicate structure to the brain. No single drug is really likely to provide a long-term survival benefit and so we need more comprehensive strategies.

I want to take you back to the moment when Josie was diagnosed in 2018 and at the time, there was this growing hype around a small molecule therapy that got into the brain called ONC201 and it's part of this new class of drugs called omiprodones. It had been discovered through a drug screen that looked for compounds capable of killing cancer cells even when they had a mutation or a loss of a key tumour suppressor gene called TB 53.

Now the drug was repositioned for treatment because a PhD student was working on this drug and looked at the original German patent and show that it got into the brain and so he looked for a disease that was characterized by P 53 mutations and so for patients with relapsed refractory glioblastoma who often harbor TP 53 mutations, they started phase 1 and phase 2 safety and tolerability studies using this new drug called ONC201.

The trial was a complete failure. The median overall survival didn't move whatsoever. There were no long-term survivalists except for this one, 22-year-old patient. Back then she was diagnosed with a thalamic glioblastoma, which would now be called a diffuse midline glioma because she harboured the mutation that all DIPG and DMG patients have this histone mutation which is known as H3K27M.

She experienced a near clear objective response which extended for almost 3 years receiving weekly dosing, one capsule per week. Now the nice thing about this study, I suppose at the time was that they did some pretreatment, preresection biopsy treatments and so we were able to assess how much of the drug was getting into the tumour, which is kind of underpinned how much of the drug we need to inform future clinical trials.

This encouraged a large-scale clinical trial in patients uniquely with the DIPG or DMG. Harbouring the H3K27 histone mutation that was open in North America when Josie was diagnosed and at the time, nobody actually knew how the drug was working whatsoever.

I wrote to the company and asked for access to the drug, and they sent me the drug and we tested it in the lab and lots of this work was done by a talented postdoc in my lab, Ryan Duchatel at the time who studied how the drug was working and whether it showed any benefit at all in DIPG, which is really the first preclinical work that was done on the drug at the time.

Remarkably at the same time, a mother from of a 8-year-old DIPG patient from Portugal sent me an e-mail and said to me that she had just purchased this drug from a German oncologist. They made contact in Frankfurt, and he requested the scans of her son Pedro. She sent them and then she was invited for an appointment, and he wrote a prescription for this drug ONC201, which she took the prescription down the road to a local pharmacy and bought the capsules over the counter.

She contacted me and said, Matt, I've just bought this capsule of ONC201, I know that you're working on it. Can I send you a capsule and can you tell me what's in it?

We collaborated with a fantastic chemist at UNSW to do NMR spectroscopy to make sure that it was the right structure. We did formulation science, and we did all the basic preclinical studies to prove that the drug was almost identical to the drug used in clinical trials and that was in 2018 and 2019. Over the next couple of years, word got out that we were testing the drug. Then we've shown that it was somewhat real to the drug used on clinical trials and European clinicians were caring for many kids throughout Europe because they had no other options and families were buying this drug from this pharmacy after an appointment with the German oncologist.

They were getting it because Germany holds a unique compassionate access law called the Healing Act, which allows doctors to prescribe lifesaving medicines if they can access them and even when they're not fully approved and so we collected the data on 28 considered families of patients that had bought German ONC201 and showed that these patients lived on average for about an additional 6 months.

Still during this time, we still didn't really know how the drug was working and so we started an Honors project with this very talented young lady, Doctor Evie Jackson, who did her Honors and PhD. Her Honors project was done throughout Josie's journey and continued on after she passed away and she's published some fantastic work to really identify ONC201 which is now called dordaviprone and has received FDA rare disease indication for DIPG works.

Our work and others identified during this time identified a key vulnerability in this tumour, that these tumours are highly dependent on a protein that's within the energy powerhouse of the cell called the mitochondria, a protein called CLPP and when activated, this protein helps breakdown damaged proteins and manages cellular stress.

When a patient takes ONC201, which is now going to dordaviprone, it works by targeting this exact vulnerability. It activates this CLP protein to toxic levels, which overwhelms the cell's ability to cope, ultimately leading to cell death.

We know this because when we use CRISPR CAS 9 mediated genetic deployment in DMG cells that are normally sensitive to the drug, we knock out the CLPP protein, the drug no longer works whatsoever. It's a clear indication that CLPP is actually the cellular target in the drug and how it works in these tumours.

Even more encouraging is that if you look at the amount of CLPP that makes up a tumour, the sensitivity to ONC201 or dordaviprone is directly related in a linear way to the amount of CLPP you need. We're trying to determine whether we can turn this into a biomarker of response to the drug, but that's a work in progress.

We were looking closely at how DMC cells responded to ONC201 because we realised that as Misty indicated, no single therapy would provide much of about for long. We performed a lot of analysis of tumours exposed to the drug and what we saw was that although even in cells that didn't respond very well to the drug, we saw an up regulation of a pathway that kind of triggered a change in the way that these cells were generating energy away from mitochondria to a less efficient way of producing energy that does not require oxygen and that's a glycolytic pathway or the Wahlberg effect, which is well characterised in cancer cells. When it does this, it up regulates ways that these tumours can evade the stress that's caused by the drug.

When this drug is taken by patients, the drug caused a huge amount of stress within the tumour and a lot of things leaked from the mitochondria mostly known as unstable molecules called reactive oxygen species and the tumours can up regulate any oxygen processes which mean that the reactive oxygen species which usually causes cytotoxic DNA damage is repaired or is dampened and this upregulates an alternative growth in survival signalling pathway called the PI3 kinase pathway.

This is kind of a serendipitous moment because this was happening in real time because when we received Josie's diagnosis and her biopsy as part of the Zero Childhood Cancer Program, of course, she had the histone mutation which caused the disease, but she'd acquired additional and several other mutations in the PI3 kinase pathway. We were working on a drug in real time to try and address the one of the mutations that was driving the malignant growth of her tumour.

Pretty soon after we received her Zero PRISM Report, I identified a new drug for DIPG called Paxalisib which was in clinical trials for adults with glioblastoma at the time to determine safety, tolerability and dose finding studies. I wrote to the company and said, look, my daughter has a DIPG, you've got a drug that gets into the brain and targets PI3 kinase, can we test it in our lab?

This work done by Ryan Duchatel and Evie Jackson in the lab tested basically how sensitive DIPG cells were compared to other high-grade gliomas and normal cells and showed that DIPG cells were about twice as sensitive to the drug as normal cells.

We were expecting to get some kind of genomic influence or biomarker of response. Were DIPG cells that had PI3 kinase mutations more sensitive? And in fact, they weren't. All the DIPG cells were sensitive to the drug.

We collaborated with Jason Kane and Ron Vistone from the Hudson Institute who are performing DMG CRISPR deletion strategies across 38 different DIPG patient drive cell line models and what they were able to show is that all cells require the expression and activity of the PI3 kinase pathway to grow. We did some more targeted validation using CRISPR, again using patient cells that grow in the lab that don't necessarily have mutations in PI3 kinase, and we were able to confirm that if you knockout PI3 kinase or PCA in this instance, the cells don't grow at all.

A lot of this work underpinned a phase one clinical trial for Paxalisib that was run out of Saint Jude Children's Hospital with Chris Tinkel and led to Paxalisib gaining FDA rare disease designation for DIPG in 2020.

The take home message was we couldn't get the drug for Josie on compassionate access and the clinical trial testing ONC201 was only open in North America. I was now part of this group that were running this clinical trial, and the clinician of the trial had a patient that was on the ONC201 clinical trial, and she had failed therapies approximately 12 months after diagnosis and asked me whether I would help him get compassionate access to Paxalisib to combine this patient.

We did, very generous in giving us compassionate access that time and when she started to receive the combination here, she had a dramatic tumour regression when coupled with rear radiation. She had more of a regression of the tumour at advanced stages than she did at diagnosis and this extended for approximately 6 months where she learned to walk again and return to school. Then she passed away from an unrelated pneumonia, which we think it's got something to do with the systemic lymphopenia that these patients have at diagnosis.

Now the first patient to receive this combination at diagnosis was a 6-year-old from Sydney and she had remarkably similar mutations to Josie, changes in the PI3 kinase pathway and this histone mutation that's seen in younger patients. She received the therapies about 6 weeks after the completion of radiotherapy, where the combination of therapy stabilised the growth of the tumour and led to a dramatic reduction in tumour volume, which extended for months and months. This patient passed away 4.2 years after diagnosis recently.

But throughout her journey, it kind of got me thinking that these responses can't be just because of the drug combination effect alone. There has to be some other systemic effect going on because often patients were seeing these weird immunologically related side effects. Often when this patient would have an unrelated side effect, she'd get a hypersensitivity reaction and rash, which would lead to discontinuing therapies and then restarting them later.

Work in the lab, started to really look at the immunomodulatory effects of these drugs both alone and in combination. But much of this data underpinned the clinical trial that we started back in 2021, which continues today, and I put update these numbers, we've now treated 176 patients of 500 in the first 3 arms which are combining Paxalisib and ONC20, which is now known as dordaviprone.

Results indicate that we've had a doubling in 2 years survival for patients that receive the therapies in the upfront setting and if you take away the patients that stopped therapy because of toxicity, this immune related toxicity, 2-year survival has gone from 10% to 32%.

This work started by a talented young student from the Karolinska Institute who moved to Australia for a placement back in 2020 and then quickly had to scurry home because there was a global pandemic in this Swedish consulate, hired a plane and took all Swedish nationals back to Sweden. She went home for a while, and we established a PhD, and she started working in my post doc mentor’s lab in Denmark.

We were looking at how these drugs might modulate the immune system because all of our work to date had used immune compromised models to test these drugs in combination. You can see that the drugs in combination ONC201 and Paxalisib or dordaviprone extend the survival of these NSG mount mice which have no functioning T or B cells by what we call a synergistic amount, but it's not curative, right. It doesn't align with what we were seeing in some patients where we have these traumatic tumour regressions.

She started to ask the question as to what OCT201 do to the tumours directly and what kind of immunological pathways would be up regulated in response to the treatment. And when she did this, she did some surface me analysis where we pop the surface off the cells and we analyse just what's being presented to the outside area of the tumour from treatment with ONC201

What she was able to show is that many of the genes and proteins that are part of this MHC Class 1 antigen presentation pathway were being upregulated and exposed to the surface of these tumours. Even in the lack of an immune system, the tumours were still presenting molecules to the outside area or to the parenchyma or tumour immune microenvironment, even though these tumours had no functioning immune cells.

This is articulated here beautifully by these IHC images which show this protein B2 marker globulin is being presented to the surface and helping this MHC Class 1 antigen presentation pathway present something that we don't really know to the surface and whether that was able to recruit immune cells.

We look at beta 2 mitoglobulin on tumour cells. You can see it's a chaperone that's responsible for taking foreign molecules out from inside a cell and typically it's an infected cell and helping this MHC Class 1 to present these neoantigens to the surface so that we can recruit T cells to the surface and the TCR receptor would bind and then engulf this cancer cell and hopefully lead to regression.

But in patients with melanoma and who see the loss of heterozygosity, meaning the loss of expression of B2M, checkpoint therapies, which have revolutionised the treatment of both primary melanoma and brain metastatic melanoma, completely fail when we lose the expression of beta 2 mitoglobulin, so this really started to get us excited about whether we can encourage an immune response and whether that was driving the response we were seeing in patients.

To do this work, we collaborated with my great friend and colleague Tim Phoenix from Cincinnati to establish his neutron electroporation model of DIPG, which basically takes these plasma DNA plasmids that are the most recurring mutations in DMG, inject them into the foetuses of pregnant mice and the mice are born with DIPG.

Ryan Duchatel established this in our lab a number of years ago and has been the pioneer of all animal studies within my lab. We're super excited to treat these mice with these drugs that show that we were going to cure them.

But we were shocked to see that these drugs no longer did absolutely anything. The survival benefit was completely lost. So that really started to scratch our heads. We added the Paxalisib drug, and we saw this minimal benefit. Again, we saw a synergistic benefit, but it's not representative of what we were seeing in the patient cohort.

I started thinking back to what patients experience. Patients at diagnosis have this lack of T cells within their circulatory system, mostly CD 4 and CD 8 and these are the cancer fighting immune cells. And so, we when we looked in the models that we were generating that had functioning immune systems with the DIPG, indeed we were seeing that these mice were now lacking the residency of these CD 4 and CD 8 T cells within their bloods.

But dordaviprone or OCT201 was able to partially if not completely reverse the lack of T cells in the circulation. When we start to look at the spleens of these mice, which is another area of lymphocyte maturation within the body, a primary source of lymphocytes. We could see in DMG mice that had functioning immune system that these spleens were dramatically smaller than our control, non-tumour bearing mice and that. ONC201 or dordaviprone was able to reverse this, meaning that we were able to get functioning immune cells going again.

We turned to the sophisticated technologies that's taking over NHMRC in the world, which is single cell sequencing to really start to identify what was going on. To do this, we looked in the one of the primary lymphoid organs, the bone marrow, which is a critical area where immune cells reside and mature and also I might add is highly innovative, meaning that signals from the brain talk to the immune system and they're no further innovative in the bone marrow and so we thought we'll look in there and we'll identify what cells were within the bone marrow of these mice that are functioning immune systems.

You can see here in a naive tumour, naive mice or a mouse that has had surgery, but no tumour implanted into the brain stem and the vehicle, meaning these mice have DMGs, we had this huge residency of T cells stuck in the bone marrow. We treat them with dordaviprone or ONC201, this reverses. We treat them with dexamethasone, which is what most patients will get a diagnosis to stem the peritumoral oedema or you know what a patient will experience at diagnosis that mirrors what we see in the vehicle setting. But dordaviprone, it overcomes this what we call a T cell sequestration within the bone marrow.

When we look at the cell populations within the bone marrow, you can see this population here that's marked T cells. There's a number of T cells within a normal bone marrow, but it's not a huge amount. These mice don't have infections. The sham has even less and but when we give a mouse a DMG, they have all of these T cells so sequestered within the bone marrow. You can see it's recapitulated here, DMG mice and a DMG mice treated with treated with steroids and when we treat with dordaviprone, these T cells seem to regress or start trafficking out of the bone marrow. This is articulated here in these violin plots.

When we look at this spatial context, and this is back in the tumour now following treatment, we see that these tumours are pretty invisible to immune cells. But when we treat with ONC201 and we start to up regulate this MHC class to antigen presentation pathway that we saw previously and now that we see that, we start to encourage a recruitment of these CD 8 positive cytotoxic T cells within the tumour, and we see this to a significant level.

However, the, the CD 4 and CD 8 cytotoxic T cells are not necessarily doing their job of fighting off the tumour in these models and potentially they are within some certain patients, and that's why we're seeing a dramatic tumour response.

There’s a lot of work going on in my lab to try and harness those features and I really look forward to working with Misty and trying to use some of these drugs to encourage a T cell maturation event and to get more T cells within the tumour and it's beautiful that Misty was able to show that memory T cells were able to rescue newly engrafted mouse with a DMG. It's showing that there is some immunity and so it really highlights that we need to take a systemic approach of combining therapies that not only harness the immune system but are also orally available and can be given to a patient diagnosis.

Let me bring this all together. DMGS are caused or arise in oligodendrocyte precursor cells, and they all carry this H3 alterations and these lead to uniform fatality of patients. But it also kind of gives us a bit of homogeny across patients where there's a feature of these tumours that's all the same.

The tumours have a number of recurring mutations, but some of them are targetable and the overexpression of CLPP within the mitochondria gives us a starting point to at least commence therapies at diagnosis while we design off the shelf CAR Ts or strategies that might include a number of other therapies.

These tumours are dependent on PI3 kinase for their proliferation. It's very difficult to target this pathway without causing systemic toxicities, and these tumours rely on the mitochondrial energy production. I really feel like if we can take all of these features, we can package it up into centres of excellence around the country to combine our knowledge and our emerging drug targets. We're really going to make great strides into leading to long term survivors for patients for DMG. But there's a lot of work to do.

OK, leads me to thank the remarkable young scientists that work in my lab who are as dedicated as I am to providing options for families. We've been remarkably blessed to be supported by so many families that have navigated similar journeys to my own and this is the young lady that just passed away 4.2 years after diagnosis that received the therapies from my lab in real time.

Of course, I do all this work in memory of Josie, but I do it for my kids to show them that, you know, remarkable things can happen if you work really hard and you're dedicated and you're supported by a fantastic network.

I've definitely been supported by an amazing network both nationally and internationally and so privileged to have fantastic funding from MRFF and NHMRC, remarkable collaborators from national and international organisations and I received a love and support of DIPG families from around the world and together we're moving towards the cure.

I welcome any questions this afternoon. Thank you.

1:05:50 Professor Steve Wesselingh
Thanks so much, Matt.

Another incredibly inspiring talk and just an incredible story.

Thank you so much and for sharing that and you know, I know you share it often, but every time it can't be easy. So, thank you so much.

We're open for questions now and if people would like to put some questions into the chat, then we can put them to Matt and Misty.

I might start with a slightly naive question, but it seemed when both of you were talking and particularly talking about the sort of oligodendrocyte origin of some of these tumours and then we have another disease, multiple sclerosis, where actually you have the opposite problem, too many T cells attacking oligodendrocytes.

I'm just wondering, is there something we can learn from the opposite, from MS, and the immunology and perhaps the therapies of MS?

1:06:55 Professor Matt Dun
Misty I can take this on notice because I often talk about this.

Great work, Steve. One of my talks is called exploiting the cell of origin and so when we stress these tumours, we cause them to subtly differentiate and they start to express MACDLR A1, which is a very similar genetic phenotype to what patients have with multiple sclerosis, which means that you get this recruitment of cytotoxic T cells, which then start to demyelinate and attack the nerves.

In another project, which I haven't talked about today, we're actually using some therapies to do that precisely. We lead to demyelination of the tumour specifically, not necessarily of the remaining brain and parenchyma and we recruit CD 8 positive T cells.

Working with an adult colleague at the Alfred, Doctor Mal Ameratunga, we're trying to start a clinical trial that combines that therapy with a checkpoint inhibitor, try make the T cells sort of get in there, target the tumour more selectively and hopefully eradicate the tumour.

The problem is we haven't been able to get access to the checkpoint inhibitor from the company. So, we're now waiting for nivolumab, which comes off patent next year, so we can buy it hopefully cheaply from a GMP facility in China and to run the clinical trial with MRFF or NHMRC supported funds.

1:08:12 Professor Steve Wesselingh
Thanks, Matt.

Thank you.

Still waiting for questions, so I'll keep going.

Just in terms of the genetics, perhaps to Misty, are the genetics that we're seeing in brain cancer, are they unique or are they replicating genetics that we see in other more peripheral cancers?

Or is it something about the environment that drives a really unique genomic picture?

1:08:38 Professor Misty Jenkins AO
It's a little bit of both, but I'll hand that one to Matt because that's more of his area.

1:08:42 Professor Matt Dun
Yes, so we have unique mutations in DIPG and DMG, particularly histone, but there's also others in bone morphogenic protein signalling.

I kind of feel that these mutations arise because not only of the cell of origin, but the developmental context of which the originating mutation is occurring and we think that these mutations happen particularly the instigating one in utero, which means that these OPC like cells are stalled in this differentiated state.

Then as we go through these waves of myelination and you can imagine the remodelling that's happening of the central nervous system during those periods, the unravelled DNA then acquires these additional mutations.

Of course, in the older patients, we do see common mutations like TP53 and PI3 kinase mutations, but I think that they're secondary events that happen as a consequence of the unravelling of the DNA. Unfortunately, most of those mutations are impossible to target. You know, the histone mutation for now is impossible to target. TP53 mutations are impossible to target.

There are only a few of them and most of the map to PI3 kinase or MAP kinase that we can actually target with individual therapies. It means that why we've had such a struggle to get precision medicine approaches to do much.

1:09:59 Professor Steve Wesselingh
Thanks for that.

There's a question here about your idea of centres of excellence.

Maybe I can expand that a little bit because we are writing a National Health and Medical Research Strategy and we've been talking about platforms and centres of excellence and other aspects.

But perhaps Misty or Matt, would you like to comment on could we design a better funding scheme which brings, I mean, both of you talked about collaboration. What would look better in terms of getting people working together and funded together, either of you?

1:10:37 Professor Misty Jenkins
I'm happy to start because I think it's a this is a really, really important question because I think what our current funding system doesn't do very well with the exception probably of the Synergy in the Centres of Excellence is really incentivise collaboration to really actually incentivise it in funding structural models and reduce efficiency, reduce redundancy across the country and actually really like, as Matt says, sort of be greater than the sum of our parts.

We've seen this happen really well in the social sciences, that collective action then we haven't really seen that translate to health and medical research in this country, I think well enough. I think it's incredibly important and also with that longer term view to really be able to invest in these long-term projects to really build the right teams around Australia that are multidisciplinary and bring all their different expertise together. It's really it's critical.

But to do that, you need a lot of trust, and you also need the right structures like MOUs, and this is where it gets really more challenging is you know, sort of forcing the lawyers of different organisations to work together and to worry less about IP and to be focused more on translating our science and I think that it's a challenge.

1:11:59 Professor Steve Wesselingh
Yeah.

Thanks, Misty, and certainly we do have experience with structures where the MIAs between universities have taken 2 or 3 years before the actual organisation can actually work.

Matt, did you want to comment on what you were thinking when you mentioned the Centres of Excellence?

1:12:17 Professor Matt Dun
Yeah, I mean along the similar lines what Misty was suggesting. One if we think about the current structures that we have where in MRFF opportunities and we identify, you know critical areas that we are going to fund. We work in a rare disease for the most part and we collaborate. We try to collaborate as best as possible with limited resources.

But you know, if Misty submits a CAR T therapy MRFF opportunity and I'm submitting a systemic therapy and although they overlap in terms of what they might be able to help each other with, I can't be a CI on her grant.

Although I declare a conflict of interest, if I was to review it, I just can't work directly in support of that that funding. I kind of feel like in these rare and areas of critical unmet need, we just need to have some way, and I don't know what the answer is to be more flexible.

You know, I want to help Misty do her work as best as possible. I know she wants to help me, but we can't both contribute to that one MRFF, for example. If there was another funding mechanism to identify centres of excellence where funding could feed in and we could all work together and addressing all of the complex legalities and IP issues, then that would be a rockable opportunity.

I think for us, where we've got fantastic hospitals, fantastic research institutes, we're willing to collaborate, we've got this unique environment where we can take every single patient that's diagnosed with these tumours and do absolutely everything for them. We can get as much information from every single study because we've got such a good coordinated system.

1:13:49 Professor Misty Jenkins AO
I think that's the other point there to just amplify what Matt just said about it being a rare, particularly in the rare disease space and brain Cancer's one example of that. But there are other examples where there's no sort of this one rule set for everyone, which I completely understand. But in this case you have one tumour come in, for example and as a lot of these samples that we get that we're doing cell surface proteomics on these paediatric brain tumours are at autopsy through the generous families that are giving that tissue set so that we can understand more about the biology.

Therefore, we all want to treat that with absolute respect and do every investigation that you possibly can on this rare tumour. I'll be doing proteomics and doing all the omics in the spatial and the single cell and the drug testing and making the organoids and you can't do all that in one lab or even a handful. You need to have large consortiums to do that and then you need mechanisms and infrastructure that enable you to be able to share the data.

1:14:50 Professor Steve Wesselingh
Wee-Ming who runs a number, runs our clinical trials has asked whether you'd comment on the 3-to-5-year funding structure or whether 5-to-8-year structures.

But then again, you know, in the commercialisation space you need to fail early and move on quickly.

Any comment on the length of funding that you know is, I mean, I suspect 3 is too little 5, 8 what are you thinking?

1:15:21 Professor Matt Dun
Yeah, I think 5 is probably a minimum.

I mean, it depends on like you say, if it's a commercialisation opportunity, there should be a few milestones that you've got a hit throughout of the timeline so you can fail early.

I think that's a great suggestion and absolutely reasonable.

But in terms of this fundamental research that takes teams of people to do their individual expertise and combine it all back together, these things do take time. Five years sounds good to me.

1:15:47 Professor Steve Wesselingh
Thanks.

Now, just a couple of drug questions.

There's a question about metformin, and I'll add my drug question too.

There's been some recent work on brain what Roche are calling brain shuttles where they put transferrin onto drugs to get them into the central nervous system.

Maybe if either of you could comment on the use of metformin as an additional drug to other treatments obviously and whether there are ways of getting these drugs into the brain better through shuttle mechanisms.

1:16:19 Professor Matt Dun
I think the metformin thing is critical for us.

When you systemically inhibit the PI3 kinase pathway, muscles secrete glucose which creates insulin feedback from the pancreas and these tumours are laden in insulin receptors. If you increase the amount of insulin, you almost get this automatic resistance to these PI3 kinase inhibitors. So that we optimise the use of metformin not necessarily to get into the brain, but to decrease or to regulate glucose homeostasis more at a systemic level and we use it at a level that's not attempting to get into the brain.

But there are paediatric brain cancer researchers, particularly in North America and I'm thinking of Michigan and it's Sick Kids who are using metformin as a therapeutic against DIPG because of the way that it impacts the mitochondria.

And so, look, I'm, I'm not of the view that you can probably use metformin in a therapeutic sense to get into the brain, but potentially if you improve uptake by alternate means and there's many other ways to improve uptake, probably not as easy as we seem to think.

It seems to be a challenge for all of us in terms of uptake, but I think that could definitely be one way to get more metformin to the tumour.

But if you're going to do any drug, you would probably make Entinostat get into the brain better than metformin because these tumours are exquisitely sensitive to proteasome inhibitors and HDAC inhibitors.

There's a whole class of drugs that we could use much better if we could get them into the brain more effectively.

1:18:00 Professor Misty Jenkins AO
Yeah and drugs like the venetoclax, which work really well against glioma but don't doesn't cross the blood brain barrier.

There's a team that are looking at getting drugs across the blood brain barrier here at the brain Cancer Centre using nanobodies and you mentioned transferrin being one of those cargo. So, using nanobodies to then pull drugs across the BBB. It's a lot of work in progress happening there.

1:18:24 Professor Matt Dun
We need a Centre of Excellence for that.

1:18:28 Professor Steve Wesselingh
All right.

On that note, and actually I’ll just read out the last message.

A friend of mine passed away from DIPG in 2022.

Just wanted to say I'm grateful for all your amazing work.

I think on that note, I'd also like to say on behalf of NHMRC and everyone across the country, thanks guys. You know, this is amazingly hard work.

You're doing so well and you're certainly giving me confidence that that we will get there, and we'll take your ideas about funding schemes on board. Absolutely.

So, thank you. Thank you so much.

1:19:02 Professor Misty Jenkins AO
Thanks for the opportunity to talk about our work today.

Thank you so much for dialling in, everyone.

1:19:07 Professor Matt Dun
Thanks, everyone.

Thanks, Steve.

1:19:10 Professor Misty Jenkins AO
Bye, Matt.

1:19:10 Professor Matt Dun
Thanks, Misty. Bye.

End of transcript.