Breaking Into the Brain: Overcoming Barriers to Understand Autism and Brain Tumors

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Daniel Simon, MD: Welcome to the Science@UH podcast, sponsored by the University Hospital's Research & Education Institute, where we explore breakthrough research, clinical innovations, and the science of transforming patient care and health outcomes.

I'm your host, Dr. Dan Simon. Thank you for listening to another episode. Today, I am happy to be joined by our guests, Dr. Matthew Anderson and Dr. Tyler Miller.

Dr. Anderson is the Co-Director of the Oxford Harrington Rare Disease Centre, a partnership between the University of Oxford and the Harrington Discovery Institute at University Hospitals. He's a professor in the Department of Pathology at University Hospitals and Case Western Reserve University, and a visiting professor at the University of Oxford.

Dr. Miller is the Paul and Betsy Shiverick Professor of Immuno-Oncology, a pathologist in the Division of Genomic and Molecular Pathology at University Hospitals Cleveland Medical Center. He is also the Director of the Cellular Therapy Core in the Case Comprehensive Cancer Center.

Welcome, Matt and Tyler.

Matthew Anderson, MD, PhD: Thank you.

Tyler Miller, MD, PhD: Thanks, Dan, for having us.

Daniel Simon, MD: Well, it's great to see both of you today. And you know, as a cardiologist who focuses on a simple beating heart, we have the most complex organ today, the brain. So, I'm here to learn, our listeners are here to learn, and we're really looking forward to your expertise that covers everything from autism to brain tumors.

So, before we begin, I always enjoy, and I know our listeners do, learning about how you got here. And so maybe we could start with you, you know, Matt, tell us a little bit about your background, your training, and how you ended up at University Hospitals.

Matthew Anderson, MD, PhD: Sure. Thanks, Dan.  You know,  really excited to join this and it has been kind of a circuitous line of work. I started out in getting an MD-PhD, and my PhD was on cystic fibrosis, which is a rare genetic disease, and I would say almost like a poster child for what therapeutics can do in a genetic disorder. The children used to die in their teens, and now they're living late into their 70s.  And that really gave me the passion for research focused on human genetic disease and particularly pediatric disorders.

I decided to go into neuropathology because I was intrigued by the brain and wanted to kind of make a move.  I went to Boston for my subspecialty training in neuropathology, and during that time, I trained at MIT for about 6 years with a Nobel Prize winner, Susumu Tonegawa, PhD.  And he was trying to dissect the circuits that allow you...circuits and molecular mechanisms... that allow you to learn things and memorize, but I thought that those approaches that he was taking would be powerful for dissecting mechanisms of brain disorders.

And then I had a lab for many years in Boston working on autism… it was sort of an emergent disorder, I felt pretty neglected. I thought there were a lot of really talented scientists pursuing Alzheimer's, and I felt that it was a neglected disease. And amazingly, within that timeframe, the genetics of autism has just blossomed, I think we have hundreds of genes now - you know in this sort of broad category of autism that are really just - many a gathering of neurodevelopmental disorders. But then as a neuropathologist, I raised my hand to be a part of a brain banking effort to understand autism better. I mean we really understand Alzheimer's and other diseases because we actually looked at the brain. You know, there are genetic forms of these conditions, but those are the rare subtypes. So, you really only understand the disease well if you have a pathologic assessment.

We found some surprising pathology that is really just getting a foothold now involving T-cell infiltrates. So, I've sort of continued that and then we were developing genetic forms of autism in mice, mapping out the circuits that drive social behavior, the ones that increase aggression, irritability and the autism. But then I was thinking that I would love to really understand how to develop drugs for these conditions that we were studying and so opted to spend time in pharma and tried to learn from the best, the folks at Regeneron, leading a pipeline of therapeutics in the neurosciences. And that's where I really came to realize how transformative these new emergent therapeutics are, like the nucleic acids and things like that, but also the obstacles that we face in developing brain therapeutics. And then I missed academics and found almost like a perfect marriage between drug development and academics here.

Daniel Simon, MD: So fortunate for you to return back to a job that allows you to do both. So, a very important nonprofit drug development engine, twinned as you're very comfortable with for-profit activities. So, great to have you here.

So, Tyler, tell us a little bit, you know, one of the things we're going to suddenly discover here is that the three of us were all from Boston and trained there extensively. But Tyler, tell us a little bit about your background and how you got to Cleveland.

Tyler Miller, MD, PhD: Yea, grew up in this like tiny little farm town in the middle of nowhere, Ohio, like 1000 people, no stoplight. My dad had a catering company and my mom worked as a nurse at the local hospital. And I went to Ohio State, and then I came up to Case Western, did my MD and PhD here at Case.  And I had done lots of undergraduate research, like 4 years of undergraduate research in breast cancer, when I came to Case, I got to decide, hey, what do I want to do for my science here? And I really wanted to tackle a disease that we didn't have any good therapies for and thinking about brain tumors, pancreatic cancer, other things that if somebody got that diagnosis, it was basically a death sentence for them. How do we help those people? And we had really good brain tumor people here at the time and still do. And so, I joined Jeremy Rich, MD, MHS, lab here, he was at the Cleveland Clinic, and Paul Tesar, PhD, who's at Case Western, and did a PhD here where we focused on how do we define sort of better targets for drug discovery and better models.

And then I went to Boston for six years, as you mentioned, did my residency at Mass General, did a postdoc at Dana-Farber.  During my PhD, there was like the immunotherapy revolution and so, I saw sort of firsthand how all of these new immunotherapies were impacting different cancers, not brain cancer, but AML and lymphomas and melanoma. I was like, I am convinced after spending, you know, 10 years doing brain cancer research that the way that we're going to cure this disease is through immunotherapy.  And so, when I went to Boston, shifted my focus from epigenetics and drug discovery into immunotherapy.

And we'll talk more about that later in what we did, but basically spent six years diving deep into how are we going to make immunotherapy effective for brain tumor patients. And then I got to come back home - basically what it felt like coming back home - to Case Western and University Hospitals to start my lab. And so here I spent 20% of my time doing clinical pathology, where I sign out molecular cases from tumor patients. Basically, if somebody has their tumor sequenced and they need to figure out what those mutations in that tumor mean, we have to write a report for that. And 80% of my time, I run a research lab trying to find effective immunotherapies for brain tumor patients.

Daniel Simon, MD: Let's start to move forward, and I think one of the things, since you're both pathologists and you're both into the structure and composition of the brain, set the stage for us by talking about the cells in the brain.

Maybe Tyler, since you're a single cell transcriptomics guy, tell us about neurons, astrocytes, oligodendrocytes and microglia. So that's what I remember from neuroanatomy. And tell us, what do those cells do and why are they so important?

Tyler Miller, MD, PhD: Yea, right, Dan, you mentioned at the beginning, like the most complex organ in the human body is the brain, and it is made of lots of - all of these different cell types, right? So, the neurons, and Matt's probably better at answering the neurons and astrocyte questions, because that's sort of what he studies. But the neurons basically connect to all the different parts of your body, as well as many different parts within the brain to form memory and speech and hearing and motor activity, and everything that we do basically comes from the brain.

Those neurons are supported by all kinds of different cells. So, you have astrocytes, which help sort of form the glue, as well as help with synaptic connections between those neurons.  

You have oligodendrocytes, which wrap the neurons with myelin to help the conduction of those signals go much faster and really allow for us to send a signal from our brain down to our toe in a very quick fashion.

You've got the immune system - in the brain the immune system is largely made-up of microglia, which are a myeloid cell, which again, we'll talk a bit more, but they have the job of surveying your brain to make sure there's no pathogens that come in there. But they also have real sort of impact on the sort of synaptic connections and supporting other cell types that are in the brain.

And then you've got a bunch of little specialized cells that are around the brain that also help impact - pericytes, which help form the blood brain barrier, for example. And then you have all the coverings of the brain and you have ependymal cells that can help sort of form the barrier between the CSF and the rest of your brain.

And so complicated system, all of them talk to each other, which I think is like the really sort of unique thing about the brain. Every one of those cells can interact with each other with paracrine signaling, sort of sending signals back and forth.

But yeah, it makes all of the diseases of the brain very complicated. And we'll talk about the brain cancer of how all of those cells are sort of also have an impact on brain cancer.

Daniel Simon, MD: So, Matt, you know, one of the problems that Tyler just alluded to is this thing called the blood-brain barrier. So, it's this special defense that keeps bad things out, but unfortunately also keeps out our therapeutics. So, tell us, what is the function of the blood-brain barrier and why is it so difficult to treat brain disease because of that?

Matthew Anderson, MD, PhD: Yeah, I think that is really one of the big limitations. It's absolutely important in terms of keeping the extracellular fluid surrounding the neurons in the proper state. When it breaks down, you get epilepsy sometimes. You get all sorts of problems. So those neurons are little machines ready to fire off at any point. And if you disturb the composition of those fluids, you know, you're really going to trigger them. So that's really what it's trying to keep in check and allows the astrocytes to kind of keep that environment normal. So that's one of the things. And then, of course, many of the drugs that get in…even the ones that are permeable to membranes often get transported actively out…and certainly, the antibodies, some of them do get in surprisingly, but they have special ways to get in but many of them do not. For example, the antibodies that are used for cancer just often really don't get in well to hit the tumor cells, and they've had great efficacy in the peripheral body, but not in the CNS.

So, I would say that this is really one of the key limitations. And while I was at Regeneron, it really became apparent to me that really the next big breakthroughs are how do we get things across that blood-brain barrier therapeutically. And a number of companies are doing it, and they have therapeutics for Alzheimer's right now that takes advantage of kind of a blood-brain barrier crossing technology that involves a specific receptor that naturally goes across to deliver things to the brain.

Daniel Simon, MD: You know, it's very interesting, one of our prior speakers talked about the use of focused ultrasound to temporarily disrupt the blood-brain barrier to deliver these Alzheimer amyloid-clearing antibodies. But then, that starts to raise all sorts of questions, right? Because we know that we have inflammation and bleeding with those antibodies. Now you're disrupting the blood-brain barrier - gets to be kind of messy. So, I'm glad that there are more sophisticated ways - potentially to get across there than it is to physically disrupt it with ultrasound bubbles.

So, Tyler, you talked about microglia as protecting from pathogens, but microglia also have a role in potentially preventing the immune system, both CAR-T and all their natural immune mechanisms to actually go after glioblastoma-like brain tumors. So, tell us, how are these microglia good guys and bad guys, and how do you manipulate them in glioblastoma?

Tyler Miller, MD, PhD: Yea, I think, what we've learned over the last, you know, 15 years is that the immune system is involved in basically every disease, right. And autoimmune diseases are things we knew it was, but there are some plenty of diseases that we didn't know that the immune system was sort of underlying - cancer is one of them and it plays a really large role in sort of cancer development and then the ability for cancer to grow in the face of the immune system.

So, microglia and then additional cells that come from the periphery – so, when you get a tumor, you basically get breakdown of that blood-brain barrier and inflammatory signals that have additional cells coming in, T-cells, but also other myeloid cells like monocytes, macrophages, neutrophils come into the brain. When they come in, they basically form this suppressive environment that tells the rest of the immune system, like the T-cells, which are supposed to come in and kill the cancer cells, to stop being active and go away, basically.

The reason for that, from an evolutionary perspective, inflammation in the brain equals death, right? If you have a really inflamed brain, you get brain swelling. It's a limited space. And so that leads to hemorrhage and people dying. And so, there are really strong evolutionary sort of mechanisms to tamp down inflammation in the brain. And probably the strongest is using those myeloid cells that are in the brain to put out suppressive signals to say, “hey everybody calm down here.” And cancer uses that to its advantage.

So, what we've done a lot of is figure out what are those programs? How might we manipulate them to enable our immunotherapies, to be effective without causing a ton of inflammation? That's the key in the brain - is like - how do we walk that line?

Daniel Simon, MD: So, in clinical trials now for GBM, what are the kinds of things that are taking place? We know that there are some CAR-T programs, there were some very interesting re-engineering poliovirus to actually go in and try to kill the malignant cells.

What's the future, do you think?

Tyler Miller, MD, PhD: Yeah, I think most of the most exciting trials that are out there are all immunotherapy-based, meaning they're trying to either use T-cells to activate the body's own T-cells to come and kill the cancer or to put engineered T-cells back in. And so, we've tried a lot of checkpoint therapy. So, this is like the immunotherapy that most people think of, I think, is like the PD-1, the PD-L1 inhibitors, Keytruda, that type of thing. We've tried that in brain tumors. It doesn't work. And there are lots of reasons why that might be the case, but we've tried it ad nauseum at this point, and it basically hasn't worked.

There are oncolytic viruses. So, you put a virus in, and oncolytic means it goes into the cancer and then lyses that cell and so kills that cell. There's a lot of interesting trials going on in that space, you mentioned the poliovirus. There's some stuff happening at Dana Farber and Brigham Women's where they're injecting a different type of virus that goes in and they're doing re-injection. So interestingly, they're going in and they're injecting 20 times into a patient and each time they're taking a biopsy, and so, we're really learning what's happening in that brain over time, which helps us then sort of create the next trial.

I think, in my opinion, the thing that I'm most excited about in brain tumors is CAR T-cell therapy. This is where we take somebody's own T-cells, we engineer them to target the cancer, and then we put them back into the person's body and have those T-cells go and attack and kill those cancer cells. And it's been really, really powerful in other diseases. It's basically cured many blood cancers, leukemias, lymphomas, that type of thing. It hasn't worked that well in solid tumors.

We're starting to understand why that's the case. Much of it has to do with that immunosuppressive environment that I talked about, which doesn't exist in the blood cancers, really, because it's a sort of systemic thing. In the tissue, you have all of those myeloid cells that are suppressing it. So, how do we target them to then allow the T-cells to go in and do a better job? I think in the brain we actually have an advantage for CAR T-cells over most solid tumors because you can take an Ommaya catheter, a reservoir in the catheter, which basically goes directly into the CSF. So, it's just like small little quarter-sized thing that goes under the skin. Then you have a catheter that runs through the skull into the ventricle, and you deliver the CAR T-cells directly into the ventricle. And they don't really go around the rest of the body, which is really advantageous if your target isn't super specific just for the brain cancer, but also maybe it's expressed in the colon or the skin. You don't have to worry about that as much because it largely stays in the brain and it's delivered directly into that tumor. So, I think CAR T-cells are the way of the future for brain tumor. I think it's our best shot at a cure. And the question will be, how do we do combinations of therapies with those CAR T-cells to make them effective?

Daniel Simon, MD: Wow, that's really exciting. I'm so glad that our National Center for Regenerative Medicine - your role in obviously now running the Cellular Therapy Corps and the Case Comprehensive Cancer Center is really going to pay off for us.

So Matt, I want to switch gears for a sec and go to the area of autism and obesity. That's your area of expertise. Can you tell us a little bit about your present ideas about the mechanism of autism and how that may relate to obesity as well?

Matthew Anderson, MD, PhD: Sure, before we jump over, I just wanted to share that I'm also a believer in immune therapeutics for cancer, glioblastoma. As a neuropathologist, looking at glioblastoma, the disease that really Ty's trying to tackle, we had an amazing case of somebody that survived eight years with glioblastoma. They didn't die of glioblastoma. They died of an autoimmune disorder. So, the immune system was attacking the tumor we found when we looked at the tissue, but also sort of acted outside of the brain tumor on the gut and caused a problem with the gut.  And that's actually what was the problem. So, these kinds of cases could very well be incredible insights right into the mechanisms.

Let me start with obesity, just to touch on it briefly. So, a little bit analogous. I was in the morgue in Boston with Harvard medical students and fellows around the table. And we had a case of somebody - and we always look at the history and see is there something that we need to sample from the brain to make the further diagnostic work targeted? This was a case of obesity and diabetes. And it just so happened my colleagues were really using the genetics of obesity, rare forms of obesity, to map the circuits. And they found precisely where feeding is driven using all sorts of new technologies and very advanced technologies to turn neurons on and off in very focal areas. So, you can really understand the wiring diagram and what drives behavior.

So, they really understood the feeding circuit. So, we said, hey, let's just out of curiosity, take this obesity case and look under the microscope at that part of the brain. Is there a pathology there? And we were lucky. The very first case we got had the T-cells, the thing we were just talking about that's useful as a cancer therapy. Well, they were actually targeting and attacking the feeding circuit in the hypothalamus in this one case of obesity. And based on this, we said, well maybe this is more common than we realized. And we collected about 25 cases. And sure enough, we found it in about half of them. This is a brand new mechanism of human obesity that we had not previously appreciated.

We're beginning to explore that. We think it could be a complement to the actual driver, because - we're really just downstream with a GLP-1 agonist, we're not acting on the primary driver - if this turns out to be true.

The same concept holds for autism. I think I referred to it a little bit in my initial discussion. There's a huge amount of genetics there, but it's this rare subset. And those do allow you to understand the circuits that control the behavioral problems that arise in autism, the reduced sociability, irritability, motor functions, intellectual disabilities and we've used them as tools to dissect those circuits, and we've broken open new mechanisms that drive these behaviors. But I also decided to look at, as a neuropathologist, bring that to bear on the disease, and sure enough, about 65% of cases collected from across the U.S. had T-cell infiltrates, a little small foci. And concurrent with that, it had what looked like was damage to the astrocytes that formed the barrier between the cerebral spinal fluid and the brain parenchyma. It's this barrier called the glia limitans made by the astrocyte. We saw damage of that. So, we think that, again, this is early days, but if it turns out to be an actual pathology, all our therapeutics for diseases are largely targeted at a pathology - Alzheimer's, you know, Parkinson's – and this is a new pathology of a larger proportion of autism.

So, I enjoy kind of the circuit dissection molecular pathway mechanism work that we've done heavily in the laboratory. We have all those techniques up and running, but I've also kind of used my training in pathology to get back to the basics and understand really what might be happening in these disorders in the more common sporadic forms.

Daniel Simon, MD: Well, this is incredibly inspiring to hear. I think one of the unifying themes of both of your work is the importance of immunity, both innate immunity and adaptive immunity. And I think as a vascular biologist who focuses on inflammation as well, and Matt, you and I have a common target that we're now looking at together, crossing one of our knockout mice with your models, I think it's very exciting to go forward.

I mean, I do have to say, in looking at the three of us, what's sort of the common link here? The common link is inflammation, incredible training in Boston at Harvard Medical School and the affiliated hospitals. I mean, I think we cover all the institutions. We got Mass General, Beth Israel Deaconess, the Brigham here. You bring in the Dana-Farber Tyler as well. And we got our stuff going there, and we're just so happy to have the two of you here now at University Hospitals - really holding on to our neuroscience band of research.

I guess the final question for both of you, in many ways, you're studying rare diseases. You, Tyler, a rare cancer - Matt, obviously, autism is not rare, but the forms of autism that you study are rare. Maybe, Matt, you could tell us a little bit - what is the Oxford Harrington Rare Disease Accelerator going to bring? I mean, obviously, it's focusing on classic neuromuscular disease in kids, but it has rare cancer, it has other diseases that certainly affect adults. So, tell us a little bit about that part of your life, which is a bigger program in rare disease development.

Matthew Anderson, MD, PhD: For sure. It's really an amazing and exciting transatlantic partnership between Cleveland and Oxford, UK. We have major individuals that have kind of a vested interest in this subject matter, with David Cameron, the former prime minister, sort of leading a large number of people that are devoted to this subject matter. And UKB Biobank has been really a key driver, Regeneron used that resource, it's unique in understanding rare genetics.

Essentially, this unique model of the Harrington Discovery Institute where we don't have to recruit somebody out of academics like I did to go to pharma, but instead, let's bring the pharma to the academician in their native setting where they have a wonderful kind of developed career and really deep expertise and very specific subject matter like Ty, for example, here in glioblastoma and others. And we can just sort of find the best individuals out there and then bring them all that expertise that I found at Regeneron.

And now why rare disease? Well, rare disease is mostly genetic disease. Genetic disease represents a target. There is a very specific thing that you have to act on. And this raises the success rate. And of course, there's a huge unmet need in these rare disorders.

There's hundreds of millions of individuals with genetic conditions that are really not treated at all. So that's one of our goals. That's one of our major missions.

The other fact is that these are actually in pathways that cause common disease. So, one can easily envision developing a rare to common sort of approach to this in the specific targets of disease as you sort of look at the sporadic forms and the genes that are involved there.

And then the other thing is these are more successful clinical trials as a very uniform set of people with one condition. So, you get a robust therapeutic clinical trial with a small n (number of participants), and now you've just demonstrated that you can act on that disease effectively, and all sorts of diseases will impact that same system, some of them sporadic. So, you've sort of cracked open delivery and efficacy for that disorders, that organ system, using that rare disease platform.

Daniel Simon, MD: Well, you know, look, research at UH is all about hope. It's bringing the latest drug, device or cell-based therapy to people who have no options. And the two of you are doing that. So, I want to thank both of you for joining me today.

We've covered a lot of ground in a short period of time, but boy, do I feel great to have the two of you leading the charge, not only in brain tumors, but also in autism and potentially new mechanisms of treating obesity.

So, to learn more about research at University Hospitals, please log on to UHhospitals.org/Research.

Thank you, Tyler.

Thank you, Matt.

It's great to be with you today.

Matthew Anderson, MD, PhD: Thanks, Dan.

Tyler Miller, MD, PhD: Thanks, Dan.

There are no conflicts of interest to report.

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