Daniel I. Simon, MD (Host):
Thank you for listening to another episode today.
I am happy to be joined by our guests, Dr.
Matthew Anderson.
Dr.
Tyler Miller.
Dr.
Anderson is the co-director of the Oxford Harrington Rare Disease Center,
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 Sherick, professor of Immunooncology, 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 Corps in the
Case Comprehensive Cancer Center.
Welcome Matt and Tyler.
Matthew Anderson, MD, PhD: Thank you.
Tyler Miller, MD: Thanks, Dan for having us.
Daniel I. Simon, MD (Host):
Well, it's great to see both of you today and you 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, 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.
really excited to join this and, it has been kind of a, circuitous, line of work.
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 seventies.
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, during that
time I trained at MIT for about six years with a Nobel Prize winner, Susu Gawa.
and he was trying to dissect the circuits that, allow you circuits and
molecular mechanisms that allow you to learn things and, 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 an.
Neglected disease.
and amazingly within that timeframe, the genetics of autism has just blossomed.
I think we have.
hundreds of genes now, 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.
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.
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 on these new emergent therapeutics are, like the
nucleic acids and things like that.
but also the obstacles that face in developing brain therapeutics.
And then, I missed academics and, found almost like a perfect marriage between
drug development and academics here.
Daniel I. Simon, MD (Host):
So, it.
for you to return back, to a job that allows you to do both.
a very important nonprofit drug development engine twin
as you're very comfortable with, with for-profit activity.
So, great to have you here.
So, Tyler, tell us a little bit, you know, one of the things we're gonna
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,
and how you got to Cleveland.
Tyler Miller, MD: I grew up in this like tiny little farm town in
the middle of nowhere, Ohio, like a thousand 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 and
did my MD and PhD here at Case.
and I had done lots of under research, like four years of
under research and breast cancer.
When I came to Case, I gotta decide, Hey, what do I want to do for my science here?
And I really want 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's lab here.
he was at the Cleveland Clinic, and Paul Tza, 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, so I saw
sort of firsthand how all of these new immunotherapies were impacting
different cancers, not brain cancer, but a ML and, and lymphomas and melanoma.
I was like, I am convinced after spending.
10 years doing brain cancer research that the way that we're gonna cure
this disease is through immunotherapy.
so when I went to Boston, shifted my focus from epigenetics and
drug discovery into immunotherapy.
and, we'll talk more about that later And what we did, basically spent six years
diving deep into how are we gonna make.
Brain or immunotherapy effective for brain tumor patient's.
And then I got come back home, basically what felt like coming back
home, to case Western University Hospitals, to start my lab.
And so here I spend 20% of my time doing clinical pathology, where I sign out
molecular cases from tumor patient's.
at basically if somebody has their tumor sequenced, then they need to figure out
what those mutations And 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 patient's.
Daniel I. Simon, MD (Host):
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, why are they so important?
Tyler Miller, MD: 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, and Matt's probably better at answering the
neurons and astrocyte questions 'cause 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 And 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 and 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 app penal 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 unique thing about the brain.
Every one of those cells.
Can interact with each other with Perkin signaling, sort of sending
sort signals back and forth.
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 I. Simon, MD (Host):
So Matt, you know, one of the problems, that Tyler just.
Diluted 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 That is really one of
the big limitations, it's absolutely important in terms of keeping the
extracellular fluids, 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 gonna 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 barn barrier therapeutically.
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 a technology that involves a specific receptor that naturally goes
across to deliver things to the brain.
Daniel I. Simon, MD (Host):
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's.
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 tumor.
So tell us, how are these microglia good guys and bad guys and how do
you manipulate them in glioblastoma?
Tyler Miller, MD: what we've learned over the last.
You know, 15 years is that the immune system is involved
in basically every disease.
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 it.
Cancer is one of them and, 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 blamed 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 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 I. Simon, MD (Host):
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 polio virus to actually go in and
try to kill the, malignant cells.
what's the future do you think?
Tyler Miller, MD: 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.
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 one, the PD L one 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 polio virus.
there's some stuff happening at, Dana-Farber 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, 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 'cause
it, it's a sort of systemic thing.
And 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 AYA.
Catheter a reservoir And the catheter, which basically goes
directly into the CSF, so it's this like small little quarter size
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 is
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 I. Simon, MD (Host):
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 core And
the Case Comprehensive Cancer Center.
Is really gonna pay off for us.
So Matt, I wanna 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, At glioblastoma, the disease that
really ties 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 a autoimmune disorder.
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.
these kinds of cases could very well be, incredible,
insights right 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, you know, 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, of 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 outta 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.
based on this we said.
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, you compliment to the actual driver that because we're
really just downstream with a GLP one 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.
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 us had, T-cell
infiltrates, uh, 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 gl matan made by the astrocyte,
And 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, Parkinson's.
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 and pathology to get back to the basics and, understand really what
might be happening in these disorders in the more common sporadic forms.
Daniel I. Simon, MD (Host):
Well, This is incredibly inspiring to hear.
I think, one of the unifying things.
Aim 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.
Knock out mice with ear models.
I think it's very exciting to go forward.
I mean, I do have to say in, looking at the three of us, you know 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, PEth, Israel Deaconess, And 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 onto our, neuroscience, band of research.
I guess you know, the final question.
is in many ways you're studying rare diseases, you, Tyler or a
rare cancer, Matt, you, 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 gonna 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 is really an am 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 Camizetrant, the former Prime Minister, sort of leading, you
know, a large number of people that are devoted to this subject matter.
and, uk b biobank has been really a key driver.
Regeneron use 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 academic And in their
native setting, where they have a wonderful kind of developed career.
Really deep expertise and very specific subject matter, like Ty, for example, here
in glioblastoma and other's, 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 is a very
uniform, set of people with one condition.
so you get a robust, therapeutic clinical trial with a small n 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 sort of cracked open, delivery and efficacy, for that
disorders, that organ system, using that rare disease, platform.
Daniel I. Simon, MD (Host):
Well, you know, look, research at uh, is all about hope.
You know, 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 wanna 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 uh.org/research.
Thank you, Tyler.
Thank you, Matt.
It's great to be with you today.
Matthew Anderson, MD, PhD: Thanks, Stan.
Tyler Miller, MD: Thanks.