A Compelling New Lupus Discovery with Jaehyuk Choi, MD, PhD

Episode Transcript
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Erin Spain, MS (00:10):
This is Breakthroughs, a podcast from Northwestern University
Feinberg School of Medicine.
I'm Erin Spain, host of the show.
In a recent episode of this show, we spokewith Northwestern Medicine, physician, Dr.
Jae Choi, about how a gene mutation foundin T-cells of patients with lymphoma could

(00:32):
hold the key to potent cancer fightingimmunotherapy for solid tumor cancers.
Today we welcome Dr.
Choi back to the show to talk aboutanother breakthrough in T-cell
research and the fight against lupus.
A chronic auto-immune conditionaffecting 300,000 Americans that
can cause inflammation in many bodyparts, including joints, skin, kidneys,

(00:57):
blood cells, brain, heart, and lungs.
These findings not only elucidate theunderlying mechanisms of lupus, but also
suggest potential therapeutic strategies.
Here with details is Dr.
Choi.
Welcome back to the show.

Jaehyuk Choi, MD, PhD (01:11):
Thank you for having me, Erin.

Let's refresh our listeners' memories a little bit.
You are a cancer researcher,specifically, you have an interest
in skin cancer and skin immunology,but today we are talking about lupus.
This is not a conditionthat you typically study.
Tell us a bit about your backgroundand what led you to lupus.

That's right.
So, it turns out that one of the mostimportant aspects of both cancer and
the skin are actually the immune system.
And one of the major drivers of theimmune system is a cell called the T cell.
And it turns out that this T cellhas very similar attributes in many
different types of diseases, includingboth cancer and autoimmune disease.
And so it actually turned outto be a natural offshoot of the

(01:54):
work that we had been doing.
We study human patients and we try to findout what are the molecular aberrations
or changes that occur in human patients.
And so our thought is that oncewe identify them, we can then
utilize them for multiple purposes.
So we recently utilized findingsfrom patients with T-cell lymphomas

(02:15):
to really discover ways to stealthe superpowers in the lymphomas to
supercharge T-cell therapies for cancer.
We use the same approach from patientswith lupus and autoimmune disease.
It turns out they have all the same cellsand all the same technologies will work.
And we were able to use this approachto identify the root cause of what we
think is one of the root causes of lupus.

(02:36):
And so we've identified thattheir T cells are not right.
If they're not normal and in fact they'redisease causing, and that we think that
by understanding the root mechanismsby which these T cells become disease
causing in lupus, we can identify, youknow, ways to actually cure the disease.

Was there a particular reason you chose to investigate lupus
to use the same approach as you usedwith your T-cell lymphoma research?

We wanted to study lupus because it's a
debilitating, incurable conditionthat affects over 300,000 Americans.
We don't have really good ways to treatthe root cause of lupus, and that's
why we don't have any cures for lupus.
All the treatments are in facttreatments, which are just ways to
make the side effects of lupus better.
And these drugs actually broadlyaffect the immune system.

(03:24):
And therefore we know that theynot only suppress lupus T cells,
but they also suppress your T-cellsto other possible diseases like
COVID-19, pneumonia or infections.
And so the net result is that thesetreatments can actually be extremely
dangerous for patients if taken fortoo long and in the wrong situations.

(03:45):
It affects not only the blood, butalso the skin, the joints, the brain,
the lungs, and as well as the heart.
We've made a lot of progress inthe last few years, but because
it's incurable, patients still diefrom lupus at an unacceptable rate.

And tell me about the team that you've assembled to look into this,
who are the experts in autoimmune diseasesand lupus who are on the research team?

My collaborator in this case is Deepak Rao, who's an
assistant professor at Brigham Women'sHospital, which is one of the hospitals
associated with Harvard Medical School.
He is an active participant intheir autoimmune network called
Accelerating Medicines Partnership,and also one of the leaders of the
Human Immunology Center at Brigham.
It turns out he and I used to playbasketball together when we were in

(04:30):
medical school, and we had this dreamof partnering together to actually cure
autoimmune diseases, diseases that hesees in his patients in his clinic.
He's a rheumatologist where we canuse the technologies we've developed to
study T cells and be able to deploy themin this very important clinical need.
Our student, Calvin Law, is actuallythe first PhD student in my lab.
Jay Daniels was the MD PhD student whoreally pioneered the other work, and it's

(04:53):
just been remarkable to see him grow froma a junior scientist to really a mature
researcher who's also equally committedto being able to cure autoimmune disease.

And the paper that we're discussing today, published in Nature.
You mentioned you found thedisease causing cells in lupus.
Tell me a little bit more about that.
What did you find?

Sure.
So, let me first startoff with an analogy.
So I think a lot of times weknow lupus affects the skin, the
brain, the lungs, and the heart.
And oftentimes we actually study whatcaused the symptoms of the disease.
And so I make the analogyfor like landscaping.
If you're looking at a weed, we oftendeal with what we see on the surface,
and that's what we've been studying.

(05:32):
But what we think we found is afundamental root cause of lupus, which is
kind of the root of the weed, and we thinkthat by actually taking out the root,
we can actually potentially cure lupus.
That's why we're reallyexcited about this.
And so from patients, we found thatthere are chemicals that are imbalance
in their blood that causes the riseof these T cells that actually promote

(05:53):
the production of antibodies, whichare a critical aspect of lupus.
It turns out if you have lupus, youhave much higher levels of these T
cells than people who are healthy.
And that these T cells seem to bechronically activated driving the
production of these antibodies againstyourself that lead to disease and
correlate with disease activity.
So our approach here has been differentthan what people have done before, which

(06:16):
has been to try to treat the effectsof lupus in the kidney or the skin.
We wanna reprogram the cells thatare actually causing the lupus.
Turn them from bad guys into good guys.
And so, what we found was that therewas a molecule that was deficient in the
blood of patients with lupus It's calledAryl Hydrocarbon Receptor (AhR) Ligands.

(06:36):
Normally these molecules are producedby bacteria in the gut, but also can
be things that you're exposed to in thebody from the outside in the environment,
chemicals in water, et cetera.
For many reasons, we found that patientswith lupus have an imbalance of cytokines
like interferon that suppress thisAryl Hydrocarbon Receptor pathway.

(06:56):
We then found that this Aryl hydrocarbonreceptor, when suppressed, actually
promote the production of cells that arepathogenic lupus, these B helper T cells,
these TPH cells, and because we think wefound the root cause of why patients with
lupus have an abnormal abundance of thisdisease causing T-cells, we hypothesized
that we could correct it by restoringthe chemical imbalance in patients.

(07:20):
And so we've done these studies with bloodcells from patients with lupus, provided
back the Aryl Hydrocarbon receptor ligandsand show that we can suppress their
ability to make pathogenic antibodies.
And so we think that this is a possibilityof not only reducing the disease causing
T cells, but actually reprogrammingthem to be a potentially good cell.

Tell me more about these cells.
In the paper you said that these cellsare in a Seesaw like balance between
disease causing and wound healing.
Can you tell me more about that?

So these cells are called T peripheral
helper cells, or B helper T cells.
They're highly elevated in patients withautoimmune disease, including lupus.
And they're much higher in lupuspatients than in healthy people.
In healthy people, in contrast, you havemuch higher levels of these cells CD96
positive TH22 cells that are thought tobe critical for wound healing in tissues.

(08:13):
We knew we wanted to targetthe B helper T cells.
But what was unexpected were thatthese cells actually live in a seesaw
with these wound healing cells.
And so we think in normal people and inpatients with lupus, you have these B
helper T cells and these wound healingcells actually living in a seesaw.
When you have a lot of wound healingcells, that helps you to be healthy.

(08:34):
And it seems to be associatedwith a lack of autoimmune disease.
And then when you have autoimmunedisease, you have really high number
of these B helper T cells, and a lownumber of these wound healing cells.
And so in general, it may be useful toreprogram T cells across many different
things, but we thought we could takeadvantage of this naturally occurring
seesaw and be able to really pushdown the B helper T cells, which would

(08:58):
naturally push up their likelihood ofbecoming these wound healing cells.
And so by doing this, we thinkwe can leverage what nature
already does in people to helpprevent this autoimmune disease.
And the added benefit is becausethey're wound healing at the sites
of lupus associated injury, likethe kidneys, the lungs, et cetera.
We think that they could actually havea disproportionate outsize wound healing

(09:19):
effect in the areas of lupus damage.

These are truly breakthrough discoveries.
Explain to me just how unprecedentedthese findings are and what it could
mean for advancement in the field.

I think what's really attractive is when
we find a molecular mechanism thatseems to explain the whole thing.
And so what we have found is in theblood there seems to be a deficiency
in these molecules called aerohydrocarbon receptor ligands, and
that this is sufficient to lead toupregulation of these B helper T cells.
And so we have, from soup to nuts, studiedthe molecules in the cells from patients

(09:51):
with lupus, and shown how molecularlythese chemicals can actually lead to the
changes in the T-cell state, leading tochronic activation of B cells leading
to the chronic activation of antibodies.
What's been really a tremendousdiscovery is that we can bring back
this molecule, rebalance this moleculecytokine in people and that if we do

(10:13):
that, especially in lupus cells, we'reable to actually turn off their ability
to promote lupus antibody production.
And so we think that the opportunity hereis to not broadly suppress the immune
system for patients with autoimmunedisease, but to reprogram the cells
that are actually causing the disease.
And in this case, what's reallyincredible is the ability not only to

(10:34):
prevent them from actually promotingthe production of these antibodies,
but actually to reprogram them to bea wound healing phenotype, where we're
hoping that they can actually leadto repairing the damage that's been
caused by lupus in these patients.

That's really incredible.
I wanna talk about some of the technologythat you used to perform this research.
It was really a critical part,some of the tools that you
used in this investigation.
Can you explain that to me?

Yeah, so we were able to combine just fundamental aspects
of T-cell biology, immunology, single cellgenetics, single cell transcriptomics,
as well as these incredible technologiesthat give us this idea of what we call
the epigenetic state of the cells.
And so by using epigenetics, we cansee how this one T cell that was

(11:17):
born, probably polyfunctional, ableto do anything, has actually become
hardwired to become lupus promoting.
And by utilizing these kind ofmolecular mechanisms from the Aryl
hydrocarbon receptor all the waythrough to the disease causing T-cell
state, we think that we're able tofind the exact places where we can
intervene and reprogram the cells.

(11:38):
I think this concept of reprogrammingthe cells that are causing disease
is actually relatively novel.
Most people try to either broadlysuppress the immune system as we
discussed, or they actually try to killthe cells that are actually in patients.
But we think there's an advantageof actually targeting the cells
that are causing lupus and flippingtheir identity because they're
already in the tissues that arewhere the disease is being caused.

(12:01):
And they're also beingchronically activated.
So instead of being chronically activatedto produce molecules that promote
lupus, we're hoping to reprogram themto be chronically activated, to produce
molecules that promote wound healing.
And I think that this kind of opportunitywill be available to us to be able to
sort of repair the damage in all theorgans where these immune cells are.

So for people who already have the disease, is this
something that you're saying couldreverse damage that's been done?

Jaehyuk Choi, MD, PhD: I think it's possible. (12:29):
undefined
We really hope so.
We don't know for sure, and I thinkthat one of the issues in lupus
is that the preclinical models aremostly based on these small mice.
You know, we know that mice are nothumans, and so, but we think that
because our discoveries are made inhuman T cells, our hope is that we can

(12:50):
translate this directly into humans andpredict what will happen to patients.

So what are the next steps at this point?
You've proven that this can bedone in the lab and the blood
samples from people with lupus.
Now we're talking about real patients whowant to see if this could be successful.
So are clinical trials on the horizon?

We're actively working on this.
The key aspect is how do we deliverthese chemicals safely and surgically
to the cells that we're targeting?
And so, our lab and Dr.
Rao's lab are activelyworking on ways to do this.
And the goal would be is to produce thesemolecules, turn them into drugs that
can be given worldwide to patients withlupus and other autoimmune diseases.

(13:29):
And again, the goal will be not onlyto treat them, but to potentially cure
them of their disease by reprogrammingdisease causing cells . Our
goal is to really make it simple.
If we can, we'd like to make it intoa pill and that we can then give to
people and then they could do better.
What we think is these cellsonly represent a small fraction
of the cells in the blood.
We just wanna leave the 90 pluspercent of the cells that are helping

(13:52):
you to defend yourself against cancerand infection intact and unchanged.
We only want to target the cells that arecausing lupus, and our goal is to do that.

So you said you're actively working on this.
So what does that mean?
Tell me about this endeavor andI know that there is a startup
or a company involved as well.
What can you share with us?

Anything we find in the lab is it's very
difficult to give to patients.
And so there has to be an intermediatestep where the intellectual property
has to be licensed by a companythat will be able to make commercial
grade drugs that can be givento people throughout the world.
So, Dr.
Rao and I have focused on finding thesetechnologies and we're actively working on

(14:33):
trying to translate this into discoveriesthat can be put into a startup that
would be able to be given to people.

What has the reaction been like in the community,
especially people who study lupus?
What has the reaction been?

It's been really outstanding.
And as an example my student CalvinLaw just presented at the plenary
session for the American College ofRheumatology, and it was just really
refreshing to see that both cliniciansand scientists could be unified in their
enthusiasm for a paper that bridgesbasic science and patient samples.
We made one of the first studiesinto the molecular mechanisms,

(15:09):
into these lupus causing T cells,which was really important.
But I think the obvious idea that thisis a root cause of the disease and
that it could potentially be addressedby chemical matter is something
that's really resonated with both theclinicians and the basic scientists.

So when a study like this is published, there is often a lot of
press, there's a lot of excitement andpeople really want to know, well, when
can we expect to see this in the clinic?
You know, when can my loved one withthis disease expect some relief?
What would you like to say to thosefolks who are listening, who are very
excited about your research and reallycan't wait to see this come to fruition?

So what I would say is that actually many of
the therapies that are out there areactually leveraging this particular
seesaw that we're talking about.
And so you may not be aware, but even ifyou're taking some of the medications that
are prescribed now, like anifrolumab, itseems to be one of the effects of cytokine
blockade is rebalancing this seesawbetween these B helper lupus causing T

(16:08):
cells and these wound healing T cells.
What I would say is that rest assuredthat you're receiving the best care
possible in the clinic, but thatthere are many medications that are
actually in development that may beactually leveraging unintentionally
the seesaw between the bad helperT-cells and the good helper T-cells.
So I think that those would be in theclinic and be available to you very soon.

(16:29):
And then what we wanna do in ourlab is to be able to really develop
next generation potential cures.
Our hope is that this will cometo the clinic within a few years.

Now we're talking about lupus today, but there's many
autoimmune conditions out therethat are really debilitating and
not a lot of great treatments.
Could you see this idea, this platform,this way of flipping the cells,
something that could be done to helpother conditions that are autoimmune.

You know, we've just been so inspired by, just
a beauty and intrinsic logic to hownature works and the T cells follow
this logic in incredible ways.
And until we have the technologyto understand it, we really didn't
understand how these diseases are caused.
But now that we can see this real threadbetween blood imbalances into how the

(17:15):
cells are programmed, into how theyproduce the molecules that cause lupus.
We think we can take the same kindof roadmap and use this for other
autoimmune or inflammatory conditionswhere our goal is to really reprogram
the cells that are causing disease,helping them to actually repair the
conditions that they're causing.
This could easily be adopted torheumatoid arthritis, as well as a number

(17:38):
of debilitating autoimmune diseases.
You know , it turns out that inflammationcan actually be the root of many diseases.
It's obviously deficientin patients who have cancer.
They can't mount the appropriateimmune response to the cancer.
It may be over-exuberant inpatients with autoimmune disease.
But we think actually it's altered inmany diseases associated with aging,
including cardiovascular, heart disease,neurodegenerative diseases, and many

(18:02):
other syndromes associated with aging.
And so we think that we can applythese very powerful tools to be able to
understand the molecular defects thatoccur in across these different diseases.
And we can now engineer newsolutions for many of them.
So our goal is to be able to reallybroadly identify new solutions for
people with a broad suite of inflammatorydiseases, which include aging in general.

This idea of team science and it takes a lot of
experts and expertise to bringsomething like this to publication.
Can you just talk about that a little bitand just the roles that everyone plays
to make a discovery like this happen?

That's a really great question.
Our goal is not to further our lab.
Our goal is really to cure diseasesand really improve human health.
And if you have that kind of ambition,I think what you should think about
is how do I assemble the right team tomake this happen as quickly as possible?
This kind of team science has been reallyarchetyped by, you know, getting to the

(19:00):
moon with the NASA, the Moonshot projects,obviously the Manhattan Project.
If you have a number of people withnon-overlapping expertise who are
smart and committed to solving theseproblems, things can go very quickly.
And Deepak and I are close friends.
We always dreamed of trying to cureautoimmune disease together and we're
really gratified this is happening Thisis a truly 50-50 collaboration with his

(19:22):
lab and really synergize our abilityto make an impact that hopefully will
help patients with these diseases

Well, Dr.
Jae Choi, thank you so much for comingon the show and talking about another
incredible breakthrough from yourlab along with your collaborators.
We really appreciate it.

Jaehyuk Choi, MD, PhD: Thank you so much, Erin. (19:38):
undefined

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