- This is Lab Medicine Rounds, a curated podcast
for physicians, laboratory professionals, and students.
I'm your host, Justin Kreuter,
transfusion medicine pathologist, assistant Professor
of Laboratory Medicine Pathology at Mayo Clinic.
And today we're rounding with Dr.
Timothy Wiltshire, assistant professor of Laboratory Medicine
and pathology in the division
of Transfusion Medicine at Mayo Clinic in Rochester,
Minnesota, to talk about what's new with CAR T-Cells.
Thanks for joining us today, Dr. Wiltshire.
- My pleasure, Dr. Kreuter. Thanks for the invite.
- Absolutely. I always like kind of kicking off with the,
you know, why is this an important topic for,
for our audience of clinicians,
laboratory professionals and students.
So, you know, why, why is CAR T important for healthcare
folks to appreciate in 2023?
- So CAR T really is a, a relatively new modality,
and I think it's fundamentally changed the,
the way we're treating some cancers.
We call these living drugs
because we're using cells as a living drug and,
and CAR T has shown promising results
and impressive response rates in patients that have already
had two or three lines of treatment already.
So it's really offering new hope to patients
who have failed multiple lines of prior treatment.
I think it's a significant breakthrough for the handful
of heme malignancies that have,
that are being treated using CAR T,
which we don't come across a lot of these in our lifetime.
That significantly changed the landscape of CAR T therapy.
If you think about it, in, in therapy a typical drug is,
is considered a success if there's a, you know,
maybe a 10% difference in overall survival
or, you know, a a a few months increase in, in survival
with CAR T, we're talking greater than 80% initial response
rates in people
that have already had prior lines of therapy.
And many of these people, the five-year survival rate
is 40 to 50%.
So it's a pretty significant number of people you know,
who respond to this type of therapy.
And like I said, these types
of breakthroughs don't happen very often
in, in cancer therapy.
I think the most powerful illustration of this is the,
the first pediatric patient named Emily Whitehead,
and if you haven't read her story, this,
this little girl's alive over 10 years
after being treated as the first pediatric CAR T patient.
We're talking about somebody that only had a couple months
to live and kind of did this as a, you know, a Hail Mary.
So this is hope not
provided through any other
conventional treatment modalities.
And I think we're still in the early stages
of CAR T development in use.
So it's a pretty exciting field.
- Wow. Well you certainly got my attention when you're
talking about what kind
of success we're, we're seeing with this.
And you know, I'm kind of reflecting on,
as you were talking about, you know, this is a living drug.
I definitely am gonna be using that
with my immunology students next week,
but these,
these are the patient's own cells, right?
And like, it it's kind of maybe a little confusing of like,
okay, this patient was on their deathbed,
how are we taking their own cells
and then turning them into this, this living drug.
Can you give us a little bit of background on like,
you know, what, what should healthcare professionals
understand about CAR T?
I mean, people might hear the acronym,
but what, what should we appreciate about these? Right.
- And I think that's the exciting thing is CAR T uses the
body's own T cells, which, you know, the, the,
the human immune system is a pretty delicate
and intricate response.
And our best, you know, our best fight, you know,
against developing cancer, I often tell lay people
that ask me what, you know, what I do?
I said, you know, I make CAR T cells
and it's really harnessing the power
of the human immune system to treat cancer
because your, your body has, you know, hundreds,
even thousands of cancer cells in it each day.
It's only when they can, you know, avoid the immune system
that they can actually develop a tumor
or it only takes one of those cells.
So I think this's an exciting class of treatments
and I think, you know, to try to get people
to understand it, we're really taking the T cells out
and genetically modifying them with a receptor
that's specific towards their tumor type.
So we can, we can make a CAR,
which is a chimeric antigen receptor that's specific for a,
a target that's expressed on the tumor.
And then we, we use some genetic modification
to basically prime these.
So as soon as that receptor is engaged,
it activates and kills the tumor.
And so it's very intriguing part for me
because one of the hallmarks
of tumor development is the evasion
of the immune response, like I said.
So we're harnessing the immense power of the human body
to reintroduce the tumor to the immune system.
So all we have to do is reintroduce 'em to each other
and they can, you know, it can have its effect on the tumor
and more specifically as opposed to, you know,
traditional chemotherapy where you're just trying
to find a therapeutic window to kill, kill the cancer cells
and not the healthy cells.
- Now I, heard you earlier in your first answer kind
of talking about, and I picked up on you,
you dropping kind of the hematologic malignancy specifically
and is that like, is it true to say that we've seen success
specifically in the hematologic cancers like leukemias,
but not necessarily like the solid tumors like maybe breast
cancer or prostate cancer?
- Correct. So obviously this is the low hanging fruit when
you're talking about a heme malignancy, it's something
that's circulating in, in the bloodstream
and is much easier access.
It's also most
of the ones we treat at this point are, are B cells.
So we have lymphomas
or multiple myelomas where there's a target such as CD 19
or BCMA that that makes it the low-hanging fruit.
So you know, there still remains a huge untapped potential
for CAR T in in several areas that is moving it closer up
to the first line therapy because you know,
data now is showing that earlier we can get the treatment
with CAR T, it's leading to higher complete remission rates
versus standard standard chemotherapy as a first line.
We're also moving into solid tumors as you kind
of hinted towards there, a lot of, a lot of difficulties
with that because obviously a solid tumor is much different
than something circulating in the body.
But there's a pretty significant amount
of research going into that.
I did actually look it up just to see,
and there's over 300 INDs with the FDA now for CAR T trials.
- Oh, and - I'm
- Sorry, can you explain IND what do you mean by that?
- Oh, sorry. So for IND, sorry, I'm in my world where that's
what we do is clinical trials.
So it's an investigational new drug application.
So this is how you run a clinical trial.
Basically you submit to the FDA
and IND basically says what drug you're gonna use,
what population you're gonna use it in
and how are you gonna manufacture it.
And so there's only over 300 of these applications with the
FDA right now running CAR T trials.
So the major push are to make these
more broadly used in solid tumors as well
as make them more effective in the tumors
that we're already treating effectively.
- Hmm. You know, one thing I'm reflecting on listening
to you, you know, I mean this, this,
it sounds like this field is just as evidence,
you're talking 300 investigational new drugs out there
is is just exploding.
And certainly there are centers, you know,
like your own laboratory that are doing a lot of this work.
You know, our listeners may be in a whole variety
of different situations.
They may not necessarily have
a CAR T facility at their hospital,
but certainly everybody,
including our student listeners will be, you know, can,
you know, look at articles
that are published in in journals, right?
That's a common practice for probably most of our audience,
you know, as an expert in this field, you know,
are there a few things that you look
for when you read an article
that's reporting about CAR T cells?
Because I think maybe the more broader public, you know,
professional healthcare, public, you know,
it's, it's a new field.
We may not understand how
to critically read this literature.
Do you have a couple pointers on on what you kind
of pay attention to or what you look for with these?
- Yeah, and I, I would have to admit I'm a little more
jaded than the the general public
because obviously I work in a GMP facility and our,
and our, you know, goal is to be able
to translate these things in the clinic.
So when I'm looking at it,
I'm looking at more at can we do this?
Is this something we can manufacture?
Because that's, you know, that's obviously an issue
translating from the bench
to the bedside, which is what we do.
But you know, definitely other things to look at.
I mean there some targets are useful and some aren't.
I mean if, if you think about a solid tumor, anytime
that grows, you know, over a specific size,
you don't have vasculature in there.
So it's difficult to see how you're gonna kill a solid tumor
unless you have something else going along with it.
So there is, you know, studies out there
that look at say like delivering a payload
or something that help penetrate a tumor more
or when they engage with a solid tumor, they're gonna,
you know, put off some, some perforins
or something that's gonna kill cells.
So definitely looking at the strategies
and how they kill them
because as we know, there's a lot of things
that can kill tumor cells in a dish
or you know, even in, you know, even in a mouse model
that aren't gonna do it in a human.
So that's kinda the lens I put on it, which probably isn't
what, you know, most, most people would look at.
But definitely looking at the, the feasibility of, you know,
I can put an art artificial, you know, CAR T in there
and kill a tumor if expressing what I need to,
but is it gonna be useful in the long run?
Because if it's not, then, I mean it's just like anything,
if you give a high enough dose of a, of any kind of drug,
you're gonna kill all the cells.
But is there a therapeutic window there?
- You know, I, I think that's a brilliant answer
for our audience to, to hear, right?
This idea and,
and you know, I'm grateful you kind of share this,
just this perspective of practicality, right?
Because I think everybody can kind of relate to that
and I think that can instantly make this literature a lot
more accessible to people that are reading it to reflect on
and, and think about these things about, yeah,
I heard you talk about, you know, access,
talking about really feasibility of things
and then you, you mentioned targets, right?
Right. And there you're talking about, you know,
what are we engineering the t-cell to go after?
Which as I understand it, that's kind
of been a limiting thing
because of, I guess I hear it described
as off target effects.
Can you kind of explain what what that is?
- Yeah, and that's really a therapeutic window
because if you find a target that's on the, the tumor
but also on healthy cells,
you're gonna be killing those as well.
So there are a few ways around that and,
and some things which kind of try to deal with that, such
as logic gated CAR T cells
where you're looking at a specific
mutation along with a target.
So you really want our on target effects without the
off-target toxicity, which, which is difficult to, to come
by if you don't have a good tumor target.
So I think that's what a lot of the, the basic,
basic research is trying to flush out some of these targets
that that can be expressed on the surface of the cell, that,
that are easy hits.
I think we've found a lot of those,
so it's getting more difficult as we go along.
But like I said, the low-hanging fruit we've gotten, it's,
it's just getting more complicated now as we look for
that ther therapeutic window
where it's expressed on the tumor
and not normal healthy cells.
- Maybe this is a good time to kind of slip into this kind
of, you know, I think CAR T is getting out there enough
that, I mean I certainly we're getting into interview season
right now as we're recording this.
It's kind of late October
and you know, we, we get certainly a percentage
of our applicant's pathology programs are applying
to pathology and expressing an interest in in CAR T.
So you know, there this has really kind
of established itself.
And so I'm curious, you know,
what's really the new work in CAR T cells that you guys are,
are really kind of working on right now?
Or are, I'm sorry, not working right now,
but what's, what are some of the new things
that have come out recently?
- Yeah, I've kind of hinted at a few of those,
but really we know
there's a major push towards living a more healthy CAR
T-cell to make them more persistent in the body.
That means avoiding exhaustion while encouraging long-term
growth because studies are showing if we can keep the CAR T
in the body and healthy for longer periods of time,
people have better responses.
So there's many ways to do that.
Shorter growth times actually using the body
as the incubator, so putting in less cells and
and allowing them to grow up within the body.
So we're also expressing different, you know,
different receptors on there such as a, a membrane bound
cytokine receptor, which causes the CAR T to grow
so it gets in the body and grows from there.
So we can deliver low lower doses,
which theoretically equals, you know, less toxicities
and side effects while making sure
that the CAR T grows while it's in there.
There's also pushes towards, you know, allo CAR T products.
We have something off the shelf.
A lot of the patients that receive CAR T
in heme malignancies are, are in dire straits
by the time they reach us.
They only have a matter of, of a short time.
So if we could come up with something off the shelf,
an allogeneic CAR T that would be useful, could,
- Could we take a little bit of a deeper dive into that?
'cause I think, you know, I, I think I, I get
where you're going, but I just wanna make sure our
listeners appreciate.
Yeah. You know, when you we're talking about CAR T
so far we've been talking about allo autologous
or from the patient's own self,
but you just said allogeneic, so from a different person
and you used the kind of phrase off the shelf ready to go.
Can you kind of maybe go back what's involved
with creating your typical CAR T what's
that timeline look like
and then that contrasted with this off the shelf idea?
- Yeah, so there's, there's now six commercially approved
CAR Ts by the FDA that can be prescribed
and they take anywhere from three to four weeks,
sometimes even a little bit more.
And there is competition for those slots.
So an off the shelf would be ready to go,
but it's also a non-self.
So as soon as it goes into the body, the body recognizes
that a as T cell
that came from somebody else and it's gonna attack it.
So some of the strategies are knocking down, say some
of the, the, you know, the MHC class molecules so
the body doesn't recognize it.
So I, I think people are working towards that,
but it's still, still the low hanging fruit is the,
you know, the alt autologous,
but it also has the drawbacks, you know,
of it takes some time to manufacture
and at a significant cost.
So. Hmm.
- So what do you see the, the future of,
of CAR T cells going?
Do you, do you think it's going to, you know,
progress along this pathway of developing,
you know, autologous constructs
that are gonna be more effective against solid tumor
and you know, we're gonna figure out more of that
access feasibility
or, you know, do you think of more of this, you know,
off the shelf is gonna be, you know,
further perfected
or, you know, is there some kind of a combination
where an off the shelf is kind of like some, you know,
in case of emergency break glass kind of product, right?
But, but you know, some of the autologous, what's,
what are your thoughts on the future for the field?
- Yeah, and you've hit on a,
on a huge debate in the field right now
of, of where this gonna move.
Because, you know, as I said, there,
there is a limited manufacturing of these
and that's, that's a huge barrier to it.
So if we get to the allogeneic, it'll be great.
I think there's significant obstacles, both, you know,
mechanistically as well as logistically and, and,
and regulatory context
because when you're genetically modifying a cell and, and,
and in this case, you know, you'd use CRISPR
to knock something out so it doesn't, you know, it's,
it not, it's recognized itself.
So that creates a whole nother layer of regulations as far
as the FDA's concerned.
So I, I think we may get there someday,
but it is more of that kind of the dream of getting to
that someday where we can take somebody's healthy t-cells
as opposed to somebody that's been heavily pretreated and,
and you know, use those for manufacturing.
But I, I think there's, there's gonna be a lot
of strides made in the, in, in reducing the side effects
as we, we get more effective and put healthier cells in. So
- Is is part of, I was just reflecting
as you're talking about, you know, when we're talking about
transplantation, right?
Which is another strategy that's used for patients
with some heme malignancies.
And when we talk about transplantation, a lot
of times there are pretty significant, you know,
inequalities, non-equity among different ethnic backgrounds
because we don't have many like
minority donors in the National Marrow Donor
program, for example.
Is access
and that kind of,
is this a more equitable kind of product that we're seeing
or are there still some struggles with, with getting equity
for different populations with CAR T?
- Yeah, sadly, no, it's not a very equitable
treatment modality because really
because one of the largest barriers is, is cost.
And, and we know, you know, from other, other data that,
you know, if you're socioeconomically disadvantaged
or minority, the cost is a seriously prohibitive factor.
So I think that's one thing that people are looking at.
And there's, there's entire companies now
that are founded on, on trying to make it a more equitable,
not just for, for the, you know, people in the US
but people outside of the US.
'cause you know, we're, you know, US, Europe, some
of the Asian countries and Australia are really the only ones
that have, you know, broad access,
what we call broad access, which is still very limited.
So I, I think that is a, a huge issue moving forward,
you know, which is in healthcare in general,
there's inequities and this one really magnifies that
because of the sheer cost of delivering a CAR T product.
- And is, is the promise of an off the shelf,
not just the emergency, but could that be a cheaper option?
- Yeah, I think much cheaper option
because I mean, if you think about it,
this is a one patient, one product manufacturing.
So we're collecting the raw material from the patient,
you know, sending it off to a, a manufacturing facility,
which, you know, significant resources to,
to have a facility like that
they manufacture and then send it back.
So the, the commercial car ts at this point are somewhere
between four and $500,000 for one dose.
So it's a, it's a significant cost to patients.
- Yeah. Yeah. Yeah. Well we've been rounding with Dr.
Wiltshire talking about the importance of CAR T
for healthcare professionals.
Dr. Wiltshire, thank you for really,
I think you've gotten given our audience a lot
to think about a better understanding of how
to read this literature
and then also to continue to kind of highlight some
of the inequities in our current system.
I think hopefully for our student listeners,
this really kind of sparks some thoughts from them.
- Yeah. Thank you so much Dr. Kreuter.
- And to our listeners, thank you for joining us today.
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