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A Mayo Clinic podcast for laboratory professionals, physicians, and students, hosted by Justin Kreuter, M.D., assistant professor of laboratory medicine and pathology at Mayo Clinic, featuring educational topics and insightful takeaways to apply in your practice.
- 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.
We invite you to share your thoughts
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to MCLeducation@mayo.edu.
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