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Hematology Portraits: Prof Brian Huntly · EHA Unplugged

0:02
Greetings and welcome to EHA Unplugged, the official podcast
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channel of the European Hematology Association, EHA.
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Hello, I am Isabella Livera, a medical writer for EHA.
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In this series, we are trying to explore the world of hematology
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through conversations with leading experts in the field.
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Today we are thrilled to have Professor Brian Huntley, Head of
0:28
the Department of Hematology at the University of Cambridge.
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Professor Huntley is a renowned clinical research scientist and
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consultant in hematology at Addenbrooke's Hospital, and he's
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known for his groundbreaking work in leukemia stem cell
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biology. Thank you for being with us
0:49
today. So to start off, we would like
0:55
to learn where your journey started.
1:00
What is your first memory of hematology?
1:05
Thanks for inviting me. It's very nice to be here.
1:07
My first memory of hematology was as an undergraduate.
1:11
You learn all about body systems, and I think even at
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that time blood kind of fascinated me because of its
1:18
accessibility. You can take a tissue sample
1:22
from literally a blood test. Many of the sort of basic
1:26
biochemical principles were worked out in blood and blood
1:29
cells, and that kind of subliminally stayed with me and
1:36
was one of the reasons that I wanted to take it up as a
1:39
clinical specialty, this mix of science and clinical medicine.
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And then I think it was one of the things that directed me
1:46
towards a sort of career in science.
1:50
Because you are a trained medical doctor and then you have
1:54
been doing research and translating that research always
1:59
to clinics. Yeah, I mean, it's a sort of
2:02
circular route. I, I, I wouldn't say that my
2:07
trajectory and my path was, was a classical one because I didn't
2:10
do much science until I, I had trained and, and specialized as
2:16
a hematologist. And then I decided I wanted to
2:19
try and do some medical science. So I did a PhD and then I've not
2:25
really looked back, but it, it certainly was the, the
2:29
application of science and the sort of basic mechanisms that
2:32
were much better studied in blood disorders and in other
2:36
disorders that made me decide to be a clinical hematologist.
2:40
And then when I was studying for my postgraduate hematology
2:43
exams, again, I wanted to explore the science more.
2:47
So that's why I decided to step back from clinical medicine and
2:52
to to pursue a PhD. And what led you to focus on
2:57
leukemia and stem cell biology? Yeah.
3:00
I mean, I think that as a practicing hematologist in the
3:05
UK, your, your practice is dominated by malignant
3:08
hematology. And to my mind, not only is it
3:12
the most common problem, it's the most intractable problem.
3:15
And it, and it continues. So this day, I mean, and I've
3:19
been a researcher in hematology for 25 years and I'm embarrassed
3:24
to say that we have improved the field, but we still have a great
3:27
deal of work to do. And the things that you remember
3:30
are probably more your failures rather than your successes.
3:34
And I study predominantly acute myeloid leukemia, which is a
3:38
very, very aggressive disease. And we still do very poorly in
3:42
terms of the numbers of patients that we cure.
3:44
However, we do cure a good number of of younger patients.
3:50
And so it was interesting, it was difficult and we weren't
3:55
really doing very well. So that was the reason for sort
3:57
of gravitating towards leukemia biology rather than studying
4:02
blood coagulation or or red blood cell disorders, which are
4:06
equally interesting. But in my practice, we're just
4:10
not as difficult problems and and I felt that that there was
4:14
more needed to be done in those than in other areas.
4:21
So your research has had several notable discoveries.
4:28
One of the significance findings was that the demonstration that
4:32
chronic and acute myeloid leukaemia may arise in separate
4:36
stem cell progenitor cells. Why is this important?
4:43
Well, I think it's, it's important to know how cancer
4:49
changes the normal behaviour of a tissue system.
4:54
And it's important to know where it comes from and how it
4:58
develops. And, and with that knowledge,
5:00
you can understand how you might be able to target it when it
5:06
develops as a full blown disease.
5:08
But also it, it, it provides the basis for working out how it
5:12
develops. And there's this concept of
5:15
earlier interception now where you can intervene earlier in
5:18
processes. And if you know the, the cell
5:21
that is giving rise to the, the problem and the cell that causes
5:26
relapses of disease, then it's easier to try and target that
5:32
that cell and to potentially eradicate the, the, the
5:36
leukemia. So we need to sort of understand
5:40
how the hierarchies of normal blood formation are aberrant
5:45
within leukemias, and that helps us to think about how we might
5:51
target leukemia stem cells for better eradication and what I
5:56
was talking about, which is trying to improve cure rates.
6:02
Another milestone in your career is that you describe what it's
6:07
the essential role for BET transcription and regulators in
6:13
AML RBT inhibitors, now a novel therapeutic approach, are they
6:20
being used? So the BET proteins are, are
6:24
transcriptional regulators and they're involved with various
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stages of transcription and they're cancer cells are
6:32
addicted to them. So they are, they're, they're
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obvious targets like a lot of these transcriptionally active
6:40
proteins, they are important for cancers.
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But over a long period of time and as single targets, the the
6:53
inhibitors have been not particularly successful, but
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they're now moving into combination studies and my hope
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is that they will be much more successful there.
7:06
You have also done work looking at the sale of origin of
7:13
malignant lymphomas. What can you say about this?
7:16
We performed a study to look at one of the mutations that is
7:20
associated with a number of forms of lymphoma called Kreb
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BP. Like the BET proteins, it's
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again a transcriptional active protein and it has a number of
7:32
functions. What we found was that if you
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lost the activity of this protein at different stages
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within B cell development, that it had different consequences.
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And we could show that malignant lymphoma was only developed when
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it was lost earlier in lymphoid development rather than within
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mature lymphoid cells. And I think this fits with some
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of the data from human studies where it's suggested to be a
8:06
very early and possibly even an initiating event.
8:10
And again, it suggests that we should perhaps be thinking about
8:14
targeting these earlier events in these earlier cell
8:18
compartments. And, and, and that's what we're
8:21
studying further at the moment and we're looking into its
8:24
effects to modulate metabolism. So now you're looking how to
8:32
target earlier stages of differentiation.
8:38
In which way study? So we we've been looking at
8:42
studies to see how these diseases develop.
8:46
We do a lot of studies which look at early mutations in
8:51
leukaemias and lymphomas and how these diseases evolve and
8:57
important processes have to occur to fully transform cells.
9:02
And we've been doing a number of studies across a number of
9:05
diseases which are trying to identify targets for therapeutic
9:09
intervention and then possibly to think about ways that we
9:13
might intervene as early as possible.
9:16
If you look across the majority of cancers and the earlier that
9:21
you initiate treatment, often the better are the consequences.
9:25
And it's not a weird science to think that we might be able to
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significantly delay the progression of earlier diseases
9:34
into more aggressive ones or possibly even think about
9:38
prevention of some of these hematologic malignancies.
9:41
And we're interested in that early biology and whether or not
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you can identify targets that you can think about intervening
9:50
as soon as you know that there's there's an issue.
9:54
So for the moment you're trying to understand what happens
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early, but there is not always then a drug or a treatment that
10:03
will come out of it. You're very interested in the
10:07
basic mechanism. The majority of the lab kind of
10:13
focuses on the mechanisms of why these things happen, why these
10:17
diseases develop, how they change through that evolutionary
10:20
process. But the, the, the, the way that
10:24
I have trained as a doctor first and a scientist second, I, I
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think you always have that line of sight to the clinic.
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You're always thinking about not just a mechanism, but a
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potential target. We almost always try to make
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comparisons between malignant tissues, whether those are
10:43
myeloid cells or lymphoid cells, and their normal counterpart.
10:48
You know, if we're looking at a leukemia stem cell, we're always
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trying to compare the differences with a normal stem
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cell and we're looking to, to find things that are specific to
10:58
the disease because they're much likely to be better targets.
11:02
You, you, you, you can't just target things that are required
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for normal stem cell function or you'll just disable blood
11:09
formation completely. And that's not going to be any
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better than the current chemotherapies that we use.
11:15
How does this research integrate with your clinical practice?
11:19
Yeah, in two ways. So, So first of all, my, my
11:22
clinical plaque practice is less than it used to be, given that
11:25
I've got a lot of administrative duties nowadays as well.
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But it's always informed my clinical practice in terms of
11:35
trying to think of better ways to treat people, more clever
11:39
ways to treat people, thinking about better combinations for
11:42
them. But I think it works in the
11:44
opposite direction as well. And I come out of clinic
11:49
sometimes quite frustrated because I can't do things for
11:52
people. So it makes me committed and
11:57
motivated to get back to the lab and to try and work a little bit
12:01
harder. Or sometimes you identify a
12:04
problem from a clinical encounter and you think that's
12:08
very interesting. I wonder how that works.
12:10
And that might give you a research idea for, for a next
12:14
project or it will inform the way that you deal with a current
12:17
project. So I I like the the way that
12:21
they work together, but it does make your life quite busy.
12:26
Do you have any specific example of something that you discovered
12:32
in a pension that you wanted to understand and took back to the
12:36
lab? But there's lots of things.
12:39
I mean, the, the most obvious one would be our group are
12:43
becoming very interested in the development of resistance to to
12:48
therapies, particularly newer targeted therapies.
12:52
And that's always really bugged me about why these patients
12:58
develop resistance because often with leukemias, it's patients
13:03
don't die from the primary disease.
13:05
They die because the disease comes back and it comes back and
13:08
it's more resistant. So I think that has informed a
13:12
whole, you know, perhaps 1/3 of my lab work on resistance to
13:16
therapeutics and and that has come from the frustration of
13:19
seeing patients relapse continuously.
13:26
So you're a member of the European Hematology Association,
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EHA, and you are a very active member.
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You're in the executive board. How has EHA influenced your
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career? I think in in quite a number of
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ways, the first international conference I ever went to was
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EHA in Barcelona in the last, the last Millennium.
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The first conference that I actually gave an oral
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presentation was EHA and during my PhD, and I was very lucky
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when I came back from the, my postdoc in the States that EHA
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gave me some money at a time when I was setting up my own
14:12
group. And that was hugely appreciated.
14:15
All of the other people that gave me money had, you know, I
14:18
had to follow a very rigorous, you can spend on this, you can
14:22
spend on that. EHA gave me the money and said,
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you know, you do what you you think is best to further your
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career. So that was both appreciated and
14:30
the freedom to do what I wanted with it, which which was
14:33
something a little bit more risky and that perhaps the
14:37
funding agencies in the UK wouldn't have allowed me to do.
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So I sort of decided that I would, you know, try and pay Jay
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back. I've sat in a lots of committees
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and and, and various organizing committees for some of the
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scientific meetings. But but it's it's great fun as
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well. So I'm you you give, but you get
15:01
back. And I think it's a very
15:02
worthwhile organization or, you know, I probably wouldn't be
15:05
doing half the things that I do, but yeah.
15:09
So I I've kind of grown up with the HA.
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I've been a member for yeah, more than 25 years it.
15:18
Has really been there for you during your whole career?
15:23
It has help you grow also being eha by the connections or.
15:28
I think it has, and it's given me a great kind of venue through
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the Congress to present my science.
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I've been lucky enough to give lots of presentations, so it's
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helped my career. It's very sociable.
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I mean, it's, it's always nice going to a nice European city in
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the summer, meeting up with your friends.
15:49
Latterly, when I've been more heavily involved in the
15:51
organization, it's given me a lot of pride to, you know, to
15:55
have organised things. So yeah, it's been, yeah, very
16:00
enjoyable, but also rewarding. So you have so many different
16:07
activities because as a you are a clinician, although now a
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little bit less, but during your life you have been very involved
16:15
with patients, also in research, I imagine in education and also
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in all these societies, specifically EHA.
16:24
Which one of these activities do you enjoy the most?
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And the science, definitely the science.
16:34
I like the variety. And you know, I get asked this
16:37
quite a lot by younger clinician scientists because it's quite
16:41
difficult to try and balance all of these variable parts of your
16:44
career. But I think it's it's good as
16:48
well because you don't get the chance to become stale and
16:53
you're moving from one thing to another.
16:56
And particularly with medicine and with science, they work on
17:02
completely different timescales. So in medicine you can see a
17:07
patient in clinic, see a patient on the ward, you can immediately
17:09
help them and, and you know, you get a lot of satisfaction for
17:13
that. In science project projects can
17:16
take years, literally years to read out.
17:19
With both of them. There are peaks and troughs, but
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they work on different time scales.
17:24
And I think they, they, they dovetail quite nicely and they
17:29
feed off each other. I do a lot of administration as
17:33
well. And that can again be quite
17:36
harrowing. But again, it can give you
17:39
pleasure. And I always say that it's very
17:41
seldom that I'm having a bad day in the clinic, in the admin and
17:47
with the science, at least one of them is giving you some
17:49
pleasure. I can certainly work a lot
17:51
harder if I'm doing one thing, then another thing, then another
17:56
thing back to the first one. If I was doing the same thing
18:00
for 10 hours a day, then I think I'd find it both boring and
18:04
tiring. But if, if you have variety,
18:07
then I think it's it's interesting and it, it allows
18:12
you to, to sort of do a lot. So you enjoy very much changing
18:17
and the. Variety of not all the time, but
18:19
yeah, in, in general, you're not having a bad time with with
18:24
everything. There's always something that
18:25
you can get satisfaction from and something that you can feel
18:28
that you've done a good job on. So looking back at all this
18:34
work, what would you recommend to a young medical doctor that
18:41
is choosing their path now? I think you've got to do things
18:46
that that you're passionate about.
18:50
It's not easy and not suggesting it is easy to you, you really
18:55
have got to want to do it because it will be difficult at
18:58
times and you'll need to fall back on something that really
19:02
excites you or drives you and motivates you.
19:04
So I would always say sort of follow your passions.
19:08
You've got to be quite disciplined with your time.
19:12
Well, I do, I do far too many things.
19:14
And most people, they do research on one thing and they
19:17
do more and more. I do biz that and that and that.
19:20
But it's, you know, it's what what interests me.
19:23
So I always I've always done what I've found interesting.
19:26
So I. Think what you do is closer to
19:28
what I used to do because I was working reading stem cells and
19:32
for me it was how does this work?
19:34
Those basic questions of what is the sale of origin?
19:39
For me, it's always what I'm thinking of when I see all
19:42
these, you know, the new treatments or everything.
19:46
Where where does this? Come from, you know, the fact
19:48
that these things keep on coming back, you know, we're either not
19:51
getting to the root or they're just developing ways around it.
19:55
So yeah, it it it it both interests and annoys me in equal
20:01
measure. And now with all the tools to,
20:05
you know, sequence everything at the same time, and with AI to
20:10
compare this in a much more efficient way, are you advancing
20:15
quicker? I think we're advancing
20:16
knowledge quicker than therapy. And unfortunately the, the, the
20:21
advances in knowledge let us know how oversimplified we've
20:26
thought about the problems. 10 or 15 years ago, we thought of
20:32
tumors as much more sort of homogeneous entities.
20:35
Now we've got sort of cell biological hierarchies.
20:39
And even if you look at things that that are supposedly the
20:42
same type of cell, you look at the genetics in them, they're
20:45
slightly different. You look at the transcription
20:48
within them, they're definitely different.
20:49
You look at the proteins, they're even more different.
20:51
So we're sort of dealing with a much more complicated problem
20:56
than we had imagined. But you know, those advances
21:03
that we've made in terms of knowledge are really translating
21:06
greatly into new drugs. There's not that many of them
21:10
that are complete step changes. I I would say that things like
21:16
CAR T cells and immunotherapy, they, they really are a whole
21:20
new sort of modality and, and they are significantly changing
21:25
things, but they again are not curing everybody.
21:28
We're catching up, but the problem's becoming more
21:31
difficult as well because our knowledge is improving.
21:35
I'm very confident that we can significantly improve on how
21:40
well we're doing. And you know, what I was trying
21:43
to get through was that we now know about how long period these
21:51
diseases develop over and we we thought they kind of happened.
21:56
It was all kind of perfect storm, everything come together
21:59
and and all of a sudden, bingo, you've got cancer.
22:01
It's not like that at all. You know, with blood cancers,
22:04
some of these complicated ones can take 20, thirty, 40-50 years
22:10
and we can detect some of these pre malignant mutations at
22:17
earlier stages. And that gives us, I think and
22:21
the opportunity to think about intervening earlier.
22:24
Now the difficulty is that patients will go 25 of those 30
22:30
years without a diagnosis. They're not patients.
22:34
We don't really have a reason to look for these disorders, and
22:40
they're not common enough for us to be able to justify whole
22:43
scale screening projects for them.
22:47
So we're getting a better idea of the sort of Natural History
22:50
of these disorders, and we're also trying to work out how
22:57
related they are because you can have different mutations which
23:02
probably do different things to the same cell and from each
23:08
other. We don't know whether or not the
23:12
generate vulnerabilities within the cell and and then the aim
23:17
would be to try and work out what those vulnerabilities are
23:19
and can we come up with therapies that are safe enough
23:25
and non-toxic enough to think about giving them to people who
23:29
are not yet patients. And there are there are
23:33
significant ethical questions. There's questions about whether
23:36
they should know because we cannot tell them confidently
23:42
what will happen. We can tell them what might
23:45
happen. So we're at that stage where we
23:49
know a lot, but we're just trying to learn a little bit
23:53
more about how to predict what would happen, because not all of
23:57
these patients with one mutation will go on to develop a
24:01
significant disease. Knowledge is great, but it
24:04
brings responsibility with it. It's easy to describe things,
24:07
but it's difficult to tell what's going to happen
24:10
thereafter. So we're at a great stage, but
24:13
we need to know a lot more. We need to predict a lot better,
24:17
identify the patients that are really going to do badly.
24:20
So is it? Each patient will have a very a
24:25
unique cancer at the end of the day.
24:27
Even in relatively simple cancers like acute leukemias,
24:30
which have between 3:00 and 5:00 mutations, if you catalogue all
24:36
of the mutations within those patients and all of the other
24:41
abnormalities that are non genetic, it's it's not crazy to
24:47
say that almost every cancer is slightly different.
24:51
But we do know that some of them are very similar.
24:55
And we take advantage of that through personalized medicine
24:58
to, to, to treat the common single mutations, the common Co
25:03
occurring mutations. If you really look hard with the
25:06
magnifying glass, they, they will all be slightly different
25:10
and the genetic makeup of every patient will be different and
25:14
the genetic, their background genetic makeup will dictate how
25:18
they respond to therapies and, and their lifestyles will depend
25:23
on that and their premorbid condition will depend on that.
25:26
So there, there's a lot of heterogeneity that we need to
25:29
factor in, but this sort of takes us into the, the, the,
25:33
the, the area of personalized medicine because it's not just
25:38
personalized for the tumor, it's personalized for the way that
25:41
the patient will respond, what other medical conditions that
25:44
the patient might have. So there are tumour specific and
25:51
tumour nonspecific areas to personalized medicine.
25:55
I'm thinking about AI because there's a lot of talk about
26:00
synthetic patients. Yep.
26:03
So with AI to create patients based on what a typical patient
26:09
will be like with what we already know.
26:13
Yeah. But at the end of the day, the
26:16
point of a clinical trial is to see also the things that we
26:23
don't know. If we're going to be basing our
26:26
knowledge on something synthetic, we're taking out a
26:29
lot of complexity that we do not master.
26:33
I think that that AI can be applied to any number of
26:39
projects to improve our understanding and hematology
26:43
that we can discuss. But in terms of synthetic
26:45
patients, the, the, the area that they're most being
26:50
discussed is to form the control group because in standards,
26:57
randomised clinical trials, even if you have more patients that
27:03
go into the treatment arm, you always have standard of care or
27:07
a placebo. Now that means that, you know,
27:10
half of your patients or a third of your patients are actually
27:14
not getting anything that might improve them above what they,
27:18
they could get outside of the clinical trial.
27:21
And so the idea of synthetic patients is to really have a
27:27
standard to compare. So if you can generate that data
27:32
synthetically, then that means that more patients can be
27:35
treated. So I think that that is a a
27:38
possible area that that we can improve trial design.
27:42
But and there are not really any standards at the moment for what
27:46
constitutes a good synthetic and set of patients.
27:51
And if you get your control arm wrong, then you can't see
27:56
anything about the patients that are treated.
27:59
So, you know, you don't want to run a clinical trial that can
28:02
say nothing just because your control arm is very poor.
28:07
So I think it's an area of very active discussion and debate.
28:12
The other people that we need to bring into that conversation
28:14
very much of the regulators because clinical trials are
28:19
generally done to improve clinical practice, but they are
28:23
often done with new agents to get them regulatory potential to
28:27
be given as standard of care. And I think that again, it's
28:32
important that these trials which cost a lot of money and in
28:36
my opinion are always done too slow.
28:39
We've got to do them properly because and there are not enough
28:44
new medications coming in. So you think, yeah, the
28:47
synthetic patients will have a place in this control?
28:50
Area I think that they will do could be that there are some
28:52
controls, but they are in some way synthetically increased in
28:57
number to allow the statistical comparisons that are required.
29:01
But I think it needs to be done through a lot of discussion.
29:04
And I know that EHA is involved significantly in these
29:08
conversations with European Affairs and the, the, the health
29:12
data steering group. And you know, these are
29:15
discussions that are occurring with EMA, so the the the
29:18
regulators at the highest level. Thank you very much, Professor
29:22
Huntley, for being with us today, for sharing your
29:25
expertise with us, and thank you to all of you for listening.
29:29
And please tune in for our next chapters.
29:32
It's a pleasure. Thank you.