Breakthroughs in the Treatment of Sickle Cell Disease

Transcript

00:00 --> 00:01Funding for Yale Cancer Answers
00:01 --> 00:03is provided by Smilow Cancer
00:03 --> 00:04Hospital.
00:06 --> 00:08Welcome to Yale Cancer Answers
00:08 --> 00:08with the director of the
00:08 --> 00:10Yale Cancer Center, doctor Eric
00:10 --> 00:11Winer.
00:11 --> 00:13Yale Cancer Answers features conversations
00:14 --> 00:14with oncologists
00:16 --> 00:16and specialists who are on
00:16 --> 00:17the forefront of the battle
00:17 --> 00:18to fight cancer. This week,
00:18 --> 00:18it's a conversation about sickle
00:18 --> 00:19cell disease with doctor Cece
00:19 --> 00:21Calhoun. Doctor Calhoun is an
00:21 --> 00:23assistant professor of medicine in
00:23 --> 00:25hematology at the Yale School
00:25 --> 00:27of Medicine. Here's doctor Winer.
00:31 --> 00:32I usually start off just
00:32 --> 00:34asking people a little bit
00:34 --> 00:34about themselves.
00:36 --> 00:37Maybe you could just tell us
00:38 --> 00:40where you grew up and
00:40 --> 00:41and where you've been and
00:42 --> 00:43how it is that you
00:43 --> 00:44became interested in
00:45 --> 00:47sickle cell disease in particular.
00:48 --> 00:50Absolutely. So I usually start
00:50 --> 00:51off with my title. But
00:51 --> 00:52since you asked me where
00:52 --> 00:53I grew up, I'm from
00:53 --> 00:55Detroit, Michigan. I'm a Midwest
00:55 --> 00:56girl,
00:56 --> 00:58born and raised, and
00:59 --> 01:00had the pleasure of doing
01:00 --> 01:01my medical school training in
01:01 --> 01:03Detroit where I'm from, in
01:03 --> 01:04my community that raised me
01:04 --> 01:05and really supported me in
01:05 --> 01:06my own medical journey.
01:07 --> 01:08It was during my time
01:08 --> 01:09in med school that I
01:09 --> 01:10had, I would say, my
01:10 --> 01:11first meaningful
01:11 --> 01:12exposure to a patient with
01:12 --> 01:13sickle cell disease.
01:15 --> 01:16And it, for me, represented
01:16 --> 01:18the nexus of so many
01:18 --> 01:19things I like. It was
01:19 --> 01:21the science. It was hematology.
01:21 --> 01:22I love the red blood
01:22 --> 01:22cell.
01:23 --> 01:23It was,
01:24 --> 01:27children and young adults with
01:27 --> 01:28sickle cell,
01:28 --> 01:30and the disease itself and
01:30 --> 01:31giving to my community.
01:32 --> 01:33And so it was there
01:33 --> 01:34that I was like, this
01:34 --> 01:35is a career path I
01:35 --> 01:37wanna pursue. I wanna be
01:37 --> 01:37a hematologist.
01:38 --> 01:40And I am a lifespan
01:40 --> 01:42hematologist here at Yale.
01:42 --> 01:43That's great.
01:44 --> 01:46And actually, you're trained
01:46 --> 01:47as a pediatrician, are you
01:47 --> 01:48not?
01:48 --> 01:50Yes. I am.
01:51 --> 01:52And I know you still
01:52 --> 01:53do a little pediatrics, but
01:53 --> 01:55you also very much focus
01:55 --> 01:57on adults
01:57 --> 01:59with sickle cell disease.
02:00 --> 02:02Do you mind just starting
02:02 --> 02:03off explaining
02:03 --> 02:04to our listeners
02:05 --> 02:08what sickle cell disease is,
02:08 --> 02:08how it
02:11 --> 02:11occurs?
02:12 --> 02:13Yeah. Absolutely. I'll do my
02:13 --> 02:15best to be brief because
02:15 --> 02:16it's something I'm really excited
02:16 --> 02:18about.
02:19 --> 02:20This is one where
02:20 --> 02:21I think we need the
02:21 --> 02:21full explanation.
02:22 --> 02:24Okay. Sounds good.
02:24 --> 02:25And including the malaria connection.
02:25 --> 02:27Oh, okay. Sounds good. So
02:27 --> 02:29sickle cell disease is a
02:29 --> 02:30disease of our red blood
02:30 --> 02:31cell, which as you know,
02:31 --> 02:33transports oxygen around our body,
02:33 --> 02:34helping to keep all of
02:34 --> 02:35our tissues healthy and safe.
02:36 --> 02:37Normally, a red blood cell
02:37 --> 02:39looks like what I describe
02:39 --> 02:40as a jelly donut. The
02:40 --> 02:42technical term, it's a biconcave
02:42 --> 02:42disc.
02:43 --> 02:44But when you have sickle
02:44 --> 02:45cell, you are born with,
02:45 --> 02:46so you inherited,
02:47 --> 02:50a genetic change wherein which
02:50 --> 02:51instead of your red blood
02:51 --> 02:52cells being shaped like a
02:52 --> 02:53jelly donut,
02:53 --> 02:55they're shaped more like a
02:55 --> 02:57crescent, banana, or a sickle,
02:57 --> 02:58which is why it's called
02:58 --> 02:58sickle cell.
02:59 --> 03:01In addition to being shaped
03:01 --> 03:02differently, they're also quite sticky
03:02 --> 03:04and quite brittle. And so
03:04 --> 03:05if we think about our
03:05 --> 03:05blood vessels
03:07 --> 03:09donut cells are carrying oxygen
03:09 --> 03:11around, very squishy, bouncing off
03:11 --> 03:12the sides of the wall,
03:12 --> 03:13delivering oxygen to where it
03:13 --> 03:14needs to go.
03:14 --> 03:16But if you replace upwards
03:16 --> 03:18of ninety five percent of
03:18 --> 03:18those cells
03:19 --> 03:20with sickled cells that are
03:20 --> 03:22shaped differently, that are brittle,
03:22 --> 03:23that are sticky, you can
03:23 --> 03:23imagine
03:23 --> 03:25maybe they're injuring the sides
03:25 --> 03:26of those blood vessels or
03:27 --> 03:28sticking to each other or
03:28 --> 03:29maybe sticking to the sides
03:29 --> 03:31of the blood vessel wall.
03:31 --> 03:32And it is that inflammatory
03:32 --> 03:34process, that inflammation
03:34 --> 03:36from damage,
03:36 --> 03:37that sick sticking together
03:37 --> 03:39and preventing the flow of
03:39 --> 03:40blood to other parts of
03:40 --> 03:40our body
03:41 --> 03:42that really is behind the
03:42 --> 03:43physiology or pathophysiology
03:44 --> 03:45of sickle cell.
03:45 --> 03:47If I can just jump in
03:47 --> 03:48for a sec, this all
03:48 --> 03:48happens
03:49 --> 03:50because of the substitution
03:51 --> 03:53of a single amino acid.
03:53 --> 03:54Is that correct?
03:54 --> 03:56That's a hundred percent correct.
03:56 --> 03:57And we found out about
03:57 --> 03:58this in the early nineteen
03:58 --> 04:00hundreds that sickle cell was described
04:01 --> 04:03as just this one small genetic
04:03 --> 04:05change has so many implications
04:06 --> 04:07for every organ in our
04:07 --> 04:09body. But that small genetic
04:09 --> 04:10change
04:10 --> 04:12leads to the gene
04:12 --> 04:14not functioning normally.
04:15 --> 04:15Absolutely.
04:16 --> 04:17And so you might say
04:17 --> 04:18to yourself, well, why do
04:18 --> 04:19we have this? You know,
04:19 --> 04:20if this is something that's
04:20 --> 04:22bad, why does sickle cell
04:22 --> 04:24disease why is it pervasive?
04:24 --> 04:25Why is it the most
04:25 --> 04:27common monogenic disorder in the
04:27 --> 04:28world? And so you kind
04:28 --> 04:29of alluded to this
04:30 --> 04:31a bit earlier in that
04:32 --> 04:33we believe that sickle cell
04:33 --> 04:35trait is protective against malaria.
04:36 --> 04:38So malaria is a
04:38 --> 04:40little kind of protozoa that
04:40 --> 04:41finds a home in our
04:41 --> 04:42red blood cells. It really
04:42 --> 04:44thrives there in a normal
04:44 --> 04:46red blood cell. But if
04:46 --> 04:47that cell is shaped differently
04:47 --> 04:47or
04:48 --> 04:49if the oxygen is lower,
04:49 --> 04:50then it can't live there.
04:50 --> 04:52So sickle cell trait is
04:52 --> 04:53protective against malaria
04:53 --> 04:54and which is why it
04:54 --> 04:56has continued to persist worldwide.
04:56 --> 04:57And do you wanna just
04:57 --> 04:58tell us for a second
04:58 --> 05:00the difference between sickle cell
05:00 --> 05:02trait and sickle cell anemia?
05:03 --> 05:05Yeah. Absolutely. So, you know,
05:05 --> 05:07like many things in life,
05:07 --> 05:08we get some from our
05:08 --> 05:09mom and some from our
05:09 --> 05:11dad. And so sickle cell
05:11 --> 05:13disease is autosomal recessive, meaning
05:13 --> 05:14that in order for you
05:14 --> 05:16to have the physical manifestation
05:16 --> 05:17of the disease,
05:17 --> 05:19you need to have one
05:19 --> 05:20part of sickle cell from
05:20 --> 05:21your mom and one part
05:21 --> 05:22of sickle cell from your
05:22 --> 05:22dad.
05:23 --> 05:25So those parents can be
05:25 --> 05:27sickle cell carriers or carry
05:27 --> 05:27the trait
05:28 --> 05:29and not have any
05:30 --> 05:30overt manifestations
05:31 --> 05:32of sickle cell disease. But
05:32 --> 05:34sickle cell anemia is when
05:34 --> 05:35you have both copies
05:35 --> 05:36and have full,
05:37 --> 05:40full fully displayed disease. But
05:40 --> 05:41so having the trait is
05:41 --> 05:42enough
05:42 --> 05:44in and of itself to
05:44 --> 05:46put be protective against malaria.
05:46 --> 05:48Yes. That is why it
05:48 --> 05:50has persisted. And when we
05:50 --> 05:52think about the mechanisms behind
05:52 --> 05:53that, there are a few
05:53 --> 05:55different theories. I think, the
05:55 --> 05:57most common theory is around
05:57 --> 05:59that cell being completely shaped
05:59 --> 06:00differently. But the other thing
06:00 --> 06:02I mentioned earlier was the
06:02 --> 06:05oxygen environment that's not conducive
06:05 --> 06:06to replication for,
06:07 --> 06:09that malaria parasite. So,
06:09 --> 06:10that is the kinda second
06:10 --> 06:12thing. If we wanna get
06:12 --> 06:13really nerdy about it. Yeah.
06:13 --> 06:15No. No. No. No. That
06:15 --> 06:15it's
06:17 --> 06:19it's it's good. And, you
06:19 --> 06:21know, in a climate where
06:21 --> 06:22there was a lot of
06:22 --> 06:22malaria,
06:23 --> 06:24you know, that is in
06:24 --> 06:25Africa,
06:26 --> 06:27then in fact,
06:27 --> 06:29it makes sense that people
06:29 --> 06:30with sickle cell trait would
06:30 --> 06:32have an advantage. They would
06:32 --> 06:33survive their malaria, they would
06:33 --> 06:34go on and
06:35 --> 06:36have children.
06:36 --> 06:38And some of those children
06:38 --> 06:39or
06:39 --> 06:41theoretically, one in four of
06:41 --> 06:43children from the that
06:43 --> 06:44that arise from two people
06:44 --> 06:46who have trait would have
06:46 --> 06:47sickle cell disease.
06:48 --> 06:49Yes. And we find that
06:49 --> 06:51worldwide, again, sickle cell disease
06:51 --> 06:53is still the most common
06:53 --> 06:53monogenic
06:54 --> 06:56blood disorder because it's not
06:56 --> 06:57just Africa, but also sub
06:58 --> 06:59but also, excuse me, India,
06:59 --> 07:00parts of,
07:01 --> 07:02Arab America, Mediterranean,
07:03 --> 07:05where sickle cell disease persists.
07:05 --> 07:07And so we estimate that
07:07 --> 07:08there are about three hundred
07:08 --> 07:10and sixty thousand new births
07:10 --> 07:10worldwide,
07:12 --> 07:13each year. So it continues
07:13 --> 07:14to remain
07:15 --> 07:16super prevalent, and the incidence
07:16 --> 07:19is also increasing. So before
07:19 --> 07:21we talk about some of
07:21 --> 07:23the complications from sickle cell
07:23 --> 07:23anemia,
07:24 --> 07:26Maybe we can take
07:26 --> 07:28another step down that sort
07:28 --> 07:29of nerdy pathway
07:29 --> 07:32as you described it. And
07:32 --> 07:33you could just explain to
07:33 --> 07:34the audience why
07:35 --> 07:35sometimes
07:36 --> 07:37in
07:38 --> 07:38very
07:39 --> 07:40young children,
07:41 --> 07:43that is after they're born,
07:43 --> 07:45that that sickle cell disease
07:45 --> 07:46isn't really much of a
07:46 --> 07:48problem at first because
07:48 --> 07:50there's still something else around
07:50 --> 07:52that that helps them.
07:52 --> 07:54So I do wanna say,
07:54 --> 07:55I believe that being a
07:55 --> 07:57nerd is very cool. Obviously,
07:57 --> 07:58I have a bias.
07:59 --> 08:00But,
08:00 --> 08:02just to answer your question,
08:02 --> 08:03absolutely. And I think we'll
08:03 --> 08:05revisit this concept as we
08:05 --> 08:06move further along in our
08:06 --> 08:07conversation. But,
08:07 --> 08:08you know, as we talked
08:08 --> 08:10about sickle cells inherited. And
08:10 --> 08:11so as you mentioned,
08:12 --> 08:13people and infants are born
08:13 --> 08:15with sickle cell. But when
08:15 --> 08:17they're younger, the physical manifestations
08:17 --> 08:19are not as prominent.
08:19 --> 08:20And it's not just because
08:20 --> 08:21children are resilient
08:22 --> 08:24and, their regenerative capacity of
08:24 --> 08:26youth is greater, but it's
08:26 --> 08:27also because of the presence
08:27 --> 08:28of fetal hemoglobin,
08:29 --> 08:30meaning the hemoglobin that we
08:30 --> 08:31make when we're a baby.
08:32 --> 08:34These cells are even larger.
08:34 --> 08:35I describe them to my
08:35 --> 08:37patients as really fat, juicy
08:37 --> 08:38cells that hold on to
08:38 --> 08:39oxygen quite well
08:40 --> 08:41and really mitigate
08:41 --> 08:42a lot of the symptoms,
08:43 --> 08:44clinical symptoms of sickle cell.
08:45 --> 08:47When we think about persistence
08:47 --> 08:48into adulthood, so people with
08:48 --> 08:49sickle cell disease who have
08:49 --> 08:51more fetal hemoglobin tend to
08:51 --> 08:52do better. And, certainly, as
08:52 --> 08:53we think about
08:53 --> 08:56our disease modifying therapies and
08:56 --> 08:57curative therapies,
08:57 --> 08:59really increasing that fetal hemoglobin
08:59 --> 09:00is something we target.
09:01 --> 09:02Wow.
09:03 --> 09:05So let's
09:05 --> 09:06talk a little bit about
09:06 --> 09:08what happens when all those
09:08 --> 09:10sticky cells clog up all
09:10 --> 09:11the blood vessels.
09:12 --> 09:14And maybe you could talk
09:14 --> 09:15about both some of
09:16 --> 09:18the common symptoms that people
09:18 --> 09:19have first, and then we'll
09:19 --> 09:20get into some of the
09:20 --> 09:21sort of
09:21 --> 09:23organ damage and complications that
09:23 --> 09:24can arise.
09:25 --> 09:27Absolutely. So the hallmark of
09:27 --> 09:29sickle cell disease clinically is
09:29 --> 09:29pain.
09:30 --> 09:31I believe that when most
09:31 --> 09:33people if you have
09:33 --> 09:35a personal connection to someone
09:35 --> 09:36with sickle cell disease,
09:37 --> 09:38then you think about
09:38 --> 09:39about unpredictable,
09:40 --> 09:41severe, debilitating pain that affects
09:41 --> 09:43their quality of life.
09:43 --> 09:44That has a lot to
09:44 --> 09:45do with the lack of
09:45 --> 09:47that oxygen blood flow, but
09:47 --> 09:48also that return of oxygen.
09:48 --> 09:50Like, if your arm has
09:50 --> 09:51ever fallen asleep and then
09:51 --> 09:52the circulation comes back,
09:53 --> 09:54but that pain is severe
09:54 --> 09:56and often equated to something
09:56 --> 09:57like a long bone fracture,
09:58 --> 09:59and can be very disruptive.
10:00 --> 10:02But because sickle cell disease
10:02 --> 10:03is a disease of the
10:03 --> 10:04red blood cell, that means
10:04 --> 10:06everywhere that blood goes, sickle
10:06 --> 10:07cells can impact.
10:07 --> 10:08And so when we think
10:08 --> 10:10about other types of organ
10:10 --> 10:10damage,
10:11 --> 10:12we we screen for,
10:13 --> 10:14eye damage like retinopathy. We
10:14 --> 10:16think about the kidneys and
10:16 --> 10:17making sure the kidneys are
10:17 --> 10:17okay.
10:18 --> 10:19Here at Yale, one of
10:19 --> 10:21our trainees is really looking
10:21 --> 10:23at the impact of neurologic
10:23 --> 10:25complications both subclinical
10:26 --> 10:28and overtly, most notably stroke,
10:28 --> 10:29which is what we have
10:29 --> 10:29a lot of data and
10:29 --> 10:31information about in sickle cell
10:31 --> 10:32disease, but people don't talk
10:32 --> 10:33about.
10:33 --> 10:35Sickle cell disease affects every
10:35 --> 10:36part of the body.
10:38 --> 10:40And typically when people are
10:40 --> 10:40diagnosed,
10:41 --> 10:43are they diagnosed as young
10:43 --> 10:43children?
10:44 --> 10:46So here in the US,
10:46 --> 10:48due to the collaboration of
10:48 --> 10:50many centers across the United
10:50 --> 10:51States and
10:51 --> 10:52tremendous advocacy efforts,
10:53 --> 10:54children with sickle cell disease
10:54 --> 10:55born in the US are
10:55 --> 10:57diagnosed on a newborn screen
10:57 --> 10:57test.
10:58 --> 10:59So many of the audience
10:59 --> 11:00may remember they have a
11:00 --> 11:01kid, and maybe they'll do
11:01 --> 11:02a heel prick and get
11:02 --> 11:03a drop of blood. And
11:03 --> 11:05it tests for many inherited
11:05 --> 11:06genetic disorders,
11:07 --> 11:08and one of those is
11:08 --> 11:09sickle cell. And what that
11:09 --> 11:11has allowed us to do
11:11 --> 11:13is detect sickle cell early
11:13 --> 11:15and intervene early because though
11:15 --> 11:16children may not have a
11:16 --> 11:17lot of pain because of
11:17 --> 11:19that fetal hemoglobin and protection,
11:19 --> 11:21they're still quite susceptible to
11:21 --> 11:22really, really,
11:23 --> 11:25severe infections that could be
11:25 --> 11:27fatal. And we diagnose them
11:27 --> 11:29and we start penicillin prophylactically
11:29 --> 11:30to really protect them and
11:30 --> 11:31give them the best chance
11:31 --> 11:33of thriving into adulthood. And
11:34 --> 11:35how long does that fetal
11:35 --> 11:37hemoglobin typically stick around? I
11:37 --> 11:38mean, you mentioned
11:38 --> 11:40that there are some people
11:40 --> 11:41who have persistence of fetal
11:41 --> 11:42hemoglobin
11:42 --> 11:43who
11:43 --> 11:45even into adulthood who may
11:45 --> 11:46have a more mild case,
11:46 --> 11:48but typically, it doesn't stay
11:48 --> 11:49around all that long. Isn't
11:49 --> 11:51that No. In people who
11:51 --> 11:53don't have sickle cell disease,
11:53 --> 11:55the hemoglobin begins to transition
11:55 --> 11:56from the mom to the
11:56 --> 11:57baby,
11:57 --> 11:58as soon as six to
11:58 --> 12:00eight weeks after birth.
12:00 --> 12:01And people who have conditions
12:01 --> 12:03of the red blood cell,
12:03 --> 12:04that hem fetal hemoglobin can
12:04 --> 12:06try to persist on its
12:06 --> 12:07own, but it really doesn't
12:07 --> 12:09last outside of the tolerant
12:09 --> 12:11infancy period, except for those
12:11 --> 12:12rare instances
12:12 --> 12:14where patients have a genetic
12:14 --> 12:16predisposition to keep that fetal
12:16 --> 12:17hemoglobin. Again, evolution is really
12:18 --> 12:19a really cool thing. Love
12:19 --> 12:21science. Humans are amazing.
12:22 --> 12:22But,
12:23 --> 12:24most people,
12:24 --> 12:26you know, it's gone when
12:26 --> 12:28they're, it it is, gone
12:28 --> 12:29by the time they're into
12:29 --> 12:31their even school age.
12:32 --> 12:33Got it. And
12:34 --> 12:35the fetal hemoglobin,
12:36 --> 12:38I mean, you mentioned transitioning
12:38 --> 12:39from maternal
12:39 --> 12:40hemoglobin
12:40 --> 12:42to to the hemoglobin of
12:42 --> 12:42the child,
12:43 --> 12:45but is that fetal hemoglobin
12:45 --> 12:46in some way related to
12:46 --> 12:47maternal hemoglobin?
12:49 --> 12:51So, you know, it switches.
12:51 --> 12:52So, you know, we make
12:52 --> 12:53all of the cells in
12:53 --> 12:55our blood. Our warehouse is
12:55 --> 12:56our bone marrow.
12:56 --> 12:57And but when we're inside
12:57 --> 12:59of our mother, she's supporting
12:59 --> 13:00us through the placenta. And
13:00 --> 13:02so as we start to
13:02 --> 13:03ramp up our own production,
13:04 --> 13:04again,
13:05 --> 13:06science is cool, humans are
13:06 --> 13:08amazing, we recognize, hey. I
13:08 --> 13:09have the capacity to make
13:09 --> 13:10my own red blood cells,
13:10 --> 13:12and our reliance on those
13:12 --> 13:13cells that were present from
13:13 --> 13:14our mother are are no
13:14 --> 13:16longer necessary. And so that
13:16 --> 13:18that first hemoglobin
13:18 --> 13:19is the fetal hemoglobin
13:20 --> 13:21that's made?
13:21 --> 13:22So I always tell my
13:22 --> 13:24patients f for heated fetal
13:24 --> 13:25hemoglobin because that's what they're
13:25 --> 13:26making when's that when they're
13:26 --> 13:28inside mom. But it takes
13:28 --> 13:30over and becomes more predominant
13:30 --> 13:31once we're outside of the
13:31 --> 13:33body. Got it. Well, we're
13:33 --> 13:35gonna have to take a
13:35 --> 13:35break now,
13:36 --> 13:37but I'm sure everyone's gonna
13:37 --> 13:39be back because you're so
13:39 --> 13:40engaging.
13:42 --> 13:43We'll be back
13:43 --> 13:45in just a minute to
13:45 --> 13:46continue our conversation
13:47 --> 13:49with Cece Calhoun, the director
13:49 --> 13:50of the sickle cell program
13:50 --> 13:51at Yale.
13:51 --> 13:53Funding for Yale Cancer Answers
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13:58 --> 14:00the midst of their cancer
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14:06 --> 14:07Smilowcancerhospital
14:07 --> 14:08dot org.
14:10 --> 14:12The American Cancer Society estimates
14:12 --> 14:14that more than sixty five
14:14 --> 14:16thousand Americans will be diagnosed
14:16 --> 14:17with head and neck cancer
14:17 --> 14:18this year,
14:18 --> 14:20making up about four percent
14:20 --> 14:21of all cancers diagnosed.
14:22 --> 14:24When detected early, however, head
14:24 --> 14:25and neck cancers are easily
14:25 --> 14:27treated and highly curable.
14:28 --> 14:30Clinical trials are currently underway
14:30 --> 14:32at federally designated comprehensive cancer
14:32 --> 14:34centers, such as Yale Cancer
14:34 --> 14:36Center and at Smilow Cancer
14:36 --> 14:37Hospital,
14:37 --> 14:39to test innovative new treatments
14:39 --> 14:40for head and neck cancers.
14:41 --> 14:43Yale Cancer Center was recently
14:43 --> 14:44awarded grants from the National
14:44 --> 14:46Institutes of Health to fund
14:46 --> 14:48the Yale Head and Neck
14:48 --> 14:50Cancer Specialized Program of Research
14:50 --> 14:51Excellence
14:51 --> 14:52or SPORE
14:52 --> 14:54to address critical barriers to
14:54 --> 14:56treatment of head and neck
14:56 --> 14:58squamous cell carcinoma due to
14:58 --> 15:00resistance to immune DNA damaging
15:00 --> 15:01and targeted therapy.
15:02 --> 15:04More information is available at
15:04 --> 15:05yale cancer center dot org.
15:06 --> 15:07You're listening to Connecticut public
15:07 --> 15:08radio.
15:09 --> 15:11Hello. This is Eric Winer
15:11 --> 15:13again welcoming you back to
15:13 --> 15:14the second half of our
15:16 --> 15:17show tonight.
15:17 --> 15:19This is Yale Cancer Answers,
15:19 --> 15:21and we're speaking with doctor
15:21 --> 15:24Cece Calhoun, director of the
15:24 --> 15:26sickle cell program at Yale.
15:27 --> 15:28So we've been talking a
15:28 --> 15:30lot about sickle cell disease
15:30 --> 15:31and some of the manifestations.
15:32 --> 15:34We haven't yet touched on
15:34 --> 15:35treatments
15:35 --> 15:37and maybe we can begin
15:37 --> 15:38talking about treatments
15:40 --> 15:43and what's available today for
15:43 --> 15:44for people who are
15:44 --> 15:46struggling to live the best
15:46 --> 15:47life they can with sickle
15:47 --> 15:48cell disease.
15:48 --> 15:49Yes. This is,
15:50 --> 15:52a interesting question, a complicated
15:52 --> 15:53question. So
15:53 --> 15:54we talked a little bit
15:54 --> 15:56earlier about how we've known
15:56 --> 15:57about sickle cell disease,
15:58 --> 15:59and its manifestations
15:59 --> 16:01for over about a hundred
16:01 --> 16:02and twenty years.
16:02 --> 16:04But really up until,
16:05 --> 16:07about nineteen ninety eight, we
16:07 --> 16:08had,
16:09 --> 16:11where the FDA approved hydroxyurea
16:11 --> 16:12for the treatment of sickle
16:12 --> 16:14cell disease. There were really
16:14 --> 16:14no,
16:15 --> 16:17disease modifying medications. We used
16:17 --> 16:18blood because it is a
16:18 --> 16:20disease a disease of the
16:20 --> 16:21red blood cell, but had
16:21 --> 16:22no interventions
16:22 --> 16:24to treat actual sickle cell.
16:25 --> 16:26In nineteen ninety eight, hydroxyurea
16:27 --> 16:29was FDA approved, and then
16:29 --> 16:30there was about a twenty
16:30 --> 16:31year gap,
16:31 --> 16:34until additional treatments were introduced.
16:35 --> 16:37Then we got Indari, which
16:37 --> 16:39is an amino acid powder
16:39 --> 16:40that's taken three times a
16:40 --> 16:42day, really thought to help
16:42 --> 16:43with,
16:43 --> 16:45that environment in which cells
16:45 --> 16:46sickle and prevent that.
16:48 --> 16:49Then we were able to
16:49 --> 16:51FDA approved Crizanlizumab,
16:51 --> 16:53which is a type of
16:53 --> 16:54infusion medication,
16:54 --> 16:56which tries to make that
16:56 --> 16:57environment less sticky. We talked
16:57 --> 16:58about how those sickle cells
16:58 --> 17:00are sticky. They stick together.
17:00 --> 17:01They block flow.
17:02 --> 17:04Also a medication called OxBryta
17:04 --> 17:07was introduced, which binds to
17:07 --> 17:08that spot where oxygen would
17:08 --> 17:09sit in the red blood
17:09 --> 17:10cell to prevent sickling.
17:11 --> 17:11But about,
17:12 --> 17:14four weeks ago, that medication
17:14 --> 17:15was abruptly discontinued.
17:16 --> 17:19And so these are options
17:19 --> 17:20to treat sickle cell disease,
17:21 --> 17:22that we have now. Now
17:22 --> 17:24you're saying Cece, but I
17:24 --> 17:25heard about gene therapy. What
17:25 --> 17:26do you mean? I thought
17:26 --> 17:27that was for sickle cell.
17:27 --> 17:28I'm picking up on the
17:28 --> 17:29vibes. Okay?
17:30 --> 17:31And even before,
17:32 --> 17:33gene therapy, we did have
17:33 --> 17:34one curative option, which is
17:34 --> 17:36bone marrow transplant.
17:36 --> 17:37We talked about early earlier
17:37 --> 17:39that the factory for our
17:39 --> 17:40red blood cells, our white
17:40 --> 17:42blood cells, and our platelets
17:42 --> 17:43is our bone marrow. And
17:43 --> 17:45so if you replace someone
17:45 --> 17:46who has sickle cell disease,
17:46 --> 17:47if you replace their bone
17:47 --> 17:49marrow with the marrow of
17:49 --> 17:51someone who doesn't have sickle
17:51 --> 17:52cell disease, who maybe even
17:52 --> 17:53only has trait,
17:53 --> 17:55then you can cure the
17:55 --> 17:55disease.
17:57 --> 17:58But that's very It's a
17:58 --> 18:00it's a it's a harsh
18:00 --> 18:01treatment too. Absolutely. And and
18:01 --> 18:01there's,
18:02 --> 18:03some number of people who
18:03 --> 18:04don't make it through that
18:04 --> 18:05treatment. Mhmm.
18:06 --> 18:07And there are many reasons
18:07 --> 18:09for that, not least of
18:09 --> 18:10which being it's important to
18:10 --> 18:11have a perfect
18:12 --> 18:13match. We wanna have a
18:13 --> 18:15perfect match for someone undergoing
18:15 --> 18:17bone marrow transplant. And
18:17 --> 18:19due to the genetic diversity
18:19 --> 18:20in us all,
18:20 --> 18:22again, we get half of
18:22 --> 18:23that needed match from our
18:23 --> 18:24mom, half of that needed
18:24 --> 18:26match from our dad. The
18:26 --> 18:27best person is usually a
18:27 --> 18:28full sibling, which isn't always
18:28 --> 18:29an option,
18:29 --> 18:31and then enters gene therapy.
18:33 --> 18:34Got it. And and, of
18:34 --> 18:36course, an identical twin wouldn't
18:36 --> 18:37do you any good because
18:37 --> 18:38that twin would also have
18:38 --> 18:40sickle cell disease. Yes. Likely
18:40 --> 18:42so. Yep. Yep. Exactly.
18:44 --> 18:45So tell us about gene
18:45 --> 18:46therapy which,
18:47 --> 18:48has
18:48 --> 18:49been talked about a lot
18:49 --> 18:50over the last year or
18:50 --> 18:52two. Yeah. It's very exciting
18:52 --> 18:53time.
18:54 --> 18:55A new time, a time
18:55 --> 18:56of still so much discovery.
18:57 --> 18:59But another time I can
18:59 --> 19:00say being nerdy is cool.
19:00 --> 19:02Science is fun because,
19:02 --> 19:04you know, we're able to
19:04 --> 19:06mitigate that challenge of not
19:06 --> 19:08having a good match by
19:08 --> 19:09allowing a person to be
19:09 --> 19:11their own match
19:11 --> 19:11for,
19:12 --> 19:13a curative option.
19:14 --> 19:15And so there are two
19:15 --> 19:16main ways in which we
19:16 --> 19:18do that now. One of
19:18 --> 19:19those is through a technology
19:19 --> 19:21called CRISPR Cas9
19:22 --> 19:23where a certain spot in
19:23 --> 19:24our genetic code can be
19:24 --> 19:25identified
19:26 --> 19:27and then removed.
19:27 --> 19:28In that instance,
19:29 --> 19:30the goal of that intervention
19:30 --> 19:32and therapy is to
19:32 --> 19:33take away that gene that
19:33 --> 19:35tells us when we're kids
19:35 --> 19:37to stop making fetal hemoglobin
19:37 --> 19:38like we talked about earlier.
19:38 --> 19:40So then your fetal hemoglobin
19:40 --> 19:41starts to ramp up,
19:41 --> 19:43and your percent of sickled
19:43 --> 19:45cells are decreasing, thus offering
19:45 --> 19:46a cure. And
19:47 --> 19:48in that setting, how much
19:48 --> 19:50fetal hemoglobin do you wind
19:50 --> 19:50up with?
19:51 --> 19:52So it can even be
19:52 --> 19:53as much as half of
19:53 --> 19:54your,
19:54 --> 19:55cells
19:55 --> 19:58making fetal hemoglobin, thus making
19:58 --> 19:59you more like a trait
19:59 --> 20:00status like we talked about
20:00 --> 20:02earlier where the symptoms aren't
20:02 --> 20:03as obvious,
20:03 --> 20:05it doesn't affect your organs,
20:05 --> 20:06the quality of life is
20:06 --> 20:08totally And half is enough?
20:08 --> 20:10It is ideally more, but
20:10 --> 20:11half is enough to take
20:11 --> 20:12you to trait status. Yep.
20:13 --> 20:14Wow. So you said there
20:14 --> 20:15were two ways of doing
20:15 --> 20:17this, I think. Yes. The
20:17 --> 20:20second way is through something
20:20 --> 20:21we say we call using
20:21 --> 20:22a viral vector
20:22 --> 20:23or using
20:24 --> 20:25the the
20:26 --> 20:28intelligence of viral viruses and
20:28 --> 20:29viral infections
20:29 --> 20:30to introduce
20:31 --> 20:32new genetic code
20:33 --> 20:33into
20:34 --> 20:35our stem cells or the
20:35 --> 20:37parent cells of our red
20:37 --> 20:37blood cells.
20:39 --> 20:40Actually, that method has been
20:40 --> 20:42around longer than the CRISPR
20:42 --> 20:43Cas9 technology.
20:44 --> 20:45And what that does is
20:45 --> 20:46it actually creates
20:47 --> 20:48non sickling hemoglobin.
20:49 --> 20:50So rather than saying, hey.
20:50 --> 20:52I wanna increase hemoglobin f,
20:53 --> 20:54and really get that going.
20:55 --> 20:56This one says, actually, I
20:56 --> 20:57want you to make new
20:57 --> 20:59hemoglobin that doesn't sickle at
20:59 --> 21:00all. And again, the goal
21:00 --> 21:02is to have a robust
21:02 --> 21:03amount of that new hemoglobin
21:03 --> 21:05around such that sickle cells
21:05 --> 21:06are not impacting,
21:07 --> 21:09the person's organs,
21:09 --> 21:10clinical manifestations,
21:11 --> 21:12and or quality of life.
21:12 --> 21:13And when was the first
21:13 --> 21:15time gene therapy was given
21:15 --> 21:16for sickle cell disease?
21:17 --> 21:18Do you mean in an
21:18 --> 21:20FDA approved setting or in
21:20 --> 21:22a research setting? In a
21:23 --> 21:24let's say a research setting
21:24 --> 21:26even. Oh, okay. So it's
21:26 --> 21:27been years, actually. I mean,
21:27 --> 21:28there's a great group at
21:28 --> 21:30the NIH led by John
21:30 --> 21:32Tisdell and Courtney Fitzhugh, who
21:32 --> 21:34are really amazing transplanters,
21:35 --> 21:36who have done the preliminary
21:37 --> 21:38work for this,
21:39 --> 21:40have been doing this for
21:40 --> 21:41many, many years. It was
21:41 --> 21:43FDA approved in December of
21:43 --> 21:45last year. So Wow. Yeah.
21:45 --> 21:46So it's still very, very
21:46 --> 21:47new, and we're still learning
21:47 --> 21:48so much.
21:48 --> 21:50And what are the complications
21:50 --> 21:51of gene therapy?
21:52 --> 21:53Yeah. So, you know, we
21:53 --> 21:54didn't talk in detail about
21:54 --> 21:56the bone marrow transplant process,
21:56 --> 21:58but it mirrors very much
21:58 --> 21:59the gene therapy process.
22:01 --> 22:02First, we have to pick
22:02 --> 22:03the right candidate. Who is
22:03 --> 22:05a person that whose organs
22:05 --> 22:06are healthy enough to be
22:06 --> 22:07able to go on this
22:07 --> 22:09journey? Who has the psychosocial
22:09 --> 22:10support that they need to
22:10 --> 22:11go on this journey? Who
22:11 --> 22:12has,
22:12 --> 22:14proximity and treat, to a
22:14 --> 22:15treatment center that can do
22:15 --> 22:16this safely. Right?
22:16 --> 22:18Once that's established,
22:18 --> 22:20then, you know, we, in
22:20 --> 22:21the gene therapy process,
22:22 --> 22:23you have to harvest someone's
22:23 --> 22:24stem cells. And so you
22:24 --> 22:26can do that through a
22:26 --> 22:27process called, apheresis,
22:28 --> 22:29which we use in sickle
22:29 --> 22:30cell to replace
22:30 --> 22:31abnormal red blood cells with
22:31 --> 22:33normal ones. But that may
22:33 --> 22:35require several rounds of that
22:35 --> 22:35procedure.
22:36 --> 22:37And while that,
22:37 --> 22:39those stem cells are off
22:39 --> 22:41being processed and made new
22:41 --> 22:41and whole,
22:42 --> 22:43the person can we have
22:43 --> 22:44to keep them healthy. Right?
22:44 --> 22:45We gotta continue to make
22:45 --> 22:46sure their sickle cell isn't
22:46 --> 22:48having a deleterious effect on
22:48 --> 22:49their body. And when it's
22:49 --> 22:51time to receive those cells,
22:52 --> 22:53this is when it really,
22:53 --> 22:54really mirrors bone marrow transplant.
22:54 --> 22:55So the person has to
22:55 --> 22:56come into the hospital,
22:57 --> 22:58They get chemotherapy,
22:59 --> 23:00which helps their body recognize,
23:01 --> 23:02make room for those cells
23:02 --> 23:03and make sure that their
23:03 --> 23:05body doesn't attack these new
23:05 --> 23:05cells.
23:06 --> 23:07That means during this time,
23:07 --> 23:09their immune system is nearly
23:09 --> 23:11zero. Right? Because this chemotherapy
23:11 --> 23:12is not just taking out
23:12 --> 23:13the red blood cells, it's
23:13 --> 23:14taking out our white blood
23:14 --> 23:16cells that help us fight
23:16 --> 23:17infection and our platelets
23:17 --> 23:19that help us, helps prevent
23:19 --> 23:21bleeding acutely. And so we
23:21 --> 23:22become their immune system.
23:23 --> 23:24We become their platelets. And
23:24 --> 23:25so they have to stick
23:25 --> 23:27with us during that. The
23:27 --> 23:28type of chemo chemotherapy that
23:28 --> 23:30they get can have impacts
23:30 --> 23:32on fertility and other organ
23:32 --> 23:32functions.
23:33 --> 23:34And then eventually,
23:34 --> 23:35after some time,
23:36 --> 23:37then those cells begin to
23:37 --> 23:39grow on their own, those
23:39 --> 23:40new stem cells.
23:40 --> 23:41And
23:41 --> 23:42so we take,
23:43 --> 23:44this is a a journey,
23:44 --> 23:45certainly,
23:46 --> 23:47and the risks are high,
23:47 --> 23:49but the reward is also
23:49 --> 23:50quite high.
23:50 --> 23:52But not necessarily for the
23:52 --> 23:54faint of heart. Oh, no.
23:54 --> 23:56Absolutely not. And, you know,
23:56 --> 23:58we think about how we
23:58 --> 23:59deliver gene therapy and keeping
23:59 --> 24:00the patient safe.
24:01 --> 24:02But one of the things
24:02 --> 24:02that I think is a
24:02 --> 24:03hallmark of,
24:04 --> 24:06a good sickle cell center
24:06 --> 24:07is
24:07 --> 24:09caring for the whole patient
24:09 --> 24:10and, you know, not just
24:10 --> 24:11when they're with us, but
24:11 --> 24:12also ensuring
24:12 --> 24:13the goal is for them
24:13 --> 24:14not to just survive, but
24:14 --> 24:16to really thrive. And that
24:16 --> 24:16means
24:16 --> 24:18how is their life affected
24:18 --> 24:19by the treatments that are
24:19 --> 24:21gonna cure them? How are
24:21 --> 24:23their families affected their children,
24:23 --> 24:24you know, really keeping them
24:24 --> 24:25whole. So
24:26 --> 24:26Wow.
24:28 --> 24:30Well, I'm sure that, in
24:30 --> 24:31the years ahead, we will
24:31 --> 24:34somehow figure out ways of
24:34 --> 24:36delivering this therapy and having
24:36 --> 24:37it be more tolerable.
24:38 --> 24:39And in the meantime, there'll
24:39 --> 24:41be some people who will
24:41 --> 24:43who are choosing to do
24:43 --> 24:44this. Yes. Yes. Certainly. I
24:44 --> 24:46think plant there are
24:46 --> 24:47more than just a few
24:47 --> 24:48people who are choosing to
24:48 --> 24:49do this because
24:50 --> 24:52of life with sickle cell
24:52 --> 24:54disease. That risk becomes worth
24:54 --> 24:55it. So
24:55 --> 24:56Yeah.
24:57 --> 24:58So I wanna
24:58 --> 24:59end,
25:00 --> 25:02on a somewhat different note,
25:03 --> 25:04and as
25:04 --> 25:05challenging
25:06 --> 25:07and horrific as it can
25:07 --> 25:08be
25:08 --> 25:09to have to deal with
25:09 --> 25:10the pain of sickle cell
25:10 --> 25:12disease and everything with it,
25:14 --> 25:15I think that
25:16 --> 25:17one of the,
25:17 --> 25:19in many ways, equally painful
25:20 --> 25:21parts is that, I think,
25:21 --> 25:22for many years,
25:23 --> 25:25sickle cell being largely a
25:25 --> 25:26disease in the US
25:27 --> 25:28that arose in people who
25:28 --> 25:29are black
25:30 --> 25:32was a disease that I
25:32 --> 25:34think people very often didn't
25:34 --> 25:35get the kind of treatment
25:35 --> 25:37that they should have.
25:37 --> 25:38And
25:38 --> 25:40I remember being a young
25:40 --> 25:41doctor,
25:41 --> 25:42and
25:42 --> 25:44I will just share that
25:44 --> 25:45the way
25:46 --> 25:47people talked about patients with
25:47 --> 25:49sickle cell disease wasn't
25:49 --> 25:51wasn't okay.
25:52 --> 25:53And
25:55 --> 25:56just like you to reflect
25:56 --> 25:58a little bit on on
25:58 --> 26:00the disparities patients with sickle
26:00 --> 26:01cell disease face
26:02 --> 26:03and how much of that
26:03 --> 26:05is due to just the
26:05 --> 26:06fundamental
26:06 --> 26:08racism that exists in our
26:08 --> 26:08society.
26:09 --> 26:11Absolutely. So, you know, we
26:11 --> 26:13know that how we deliver
26:13 --> 26:13care,
26:14 --> 26:15and
26:16 --> 26:18our capacity as providers and
26:18 --> 26:20ultimately health outcomes are driven
26:21 --> 26:23by larger things. So we
26:23 --> 26:24know that
26:25 --> 26:25as prejudice
26:26 --> 26:26and racism
26:27 --> 26:29infuses into our institutions,
26:29 --> 26:31those affect our policies.
26:32 --> 26:34Those policies affect our environments.
26:34 --> 26:36Right? Whether it is a
26:36 --> 26:37living environment,
26:37 --> 26:40funding environments for research and
26:40 --> 26:40innovation.
26:41 --> 26:43And those things affect ultimately
26:43 --> 26:43diagnosis,
26:44 --> 26:45treatment, and then really mortality.
26:46 --> 26:47It's not even in just
26:47 --> 26:49sickle cell disease. We know
26:49 --> 26:50that that is across the
26:50 --> 26:51board. I think most notably,
26:51 --> 26:53we saw that. Most recently,
26:53 --> 26:54we saw that during the
26:54 --> 26:55COVID pandemic.
26:56 --> 26:57And then also when we
26:57 --> 26:58look at data around,
26:58 --> 27:00black infant and maternal mortality.
27:01 --> 27:01Absolutely.
27:02 --> 27:03The stigma with sickle cell
27:03 --> 27:04disease
27:04 --> 27:06mirrors the stigma
27:06 --> 27:07of being
27:08 --> 27:09an African American
27:09 --> 27:11in the US health system.
27:11 --> 27:12And then also having a
27:12 --> 27:14disease that
27:14 --> 27:15has pain, which is treated
27:15 --> 27:17by opioids. Right? So there's
27:17 --> 27:18this other layer.
27:19 --> 27:20We see that come up
27:20 --> 27:21in funding,
27:22 --> 27:23again, which which is which
27:23 --> 27:24for us drives a lot
27:24 --> 27:26of innovation like gene therapy.
27:26 --> 27:27We see the funding disparities
27:27 --> 27:29between other diseases, like people
27:29 --> 27:30like to compare to CF
27:30 --> 27:32a lot, which is another
27:32 --> 27:32rare disease.
27:33 --> 27:35We see that in provider
27:35 --> 27:37CF meaning cystic fibrosis. Yes.
27:37 --> 27:39Cystic fibrosis. I'm so sorry.
27:40 --> 27:41Yes. Cystic fibrosis.
27:41 --> 27:43We see that in,
27:43 --> 27:44provider attitudes,
27:45 --> 27:47like in training, like what
27:47 --> 27:48you just mentioned and kind
27:48 --> 27:49of, like, working on that
27:49 --> 27:50stigma.
27:51 --> 27:52We see that,
27:53 --> 27:53in
27:54 --> 27:56how society views persons with
27:56 --> 27:57Sickle Cell Disease as well.
27:57 --> 27:59And it's a very salient
27:59 --> 28:00and current issue. I think
28:00 --> 28:02what we are doing now,
28:03 --> 28:05acknowledging that this exists and
28:05 --> 28:07then thinking about in the
28:07 --> 28:08scope of our own power,
28:08 --> 28:09how do we change that?
28:09 --> 28:11So is it educating our
28:11 --> 28:12peers? Is it making the
28:12 --> 28:14right decision for the right
28:14 --> 28:15patient at the right time?
28:16 --> 28:17Is it creating space and
28:17 --> 28:20acknowledging the historical disparities and
28:20 --> 28:21inequities that have led to
28:21 --> 28:22this point? You know, there's
28:22 --> 28:25so many ways to to
28:25 --> 28:26address this issue that continues
28:26 --> 28:27to remain pervasive
28:28 --> 28:29in our industry.
28:29 --> 28:31Doctor Cece Calhoun is an
28:31 --> 28:33assistant professor of medicine and
28:33 --> 28:35hematology at the Yale School
28:35 --> 28:35of Medicine.
28:36 --> 28:37If you have questions, the
28:37 --> 28:39address is cancer answers at
28:39 --> 28:40yale dot e d u,
28:40 --> 28:41and past editions of the
28:41 --> 28:43program are available in audio
28:43 --> 28:44and written form at yale
28:44 --> 28:46cancer center dot org. We
28:46 --> 28:47hope you'll join us next
28:47 --> 28:48time to learn more about
28:48 --> 28:49the fight against cancer.
28:50 --> 28:51Funding for Yale Cancer Answers
28:51 --> 28:53is provided by Smilow Cancer
28:53 --> 28:54Hospital.

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Breakthroughs in the Treatment of Sickle Cell Disease with guest Dr. Cece Calhoun, December 1, 2024