Immunotherapies for Cancer

May 17, 2021

Information

May 16, 2021

Yale Cancer Center

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00:00Support for Yale Cancer Answers
00:02comes from AstraZeneca, dedicated
00:05to advancing options and providing
00:07hope for people living with cancer.
00:10More information at astrazeneca-us.com.
00:14Welcome to Yale Cancer Answers with
00:16your host doctor Anees Chagpar.
00:19Yale Cancer Answers features the
00:20latest information on cancer care by
00:23welcoming oncologists and specialists
00:24who are on the forefront of the
00:27battle to fight cancer. This week,
00:29it's a conversation about immunotherapies
00:31for cancer with Doctor Carla Rothlin.
00:34Doctor Rothlin is Dorys McConnell Duberg Professor
00:35of Immunobiology
00:37and professor of Pharmacology
00:38at the Yale School of Medicine,
00:41where Doctor Chagpar is a
00:43professor of surgical oncology.
00:45Carla, maybe we can start off by you telling
00:48us a little bit about yourself
00:51and what you do.
00:53I was born in Argentina
00:56and it is in Argentina where I did
00:59all my initial training in science.
01:01I studied biochemistry in pharmacy at the
01:04University of Buenos Aires and did
01:07my PhD at the University of Buenos Aires.
01:10And interestingly,
01:11it was in a very different area of research.
01:14My PhD was in Neuropharmacology.
01:16And then now almost 20 years
01:18ago I came to the United States.
01:22I came in particular to California
01:24to the Salk Institute,
01:26where I did my postdoctoral training,
01:29and it was there where I became
01:32fascinated by immunology and where I
01:34started to learn about immunology,
01:37and I know today we're going
01:39to talk more about it,
01:41and after doing my postdoc
01:44at the Salk Institute about
01:4612 years ago I moved to Yale,
01:49where I started my own lab and I'm
01:52at the Department of Immunobiology.
01:59I've had a wonderful time here and I'm very
02:01fortunate to have been able to
02:04start my lab at this
02:06wonderful University.
02:07So tell us more about what your lab does
02:11and what you study?
02:12We are very interested in
02:14understanding the immune response.
02:16But in particular,
02:17what we're interested in understanding
02:20is what are the mechanisms that regulate
02:23how much the immune response will be.
02:26So how do you regulate the
02:28magnitude of the immune response?
02:31And also how long that
02:33immune response will be?
02:35How do you regulate the
02:37duration of the immune response?
02:39And as you can imagine,
02:42understanding the regulation of the
02:44magnitude and the duration has
02:46tremendous implications every time.
02:47They mean responses turn on,
02:50so those are the
02:53two fundamental features of the
02:55immune response that our lab
02:57centers around.
02:58Right now when we're in the
03:00middle of this covid pandemic and
03:03people are getting vaccinated,
03:05I think a lot of people are thinking
03:08about the immune response in terms
03:10of vaccines and how long that
03:13immunity from the vaccine will last.
03:16Has your lab thought about that?
03:20How do we gauge how
03:23long an immune response will last
03:26from a vaccine, for example?
03:29That's a very,
03:31very interesting question.
03:32When you think about the
03:36duration of the immune response,
03:38you would probably want to also think
03:41how the immune system is built.
03:44So it turns out that the immune system
03:47in mammals, and in humans,
03:49has two big divisions.
03:53One, which is called innate and we are all
03:56born with that type of immune response.
03:59And it's the very fast, quick response.
04:02And then there's another one which is
04:05called adaptive and that is more tailored,
04:08more specific to each of the pathogens that,
04:11for instance,
04:12we can encounter when we're thinking
04:15about the duration of the immune
04:18response in the context of vaccines.
04:20We are thinking that we really
04:23want to activate those cells of the
04:26adaptive immune system because they
04:28have the peculiarity that they can
04:31remember, they have memory and that
04:33is very important to understand.
04:36Our lab has focused primarily on trying
04:39to understand what regulates the
04:41duration of the more initial immune
04:44response of this innate immune response,
04:46and the reason why that is
04:49also very important is that
04:52a response is not so much
04:54directed to the pathogen to the
04:56microorganism that is infecting us.
04:59It can be broader and therefore
05:01can potentially have some
05:03adverse effects.
05:05For instance,
05:05inflammation forms part of this
05:07very first innate immune response,
05:10so we absolutely needed to get the
05:12system going to get the immune
05:14response going which is absolutely required
05:17for inducing this immune response,
05:19but it cannot go on forever.
05:22So our lab has really focused on
05:24trying to understand what dictates
05:27the duration of this initial
05:29innate immune response.
05:31So when
05:32you talk about the innate immune response,
05:35is that kind of like if somebody got
05:39infected with covid, whether they
05:41produce a response against that,
05:44or is that still more the
05:47other longer term response where
05:49you develop a memory?
05:52It's more the first type of response,
05:56so in our system, our
05:59immune system, is capable in that it can
06:03first recognize general changes.
06:05And let's say maybe we are infected just
06:09with a bacterial, with a virus, right?
06:12And it can detect that and the cells that
06:15are involved in detecting that initially
06:18are the source of this first response.
06:22This innate immune response.
06:23That can detect that we've been infected
06:26with a bacteria or with a virus.
06:29Or with the fungi or parasite.
06:32Now, as I was alluding to, there is this other
06:36more sophisticated adaptive immune response,
06:37and that takes a little bit longer
06:40to be triggered, is triggered by
06:42first the innate,
06:44and has that memory capacity.
06:46And what is beautiful also about this
06:49adaptive response is that it has the ability
06:52to distinguish which bacteria is infected.
06:54Or which viruses is infecting us.
06:56So just to take the example of a virus.
07:00For instance,
07:01our adaptive immune response
07:02to COVID-19 to SARS CoV2
07:04will be different than,
07:06for instance influenza.
07:08So the adaptive immune response can
07:10distinguish that and our lab focused
07:12more on the very first response that
07:15realizes that you have a virus,
07:17but maybe doesn't realize which
07:19viruses or realizes that you've
07:21been infected by bacteria,
07:22but doesn't really realize
07:24which type of bacteria.
07:26But this first response is fundamental
07:29and the very interesting aspect of
07:31it is that we are born with it.
07:34That's why it's called innate.
07:35So as soon as we are born,
07:38we are able to react to these
07:41microorganisms.
07:42And then as we are exposed to them,
07:45we are able to induce this
07:47adaptive immune response.
07:48This learned response,
07:50that is the one that then will confer
07:53memory and that will be more specific.
07:55Carla, when your lab studies
07:58this innate immune response,
08:00this initial response that hey,
08:02there's something foreign in my
08:04body and that will help trigger
08:07the more adaptive response you had
08:09mentioned that you're looking at,
08:12kind of the magnitude and the
08:14duration of that innate response,
08:16but it seems that the innate response
08:20is a little bit shorter than
08:22the longer term adaptive response.
08:26So how important is the magnitude
08:28and the duration of the
08:31innate response and why did you choose to
08:34look at that?
08:36That's absolutely a very important question.
08:37So of course my answer will be that it is
08:40very important and let me elaborate why.
08:44So in the field we have learned by
08:46the time we were starting to
08:49focus on trying to understand what
08:52regulates the magnitude and duration,
08:54we already knew a lot about
08:56what triggers this innate immune response.
08:58And that was fundamental, right?
09:00So we understood the rules
09:02by which thee immune response
09:04is engaged, but as I was saying,
09:07this is the very first response.
09:09It's the one that tells us all we
09:12have a bacteria or we have a virus
09:14but cannot really distinguish between
09:16the type of bacteria or the type of
09:19virus and therefore is very broad.
09:22It doesn't really help us to only
09:24attack the bacteria or the
09:27virus or the parasite and it also can't,
09:29when a function is triggered,
09:31it can also
09:33induce what you could call collateral
09:35damage and it can affect your own cells.
09:38The classical example is that inflammation is
09:41a key part of this innate immune response,
09:44and as you can imagine,
09:46inflammation can be very good
09:47to help eliminate pathogens,
09:49but can also affect our own body.
09:51So we absolutely need this response when you
09:54get injured or when you have an infection.
09:57But the problem is what happens if you
10:00react way too much or if you react forever,
10:04and so that became a key interest
10:06of our lab trying to understand
10:08what dictates how much
10:10you should respond so that you can attack
10:13the pathogen but not yourself and how
10:16long you should respond so that once
10:18you have eliminated the passage and
10:20you don't keep on reacting against
10:23something that is not there anymore.
10:26So over the years we have been
10:28able to identify key breaks of
10:30the innate immune response.
10:33Why did you choose to look at
10:35the innate response and why is the
10:38magnitude and duration of that so
10:41important?
10:43As I was alluding, we
10:46require this very first innate
10:49response and at the time we started
10:52to become interested in understanding
10:54the regulation of the magnitude and the
10:57duration of the innate immune response,
11:00we already knew quite a lot what
11:02triggers this innate immune response.
11:04So that was fundamental work
11:06that allows us to understand
11:09that you need this response,
11:11but if features of this response as I was
11:15saying before is that it is triggered when,
11:18for instance, you encounter bacteria
11:20or a virus or parasite or fungi.
11:23But it's pretty broad and therefore
11:26it not only reacts against the
11:28microorganism or the macroorganism,
11:31but it can also affect your own self.
11:35For instance,
11:36a classic aspect of the innate
11:38immune response is what we
11:40usually call inflammation and so you
11:43can imagine that if this very broad
11:46immune response is way too high,
11:48or if it lasts forever,
11:50it can really induce what
11:53is known as collateral damage.
11:55It can really start affecting your own body,
11:58the way the system is built
12:01is that you kind of turn
12:04on this initial fire
12:06that then allows the induction of the more
12:09sophisticated adaptive immune response.
12:11But then you need to put off this fire,
12:14and that's when these molecular
12:16mechanisms that regulate how big
12:19the fire will be and how long
12:21the fire will be come into play.
12:23And you can imagine that then
12:25they become very important.
12:27You really need to regulate
12:28how much and the duration,
12:30so that then you don't start affecting
12:32your own self and this is what could
12:35happen in some type of diseases such
12:37as chronic inflammatory diseases or
12:40autoimmune diseases where you start
12:42affecting your own self.
12:44And so as
12:45we think about the implications for cancer,
12:48I mean what you're describing makes
12:50me think about things like hepatitis,
12:53where you can have hepatitis,
12:56which then causes inflammation
12:57and fibrosis and sets you
13:00up for hepatocellular carcinoma.
13:02Is that kind of the area that then
13:05brought you to thinking about cancer?
13:08Or where does the cancer angle come in?
13:12Yeah, that's a very very good analogy.
13:15So it turns out that absolutely,
13:17you're right.
13:18You have situations where you have
13:20this very chronic inflammation.
13:22This persistent
13:24activation of this innate immune response,
13:27and we know that chronic inflammation can
13:30absolutely increase the risk of some cancers.
13:32But the answer is not just
13:35so black and white.
13:36So what we're starting to learn is that
13:39there are different types of inflammation.
13:42One like the one you described,
13:44very well known to increase
13:46the risk of cancers,
13:47but there are other potential
13:49types of inflammation,
13:50and this is actually the area
13:52of much
13:53ongoing investigation in the whole field.
13:55What are the different types of
13:57inflammation that you have in cancer
14:00and how do they contribute to the
14:02concern and the analogy that I
14:04would make is that let's say you
14:06sometimes want to induce a little bit
14:08of this fire to mount a good
14:11immune response against the cancer,
14:12but you don't want to use too
14:15much that
14:16may be detrimental,
14:17so we are still at the level of
14:20trying to understand what are the
14:23different types of inflammatory
14:25responses in cancer and how they
14:28contribute to mount a good immune
14:30response against cancer or how they
14:33might contribute to actually favor
14:35cancer progression.
14:36And so when you're
14:39talking about mounting an
14:41immune response against cancer,
14:43it reminds me of things
14:45like immunotherapy.
14:47As we think about cancers
14:49and when we think about immunotherapy,
14:52we often think about revving
14:54up that immune system because so many
14:57cancers can hide from the immune system.
15:00So I wonder whether part of your
15:02work has to do with immunotherapy.
15:05But first we have to take a quick
15:08break for a medical minute,
15:10so please stay tuned for more information
15:13about immunotherapy and cancer
15:14with my guest Doctor Carla Rothlin.
15:17Support for Yale Cancer Answers
15:20comes from AstraZeneca, working to
15:23eliminate cancer as a cause of death.
15:26Learn more at astrazeneca-us.com.
15:29This is a medical minute about Melanoma.
15:32While Melanoma accounts for only
15:34about 4% of skin cancer cases,
15:36it causes the most skin cancer
15:38deaths when detected early,
15:40however, Melanoma is easily
15:42treated and highly curable.
15:44Clinical trials are currently underway to test
15:46innovative new treatments for Melanoma.
15:48The goal of the specialized programs
15:51of research excellence in skin cancer
15:53or SPORE grant is to better understand
15:56the biology of skin cancer with a focus
15:59on discovering targets that will lead
16:02to improved diagnosis and treatment.
16:04More information is available
16:06at yalecancercenter.org.
16:07You're listening to Connecticut Public Radio.
16:11Welcome
16:12back to Yale Cancer Answers.
16:14This is doctor Anees Chagpar
16:16and I'm joined tonight by my
16:18guest doctor Carla Rothlin.
16:20We're talking about immunotherapy
16:21for cancer and right before the break
16:24Carla, you were telling us about
16:26the work that goes on in your lab.
16:29Really looking at the innate immune
16:31response and the magnitude and duration
16:34of that response and I wonder
16:36how that really pertains to cancer.
16:38And right before the break,
16:40you mentioned that it's not
16:42only thinking about
16:43the inflammation and collateral
16:45damage that can occur that may
16:48predispose patients to cancer,
16:50but it's also in looking at
16:52the immune response that your
16:54body mounts against cancers,
16:56which makes me think more
16:58about immunotherapy.
16:59So can you talk a little bit about
17:02how that works and what work you've
17:06been doing in that regard in your lab?
17:10When we think about the immune response
17:14against cancer, I think it's very
17:16important to recognize that you
17:18know the immune response evolved
17:20to protect us against pathogens.
17:22So when we mount an immune response against
17:25something that has changed in our body,
17:27such as is the case of cancer cells,
17:31we're going to go through the same rules.
17:34So as I was saying at the beginning,
17:37the very first innate immune response
17:39is absolutely essential for allowing
17:41us to mount an immune response,
17:43for instance to a microorganism.
17:46And it turns out that of course
17:48is going to be essential to mount
17:51a good immune response to cancer.
17:54Now when we start analyzing the immune
17:56response that the body mounts against cancer,
17:59we realize that there are a fraction of
18:02patients in which the immune response has
18:05effectively occurred, and probably during the years,
18:08it has tried to control that cancer,
18:10and so in those patients in which
18:14the immune response has occurred
18:16it could be that maybe now the immune
18:19response is kind of tired,
18:21many people refer to it as exhausted,
18:23and what happens is that those
18:25cells that have the memory,
18:27those cells of the adaptive immune
18:29response that can really go and kill the
18:32cancer cell right as they would have done
18:35it if they were responding to a micronysm,
18:38now they're responding to a cancer cell.
18:40They can become tired,
18:41and so a large fraction of the current immunotherapies
18:44are centered on reactivating those
18:47for instance T cells,
18:49adaptive immune cells that have become tired,
18:52and this has been absolutely revolutionary
18:54in the treatment of patients.
18:56So you can see how understanding the
18:59fundamentals of the immune response
19:01has translated into effective new
19:03therapies for cancer patients.
19:05But it turns out that not all the
19:09patients have been able to mount a
19:11good immune response to the tumor.
19:14In some patients,
19:15there are no T cells to reactivate.
19:18They never were activated in the 1st place,
19:21and that's where our thinking came in.
19:23That's where turning on this you know,
19:26fire not too big,
19:27but turning it on a little bit
19:29might allow us to really keep the
19:32immune response against the cancer.
19:34And so a lot of current efforts in
19:37immunotherapy are centered on this
19:38initial response because we
19:40realized that in some patients it
19:43might not have occured.
19:45And so we need to turn this on.
19:48Or in some patients it may also
19:51have gotten tired and we need to
19:53reactivate it.
19:54So how exactly do you do that?
19:57Because I think when I think about
19:59cancer cells, I really think about
20:02normal cells that have gone awry,
20:04and so is it, perhaps that the body,
20:07especially in low grade cancers,
20:09cancers that look very
20:11much like normal cells,
20:12but that are just a little bit
20:15deranged that the body may not
20:18recognize them as being foreign.
20:20And how do you kickstart that
20:23innate response?
20:23We're talking about this very early stage,
20:26where cells are changing from being
20:28normal to to abnormal right from
20:31this premalignant to malignant stages
20:32and again our immune system,
20:35the innate immune system is very
20:37sensitive to changes in the tissue.
20:40So instead of recognizing changes
20:42in terms of mutations that may
20:44have arised in that cancer,
20:46Which is something that is much more
20:49recognized by the adaptive immune system,
20:52they can recognize if there
20:54has been a change in that issue.
20:57If maybe some cells are not
20:59functioning in the right way,
21:01and so those are things that we're
21:03very interested in understanding
21:04at the molecular level,
21:06what leads the activation
21:07of these innate immune cells?
21:09And then what is it that maybe
21:12changes that may appear
21:14like a wound that might affect
21:17the biology of these innate immune cells.
21:20Can you give us some glimmer into
21:23what those mechanisms are of actually
21:25kickstarting that immune system,
21:27because many of the people who are
21:30listening to this show are are thinking,
21:34that's great. You're studying
21:36it at the basic science level.
21:39But really, where we are interested in
21:42going is how do we actually conquer
21:46cancer at a patient level and so
21:50can you give us a sense
21:52of what are kind of the molecular
21:55mechanisms that you're looking at
21:58and how might we change those
22:01so that for actual patients we can
22:03potentially use this to make a difference?
22:06Absolutely this is where
22:09again basic science comes in.
22:11And I think this is where we need
22:14to understand fundamental biology.
22:16So the approach that we take is trying to
22:20understand what triggers this first response.
22:23To do this, we make use of models,
22:25sometimes it is not so easy to
22:28study this directly initially in a patient,
22:31but we can take models where we can induce
22:34for instance the transformation of a
22:36cell or we can induce an infection and
22:39this is very important because as I said,
22:42the principles are going to be pretty
22:44much shared with the immune response to
22:46infection and so in these models which
22:49are in many occasions animal models,
22:51what we try to do is to
22:54try to detect how the cells of the
22:57innate immune system these first
22:59responders react to a cell that is
23:03changing either because there has
23:05been an infection and a wound or
23:08because it's has been mutated and so
23:10we do this with advanced techniques
23:13that allow us to understand what
23:15is changing in the immune cell.
23:18Now a very important aspect
23:20I think is to then try to go to
23:23patient samples and understand whether
23:25those features that we saw change in
23:29the context of an infection or in
23:32the context of a model of cancer
23:35in an animal model,
23:36are also detected in the context of
23:39a transformation of a cell and the
23:42response to this in the patient.
23:44So I think going from this very
23:46fundamental basic approaches to taking
23:48some translational approaches and
23:50trying to understand whether the same
23:53changes are observed is very important.
23:55But then again,
23:56I think we need to go back to the
23:59experimental models because once we
24:01understand what those changes are,
24:03we would like to
24:04intervene and modulate
24:06them so we can maybe turn on
24:08that fire a little bit more.
24:10Maybe induce that immune response a
24:12little bit more, and to do that again,
24:14we need to go to the model.
24:16So we start with the model, we validate
24:19and understand whether it is the same
24:21in a human setting and then we go back
24:23to the model to try to understand how
24:25we can change it to make it better.
24:27And it is this iterative type of
24:30experimental approach
24:32from the model to human samples
24:34to the model that has led
24:35to a lot of new ways to change the
24:38immune response and I am confident
24:39that we will allow us to understand
24:42what we need to change in those
24:44patients that have mounted an
24:46immune response to cancer.
24:48So tell us more about some of these
24:51interventions that you've tried and how
24:53they work in in the models and and what
24:57prospects there are to actually having
25:00the same intervention in patients.
25:04And then just as a second
25:06piece to that question,
25:08when you talked earlier
25:10about this collateral damage,
25:12you wonder about when you
25:14actually take that into patients.
25:16Whether there will be collateral
25:18damage as well as you
25:20continue to light that fire,
25:22or whether you've really gotten
25:23it down to the point where you
25:26can modulate that very well
25:27to limit that collateral
25:29damage.
25:30Let me give you this with an example.
25:34So as I said, we try to understand
25:36what are those ways to regulate right?
25:39The magnitude and duration.
25:40And again, we went from the animal models to
25:43some human samples.
25:45And in doing that we identified
25:47genes that encode for molecules
25:49that are those regulators.
25:51And some of those genes and then
25:54those proteins that are encoded by
25:56this gene are a key focus of our
25:59lab and they're called TAM receptors.
26:01Tyrosine kinase is the interesting
26:03aspect of this is, as I said,
26:05they are like the brakes of this
26:08innate immune response.
26:10And these proteins can be targeted by drugs.
26:14So these proteins are in
26:17innate immune cells and when you
26:20activate this protein it will act as
26:23a break of this innate immune cell.
26:26It will put down this fire.
26:29What we can do is we can work
26:32and develop molecules that inhibit
26:34the function of this protein.
26:37Or we can also generate animal models
26:40that do not even have this protein.
26:44And so what you would predict is that
26:47if you do not engage this break so well,
26:50you will mount a better fire,
26:53so we will be able to regulate
26:55the magnitude of this response,
26:57and so that's what we have discovered.
27:00And so going from the animal
27:02models to human cells,
27:03we now know that we can use small
27:06molecules that inhibit this proteins,
27:08and that allows a better fire.
27:10And we know that in animal
27:12models these can lead
27:14to the ability of these
27:16animals to mount a much
27:18better immune response against cancer.
27:20So we are actually right now at the
27:22process of starting to translate this
27:25into humans through investigator
27:27initiated clinical trials.
27:28Actually here right here
27:30at Yale Cancer Center,
27:32so we can try to understand whether
27:35these drugs, which we know are safe,
27:37can ignite just a little bit more
27:41this fire and you asked me the question,
27:45how do I ensure that
27:47it's not a big fire that
27:49will induce collateral damage?
27:51That's a very very important
27:52question to answer.
27:54I think that brings me back
27:55to my initial training,
27:57which was really in pharmacology,
27:58in Neuropharmacology, but I learned,
28:00I think a lot about pharmacology,
28:02and that's where drugs
28:04give you the ability to
28:06think a lot about the dose is the
28:08regimens, how you're
28:10going to try to modulate this in vivo
28:13and that becomes very important.
28:14So how much you would give
28:16of this drug may be
28:18whether you will deliver it just
28:20to the tumor site so you don't
28:22start a fire everywhere,
28:24and that's an aspect that will
28:25be very important into making
28:27sure that this can truly help the
28:30patients eliminate the cancer and
28:31not induce fires in places that we
28:34don't want to.
28:35Doctor Carla Rothlin is Dorys McConnell Duberg Professor
28:38of Immunobiology
28:39and professor of Pharmacology
28:41at the Yale School of Medicine.
28:43If you have questions the addresses
28:45cancer answers at yale.edu and
28:47past editions of the program are
28:49available in audio and written
28:51form at yalecancercenter.org.
28:52We hope you'll join us next week to
28:55learn more about the fight against
28:57cancer here on Connecticut Public Radio.