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Immunotherapies for Cancer

May 17, 2021
  • 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
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  • 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.