COVID and Cancer Research

August 03, 2020

Information

August 2, 2020

Yale Cancer Center

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email: canceranswers@yale.edu

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00:00Support for Yale Cancer Answers comes from
00:04AstraZeneca, dedicated to advancing options
00:07and providing hope for people living with
00:11cancer. More information at astrazeneca-us.com.
00:14Welcome to Yale Cancer Answers with your
00:17host doctor Anees Chagpar. Yale Cancer
00:19Answers features the latest information
00:21on cancer care by welcoming oncologists
00:24and specialists who are on the forefront
00:27of the battle to fight cancer. This week,
00:30it's a conversation about Cancer
00:32Research and COVID-19 with Doctor Akiko
00:34Iwasaki. Doctor Iwasaki is the
00:36Waldemar Von Zedtwitz Professor of Immunobiology and Molecular, Cellular and Developmental Biology
00:39and a Professor of molecular cellular
00:41and developmental biology at the
00:43Yale School of Medicine
00:44where doctor Chagpar is a
00:47professor of surgical oncology.
00:49Akiko, I know you
00:52from all of your work in cancer,
00:55but maybe we can take a step
00:57back and you can tell us a
01:00little bit more about yourself
01:02and your background.
01:03Sure, I am an immunologist.
01:06My love has been studying how
01:08immune responses are generated
01:09against different viruses.
01:11So over the years we've learned
01:13a lot about the immune system
01:15through studying infection with
01:17a variety of viruses, including
01:20herpes virus, influenza virus,
01:21rhinovirus,
01:22and many others.
01:24So what we've been able to do is
01:27leverage this understanding of
01:29antiviral immunity to apply it to cancer.
01:33For example,
01:35we've been understanding how T
01:37cells are activated against viruses
01:39and how they migrate throughout
01:42the body to fight against viral
01:45infection and we leverage this
01:47understanding to apply it to
01:49a local tumor environment
01:51where we can trigger T cells to
01:53be recruited to a particular site,
01:56in this case a tumor to be able to
01:58attack the tumor cells better.
02:01And that really sounds
02:04a lot like immunotherapy,
02:05which has been such a huge advance,
02:11It is a form of immunotherapy.
02:14So this strategy that I'm
02:16describing is called Prime and pull.
02:19A prime describes the fact that
02:21we are priming T cell response
02:24against a specific antigen,
02:26so in this case we are
02:29targeting tumor antigens.
02:30And pull refers to the fact that
02:33we are eliciting TCL recruitment
02:35to the site using chemo coins,
02:38so this is a two step vaccination strategy
02:42to target the immune cells to
02:44the site of tumor growth and it's
02:47a little bit more specific than
02:49a checkpoint inhibitor therapy,
02:51where we're kind of taking out
02:54the brake from all T cells.
02:57But in our case we are targeting
03:00specific specific antigens that
03:01the tumors expressed with a
03:03targeted prime and pull approach,
03:06How do the viruses play
03:09into that prime and pull approach?
03:13Right, we are targeting
03:15viral induced tumors such as human
03:18papilloma virus induced cervical tumors,
03:21and essentially what we're doing
03:23is to stimulate T cells against
03:26the virus antigens with the prime
03:29and pulling them into the site.
03:32In this case, the cervix, using chemokine
03:35or a chemokine inducing agent,
03:38so that's where the virus comes in.
03:42Viruses actually cause
03:43many different types of tumors,
03:45including cervical cancer,
03:47and we're kind of using virus as a tag
03:50to be able to stimulate the specific T
03:53cell immunity against those tumor cells.
03:56That's kind of interesting.
03:59You take these T cells and
04:02you prime them to this virus so that
04:05you can kind of attack the cancer.
04:08But recently your research has
04:10kind of shifted now that we're
04:12all thinking about another virus,
04:14being COVID-19, so tell us how that pivot
04:18happened.
04:22When the news about COVID-19 started to emerge,
04:25we quickly reorganize the laboratory so that
04:28we can all focus on the COVID-19 research.
04:32So I remember having a lab meeting
04:35asking the lab members if anybody's
04:38interested in working on COVID-19
04:41and to help with the COVID-19
04:44testing throughout the community.
04:46And virtually everybody stepped
04:48up to the challenge.
04:50So essentially everyone you know
04:52just sort of one day stop doing
04:55their other research to focus
04:57on COVID-19 very quickly.
05:00And you were previously
05:02studying things like cancer related
05:05viruses, HPV and and so on.
05:08How is COVID-19 similar versus different?
05:11And how could you
05:14focus on another virus?
05:17The advantage of what we've
05:19been doing is that we weren't
05:21focusing on any particular virus.
05:24So as I mentioned,
05:26we've been studying genital herpes
05:28influenza virus causing the flu symptoms,
05:31rhinoviruses in the nose,
05:33and so we were pretty
05:35versatile to begin with,
05:37so we were able to quickly focus on
05:40COVID-19 because of our expertise
05:42in the respiratory virus infection,
05:44and it wasn't that much of a leap for us
05:49to pivot to COVID-19.
05:51Is COVID-19 like every
05:52other virus, though?
06:00Many of us have experienced
06:02rhinovirus, the virus
06:04that gives us the common cold,
06:07but it doesn't have the impact
06:10that COVID-19 has had,
06:11so in terms of the virus itself,
06:14are they different?
06:16Oh yes, every virus is very
06:19different in
06:21its unique way of evading the
06:24immune system and to transmit
06:26from one host to another.
06:28And so even though we were
06:31studying other respiratory viruses,
06:33COVID-19 is by far the most severe
06:36and contagious virus
06:38we have shifted to studying
06:41and part of it has to do with
06:45the fact that none of us had
06:48any pre existing immunity to this virus.
06:51I would imagine
06:55that when this pandemic hit and
06:57many researchers like yourself and
07:00people in your lab started to try to
07:03figure out in a very rapid fashion
07:05what was going on with this virus,
07:08I mean, the fact that you were
07:11actually studying immunity in terms
07:14of viruses and how you could get
07:16your immune system to attack
07:19seems to be really relevant because
07:22as we try to figure out how
07:24can people resist this virus,
07:26which is completely novel to all of our
07:29immune systems and potentially develop
07:30a vaccine, that is really interesting.
07:33Tell us a little bit more
07:35about what you did in your lab
07:38to move that research forward.
07:41Yeah, so as you say,
07:43we were very fortunate to be in a
07:46position we were because of our previous
07:50experience as well as understanding
07:52in general about antiviral immunity
07:55to be able to quickly tackle some
07:58of the key aspects of COVID-19.
08:02So for instance we are studying in
08:04real time in response to COVID-19 from
08:08patients that enroll in our study
08:11and trying to figure out what type
08:14of immune responses confer protection in
08:17recovery versus which of those
08:21responses lead to wars,
08:22disease outcome, and even to death.
08:25So we were able to mobilize the
08:28team to be able to look at these
08:32issues and the fact that we were
08:35able to do this also has to do with
08:39collaborators, we have a large,
08:42large network of collaborators who are
08:46recruiting patients into the study who
08:50are collecting samples, archiving samples,
08:53analyzing clinical data sets,
08:55and just a whole variety of tasks that
08:58are needed to happen in order for us
09:01to study our response to COVID-19.
09:04So we're very fortunate to be
09:06in a place where we can do this.
09:08And what have you found so far?
09:12We're finding,
09:15as I mentioned in real time,
09:17some patients that come in the hospital,
09:20do well and they
09:22recover and they get discharged.
09:25And others go on to develop worst
09:28disease and what we're finding is
09:30that the immune response during
09:33the first 10 to 12 days of symptom
09:36onset can really inform us about
09:38how they might do in the future.
09:41So it's almost like we can predict
09:44the disease trajectory of patients based
09:47on the very early immune signatures
09:50that we're detecting from patients.
09:53That seems to make
09:56sense because we know that people
09:59who are immunodeficient or immuno
10:02compromised tend to have more
10:04severe illness with COVID-19.
10:06But aside from NOTE Confidence: 0.914561450481415
10:09not having an immunodeficiency,
10:11do we know in normal people?
10:14I mean we've heard on the news
10:17people who are otherwise perfectly
10:20healthy succumbing to COVID-19.
10:23Do we know what it is about their
10:26immune system that puts them more at
10:28risk and perhaps more importantly,
10:31do we know what we can do to
10:34mitigate that to ramp up people's
10:37immune systems to potentially give
10:40them a boost or a test to make
10:43sure that their immune system is
10:45strong enough to fight this virus?
10:53I think we're getting there.
10:55I would say we're not there yet, but we are
10:59understanding a lot
11:02at least with respect to the immune response,
11:05how patients are responding to this virus
11:08and what that does to viral clearance
11:11versus disease such as cytokine storm.
11:14And to get back to your question about
11:17some people who are otherwise very
11:20healthy or have gotten COVID-19
11:23and did very poorly with this disease,
11:25part of it has to do with the viral exposure.
11:29Iff you're being
11:32exposed to a large dose of virus,
11:35and if you're inhaling that virus
11:37into the deep respiratory area,
11:39then that might cause a different type
11:41of disease than if you were getting
11:44just a few viral particles up your
11:47nose and they're just sort of remaining
11:49in the upper respiratory tract,
11:51and so one has to do with the
11:54viral exposure in the dose,
11:56and the other has to do with what I was
11:59talking about the person's propensity to
12:02develop different types of immune response.
12:06So for instance,
12:07though people who are doing well with
12:10this disease appear to focus their
12:12response in tissue repair mechanisms,
12:15so people who can secrete growth
12:17factors to repair the damage in
12:20the lung are doing better,
12:22while those people who are initiating more
12:25of the cytokine storm type of response,
12:28even early during the infection
12:30tend to do worse,
12:32so I think a lot has to do
12:35with viral dose exposure.
12:37The route of exposure as well
12:39as the propensity of developing
12:41different types of immune responses.
12:44Tell us a little bit more about this
12:47cytokine storm response. What is that exactly?
12:53You often hear about the cytokine storm.
12:55It's essentially what happens when
12:57the immune system is triggered by the
13:01virus infection in a matter without
13:03having any brakes.
13:06So usually what happens during
13:08an infection with a virus is
13:11that the viruses meet rigorous
13:13cytokine response,
13:16but quickly the innate and adaptive
13:19immune response contains that virus.
13:21So that the response is
13:23tapered down within
13:26a few days,
13:28whereas in this case of COVID-19,
13:31some patients are having this very
13:34prolonged and uncontrolled cytokine release.
13:36And when that happens the cytokines
13:39themselves could have toxic impact
13:41on delicate tissues such as the
13:44lung and the microvasculature
13:46that are surrounding the Alveolae.
13:49So it's really having a negative
13:52impact rather than trying to contain
13:54the virus and so one of the key
13:57hallmarks of disease progression appears
13:59to be having these kind of cytokine
14:02storms even during early infection.
14:05So it will be
14:07important to understand which
14:09people have which kind of response
14:12so that we can kind of predict
14:14how people will do to COVID-19.
14:16We're going to learn more about
14:19that right after we take a short
14:22break for a medical minute.
14:24Please stay tuned to learn
14:26more about COVID-19 and cancer
14:28with my guest doctor Akiko Iwasaki.
14:31Support for Yale Cancer Answers comes from
14:35AstraZeneca, working to change how cancer
14:38is treated with personalized medicine.
14:40Learn more at astrazeneca-us.com.
14:44This is a medical minute
14:46about colorectal cancer.
14:47When detected early,
14:49colorectal cancer is easily treated
14:51and highly curable and as a result,
14:54it's recommended that men and women
14:56over the age of 50 have regular
14:59colonoscopies to screen for the disease.
15:01Tumor gene analysis has helped
15:04improve management of colorectal
15:05cancer by identifying the patients
15:07most likely to benefit from
15:09chemotherapy and newer targeted agents,
15:11resulting in more patient
15:13specific treatments.
15:14More information is available
15:16at yalecancercenter.org.
15:17You're listening to Connecticut public radio.
15:22Welcome back to Yale Cancer Answers.
15:24This is doctor in East shag
15:26part and I'm joined tonight by
15:28my guest Doctor Akiko Iwasaki.
15:30We're talking about her research looking
15:33into COVID-19 an right before the break.
15:35Akiko, you were talking about how
15:38you were really looking at the
15:40immune response and using this to
15:43predict who is going to do
15:45well versus who was not going to do
15:48well after a COVID-19 infection and
15:50one of the things you mentioned was
15:52that there was a difference between
15:55people who mounted an immune response
15:57that was really localized where they
16:00had an ability to repair tissues versus
16:03people whose immune response was
16:05this quote cytokine storm kind where
16:08their immune system went crazy
16:10and started attacking all kinds of
16:13things and those people did less well.
16:16So my question to you is, do we know
16:19which kind of people are which?
16:25Am I going to be the kind of person who
16:29is going to have a localized response,
16:32or whether my immune system will goes crazy.
16:36Are there factors that predict that?
16:38Either my medical history
16:40if I have autoimmune conditions,
16:42for example, race, gender, age?
16:45What goes into that? Do we know?
16:49We're starting to find out that there
16:52are certain factors. a host of factors
16:55that affect how people respond in a
16:58matter of protective versus
17:01non protective and harmful and
17:03one of the factors that we're finding
17:06is that women tend to do better with
17:10COVID-19 disease than men and this
17:13has been reported throughout the world
17:15and we are honing in on why that is.
17:19Why sex makes a difference in our
17:21ability to fight off this infection,
17:24and one of the things
17:26coming out from this study,
17:28which is supported by Women's
17:30Health research at Yale,
17:32is the fact that women make better
17:35T cell response,
17:36while men tend to make these
17:38cytokine storm type of response,
17:40especially as they age.
17:42That's really interesting.
17:43Do we know why that is?
17:46I mean, does that have something to
17:49do with estrogen versus testosterone?
17:51Mind you, we would
17:54expect that as women age,
17:56their estrogen levels go down,
17:58so what might be the
18:01underlying mechanism of that?
18:03That's a great question.
18:06We don't know whether sex hormones
18:09like testosterone or estrogen can
18:11be the only answer to this question.
18:14And especially as you say we're looking
18:17at patients in the age group of
18:2070s, eighties, 90s
18:23and these sex hormones may not be
18:26playing a big role and so the
18:29molecular underpinning of why
18:31women do better is still unclear.
18:34But what we do know is that if
18:37you plot age and T cell response
18:40in the different sex groups,
18:42women tend to age better in terms
18:45of T cell immunity that even
18:48older women are able to mount
18:51a pretty robust response
18:53during this COVID-19 infection.
18:55Whereas men who age in the
18:58older group tend to really be poor
19:01inducers of T cell response
19:03and that correlates with
19:05their poor prognosis
19:07in the future,
19:09so it really is painting a picture that
19:13women tend to age better with the immune
19:18response.
19:21I wonder too,
19:23there are certain autoimmune
19:26conditions, so things like
19:28Hashimoto's thyroiditis for
19:30example where your immune system
19:33attacks your thyroid that are more
19:36prevalent in women versus men.
19:38So is it that women have
19:41a stronger immune system?
19:43Or is it that their immune system just
19:46tends to be better regulated against
19:50COVID-19 because men have more likely
19:53this cytokine storm condition.
19:57Yes, so it is true that many auto immune
20:01diseases have female prevalence,
20:05and it's also true
20:08that for other viruses women do
20:11tend to make better immune response.
20:15Even for flu vaccines,
20:17it's been shown that women mount a better
20:20antibody response to vaccines,
20:23so it may be that women,
20:26because of their capacity
20:28to mount a better immune response,
20:31they're doing better with this
20:33COVID-19 disease, whereas men,
20:35especially as they age,
20:37they fail to mount a
20:39very good adaptive immune response,
20:42and therefore they are secreting
20:45more cytokine because of their
20:47inability to kill the infected
20:49cells and control the virus
20:52better.
20:57Do we know
20:59for women, what are predisposing
21:02factors that make women do worse?
21:04So are there other factors
21:07than gender that may play a role
21:10or that may interact that would
21:13predispose one woman to do well
21:16versus some women to do poorly?
21:19That's a really good question.
21:22We don't really know what other
21:24factors influence how women tend
21:27to do worse with this disease.
21:29One of the things that we obtained from
21:33this particular study is that women
21:36who tend to make cytokine response
21:38like the cytokine storm type of
21:41response do worse with this disease.
21:44So even if they are able to
21:47mount a robust immunity
21:49if there are also triggering the cytokine
21:53response then they tend to do poorly,
21:56so it's really a balance
21:58between their ability to Mount,
22:00regulate the cytokine response
22:02at the same time as mounting a
22:06robust T cell response that tend to
22:08dictate their disease trajectory,
22:11but we don't
22:12know aside from gender,
22:14what really causes people.
22:16Some people to have more of
22:19a cytokine storm response. Is
22:22not. Right, so the one thing other
22:25than the age, which is a very
22:29clear sort of disease risk factor.
22:32The other thing that came
22:35out of this study is the BMI.
22:38So especially man who tended to do
22:41worse with this disease had higher BMI.
22:45So yeah, obesity is contributing
22:47to disease progression,
22:49especially in men, not so much in women.
22:53So what makes women suffer
22:55from worst disease outcome?
22:57It is still unclear.
22:59And so in men, is it that their BMI
23:02actually changes their immune response
23:05such that higher BMI is associated
23:08with more of this cytokine storm?
23:11Or is it working through
23:13another independent pathway?
23:15Yeah, another really great question.
23:17That's something that we are
23:19planning to look at more carefully.
23:22So our first study is currently
23:25posted
23:29and we've done this first analysis.
23:31But there are a lot of questions
23:34that we want to dig into, one,
23:37including the BMI question and the other
23:40including whether a sex hormone or
23:42other parameters are associated.
23:44Women can explain some of the
23:47features that we're seeing.
23:49And I guess the other question
23:51that I have is
23:54sadly we can't do much about
23:56the gender that we're born with,
24:02but in terms of
24:10people who are transgendered,
24:13people that have changed their gender,
24:15what happens to their
24:17immunity and therefore their
24:19risk in terms of COVID-19?
24:22Another really great question.
24:24Unfortunately,
24:24because of the number of patients
24:27recruited being rather limited,
24:29it's less than 100 patients,
24:31we didn't have enough to
24:34dissect what happens to
24:36transgendered people in our cohort,
24:38but that's something we would
24:40love to get into in the future,
24:44especially once we understand better the
24:46molecular basis for the differences in sex
24:50we can actually attract those
24:52molecules to see what happens in
24:55transgender settings and whether
24:57that would dictate their ability
24:59to mount a protective immunity or
25:02a more harmful immune response.
25:04Yeah, I mean I think it's going
25:06to tie in as well to your studies
25:09that you're planning in the future.
25:12Looking at hormones,
25:13and certainly people who
25:15have to take exogeneous hormones as
25:18they are transitioning that may
25:19certainly play a role and
25:22then I guess the other question is OK,
25:25let's suppose that you have
25:27whatever immunity you have,
25:28and let's suppose that you
25:30there is a way to know
25:33for example,
25:34could you take a blood
25:37specimen from me and tell me,
25:39you're more likely to
25:42have a cytokine storm reaction
25:44versus you're more likely to have
25:47an adaptive response.
25:49I mean,
25:50is there a way to tell that
25:52just in people in general?
25:55Yeah, so that would be the
25:58next step.
26:00Right now we're focusing on
26:02infected people to try to understand
26:04these seeming differences,
26:06but ultimately what we want to
26:08do is to be able to predict
26:11before the infection
26:13whether a person might do better
26:15or worse from this disease and
26:17what we can do to intervene
26:20with the disease process.
26:22So another element that we're
26:24looking into is the genetics.
26:26Are there genetic differences
26:27between people who do worse versus
26:30who recovers from this disease?
26:32Even accounting for all the
26:34other parameters we discussed,
26:35such as aging and BMI or their
26:38genetic differences that we can
26:40look into and that may be able to
26:43play into this prediction
26:45of whether a person might do worse
26:48or better with this disease.
26:52Have you found any racial
26:55differences that might give you
26:57a glimmer into genetics?
27:01Those types of studies
27:04really require thousands of agents,
27:06and currently this particular study
27:08is focused on a handful,
27:11about 100 patients,
27:12and so the genetic studies that's
27:15ongoing at Yale
27:17are really in recruiting
27:19thousands of patients
27:21to be able to look at these issues
27:25and so I'm hopeful that those
27:28answers will be forthcoming.
27:30I realize that
27:34probably the next step is
27:37how exactly do you intervene?
27:39I mean, because regardless of whether
27:42you could tell me that
27:44I'm more likely to have a cytokine
27:47storm response, or I'm more likely
27:49to have an adaptive response,
27:51are there ways that we can intervene
27:54that would help us to
27:56have a better immune response,
27:58whether to COVID-19 or anything else
28:01whether that intervention is a
28:04drug or some sort of
28:08intervention like that or whether
28:10it would be something like
28:13a particular dietary
28:15intervention or getting more exercise,
28:17which seems to be the cure all
28:20for everything these days and
28:22certainly would help with the BMI,
28:24at least in men,
28:27do we have a sense
28:29either from your current work or from
28:32your previous work of what things might
28:35actually be helpful in terms of changing,
28:38or even is it possible to
28:40change people's innate
28:41immune response from one that
28:43is a cytokine storm to being a
28:46more adaptive immune response.
28:49Yes, there are ways to intervene.
28:52For instance, I mentioned that men
28:55who developed cell immunity
28:57tend to do worse from COVID-19.
29:00What this tells us is that we should be
29:04enhancing their T cell response in order
29:07for older men to fight this disease better.
29:11So a vaccine that might stimulate good T cell
29:16response might be a way to at least prevent
29:20future infection
29:22and disease in older men,
29:25and similarly women who have these
29:28cytokine storms tend to do worse
29:30even if they had good T cell immunity.
29:34So this means that interventions
29:37such as monoclonal antibodies to
29:40block cytokines might be a good
29:42option for women who already exhibit
29:45early levels of these cytokines,
29:48and getting back to other interventions,
29:51non hospital interventions,
29:53obviously getting exercise and getting
29:56enough sleep and reducing
29:59stress is in general very helpful,
30:02but we've also done a study
30:05where we fed animals
30:07ketogenic diets and ketogenic diets
30:10protected these mice from disease that
30:13happened after influenza infection
30:15and what the impact it had was
30:19interesting because it increased these
30:21innate like lymphocytes,
30:23the Gamma Delta T cells in the
30:26lung and they were better able
30:28to fight off influenza infection,
30:30so there may be a dietary way
30:33of preventing severe diseases
30:35from respiratory infections.
30:47If you have questions the address is
30:50canceranswers@yale.edu and past editions
30:52of the program are available in audio and
30:54written form at Yalecancercenter.org.
30:56We hope you'll join us next week to
30:59learn more about the fight against
31:02cancer here on Connecticut public radio.