Cancer Immunotherapy Research Updates Panel at 2019 CRI Immunotherapy Patient Summit in Boston

Cancer Immunotherapy Research Updates Panel at 2019 CRI Immunotherapy Patient Summit in Boston

– [David] Thank you,
everybody, for joining. So I’d like to start
off and have each of you if you don’t mind maybe Kimmie I could ask you to start here. What your current focus of research is and how that may tie
in with immunotherapy? And then Justin and Susanne,
if you wouldn’t mind as well. – So I’m one of the
medical oncologists here specializing in gastrointestinal cancers. Clinically, I treat
patients with all types of gastrointestinal malignancies but my research focus is
specifically on colorectal cancer. As many of you may know immunotherapy has not
worked as well compared to other tumors as in colorectal cancer and so much of our research focus is trying to figure out
why and how we may be able to make immunotherapy more
effective for the many patients that we have with colorectal cancer and other gastrointestinal malignancies. – So Justin Gainor I’m actually from across town
at Mass General Hospital. My focus is on thoracic
cancer, so mostly focused on the treatment of lung cancer both non-small cell and
small-cell lung cancer. So clinically, I see patients with lung cancer, esophageal cancer. My research is focused on
a few different things. I do a lot of clinical trial work. So testing various
immunotherapies in lung cancer. I think lung cancer has been an example of a disease where it was
surprising, I think, to all of us. In 2012, we saw the initial
evidence that lung cancers could respond to these
checkpoint inhibitors and that’s really opened
up an explosion of research into these checkpoint
inhibitors in lung cancer. So I run a lot of clinical
trials focused on that but also trying to identify
predictors of response. As you just heard from Dr. Reardon This is really a critical area of need trying to find who’s
going to benefit most thinking about ways where we can find if someone may not be as responsive trying to think about combinations. Who may benefit most from a combination? So I do a lot of genomics
research and work closely with our pathologists on trying to identify these biomarkers of response. And then lastly, I direct
our phase one immunotherapy portfolio at Mass General so trying to think about
these novel combinations of new immunotherapies and how
do we combine them together and that spans not just lung cancer that spans actually many, many
different types of cancers. – [David] And Susanne? – Yeah, my name’s Susanne Baumeister. I’m a pediatric oncologist and stem cell transplant physician both at the Dana-Farber Cancer Institute and Boston Children’s Hospital and clinically, I treat patients who need a stem cell transplant
or a cell-based therapy to treat their childhood cancer predominantly hematologic malignancies. My research focus is developing novel mostly cell-based therapies for children with hematologic malignancies
who don’t respond to the standard therapies or relapse after standard therapies or even after a stem cell transplant. And Dr. Reardon gave us a
nice overview of CAR T-cells which are a very exciting,
new cell-based therapy and the groundbreaking
success with CAR T-cells that has really shown
or proven the principle how effective they can be those T-cells are directed
against a certain epitope or antigen expressed or found on the surface of leukemia cells in one of the most common pediatric leukemias B-cell acute lymphoblastic leukemia. And this is a very good antigen
because it is only found on malignant cells in this leukimia but not generally on
healthy cells in the body with the exception of B-cells which are a part of the immune system and whose work in the body can be replaced if they get targeted by the T-cells. But we have a lot of work
to do to treat patients who don’t respond to this
CAR T-cell treatment but also with other malignancies
such as myeloid leukemias and pediatric solid
tumors to really identify what kind of cell-based
approaches can we develop to help those patients. – So let me ask, this has been a very exciting past several years here. Share with us some of your perspective on how immunotherapy treatments have changed how you and your colleagues are treating patients with
these types of cancers that you focus on and
specialize in the care of and maybe we can just come back in the reverse direction
and start off with Susanne and maybe elaborate a little bit further about some of the approaches
you were just talking about. – Yeah, I think for us
really, a CAR T-cell therapy for a CD19 positive B-cell malignancies has been groundbreaking
in the sense that majority of patients with B-cell
acute lymphoblastic leukemia can be cured with the standard treatments but there is a percentage about 10% or so who relapse or don’t
respond to standard treatment and previously, we really did
not have very good therapies to support those patients. We’d take patients to a
bone marrow transplant but even after bone marrow transplant there’s the possibility of relapse. And we really, now have an immunologic toolbox
that’s unprecedented. One is these CAR T-cell
therapies that can induce sort of on the range of 70, 90%
of complete remissions in patients who were not respondive to these other standard treatments. But I should mention, we didn’t discuss that in the kind of overview but there’s also additional
immunotherapy approaches. For example, biospecific
engagers which are molecules that can be given to a patient that basically bring together
the T-cells that are already in their body to the leukemia
and help them work against it and also, antibody toxin
conjugates that can react with some molecules on leukemia cells that can be given to a
patient, that can have also actually induced very favorable responses. So for us that has changed
the landscape a lot in terms of those refractory
or relapsed patients what we’re able to offer them. This is for B-cell acute
lymphoblastic leukemia. – Yeah, and from my perspective which is a focus on cancers
of the brain and spinal cord we have, unfortunately there
are leukemias and lymphomas cancers of the blood, and
lymph organs that can spread into the brain and the spinal cord and when that has historically happened unfortunately, that usually is or historically has been
something that we’ve not been able to effectively treat or had
very little success about. And these immunotherapy approaches the adoptive cellular
therapies in particular have been able to help
a subset of patients when the cancer can metastasize or spread into that area as well and we’re very fortunate to
have that additional aspect of treatment which has really
helped transform the therapy for many of those patients who otherwise wouldn’t have much to offer. And that’s actually true
in my field for cancers in the central nervous system the brain, and the spinal cord when they start elsewhere
in the body and then spread that the immunotherapies
can even be effective when they’ve spread and
now growing in the brain or elsewhere in the body. So that’s an aspect that has really been important and transformative. Justin, how about for you? How have immunotherapies
changed how you treat patients? – So it’s really revolutionized how we’ve treated our patients. When I first started taking care of patients with lung cancer about 20% of them would
have some genetic change where I could use a targeted therapy so a pill-based approach which is distinct from immunotherapy but pretty much everyone else the other 80%, our standard
approach had been chemotherapy. And unfortunately, chemotherapy although it has some activity it didn’t have that durable activity and we knew that lung cancer
is a tough cancer to treat and that it generally
carries a poor prognosis. Over the last several years, though we’ve now seen that for
most of my patients now their standard treatment’s
actually immunotherapy and I’m trying to make the decision whether to add chemotherapy or not and so trying to use some of
these tests that you heard these biomarkers to try
to make that decision. And so it’s changed my clinicing changed my clinic experience really seeing some terrific
responses to these drugs and it’s a bit strange for me as someone who treats solid tumors
where now we’re starting to have conversations of when to stop treatment in someone
with a metastatic cancer and starting to have people
come into my clinic four or five years after they
started immunotherapy. They’re now off all treatment
for a couple a years and the conversations
are just very different. We’re no longer talking about symptoms we’re talking about what
graduation they went to over the weekend. So that to me has been
really transformative and what we’re now seeing
is that the success that we’ve had in the metastatic setting so stage four cancers, we’ve now tried to take these drugs earlier and earlier into the disease course. So starting to use now immunotherapies mainly these checkpoint inhibitors in patients with stage three lung cancer so combining these drugs with
standard chemo and radiation. And there’s actually an
approved drug in that setting and now, we’re having
several clinical trials exploring combining these
drugs with things like surgery so actually using immunotherapy first to try to shrink the tumor and try and make it easier to then remove it. And I was just in our
clinic the other day and one of my colleagues
said, “Hey, look at this.” One of my clinical trials, a patient just received chemotherapy immunotherapy and when the surgeon went
to take the tumor out they removed the lung and
there was no viable tumor left. It was a complete pathologic response. There was nothing there. I think this is the promise
of cancer immunotherapy. But I also recognize that
these drugs don’t work in everybody, and so trying
to also strike that balance. What do we do when these drugs don’t work? And I think that’s
where, all of us up here are talking about all
of the research we do and trying to really push the reach of these drugs further and further. – [David] How would these drugs help you in your practice every day for– – So the biggest impact–
– genome cancers. – Of immunotherapy in colorectal cancer has been in a rare subtype of
colon cancer called MSI-high and that stands for
microsatellite instability high and it’s a defect in
how mistakes in our DNA and genetic code are
repaired that allows cells to accumulate many,
many different mutations or errors in their DNA, and that can lead to the formation of a type
of cancer that has shown to be very responsive to
these checkpoint inhibitors. And unfortunately, it’s
a very small subset of colon cancer patients,
but in that small subset it’s probably around three or 4% of metastatic colon cancer patients. We have seen just absolutely
phenomenal responses to the point where the most
transformative thing for me has been that now we can actually see that metastatic disease
can possibly be cured. If I could tell a story I saw a 36-year-old gentleman who had an MSI-high colon cancer where he had metastases
pressing on his spine and his liver, and his lymph nodes really throughout the
body, three young kids very sick and symptomatic and we treated him on
a clinical trial here of nivolumab and ipilimumab so a combination of the
checkpoint inhibitors that you all heard about today. And after just five doses his cancer has completely melted away in all the different spots and he’s actually been off
treatment for almost three years not on any of the immunotherapies anymore and still there’s no sign of the cancer. So that is something that
we previously never imagined could be possible and is now possible and our focus now is to try
to translate that success into the more common type
of colon cancer that we see as well as other gastrointestinal cancers. – Well, with all of the
excitement that’s been generated over the last few years
with these treatments and these remarkable
stories that we’re hearing there’s a lot of hope and
hype that’s been built up and you can go onto the internet and hear and see all kinds
of information out there. And unfortunately, the
reality is that these drugs aren’t working for everybody and I thought maybe we could
spend a little bit of time it might be helpful for our audience to hear some of your thoughts about some of the maybe misperceptions
that may be out there or information we may be
needing to better understand to help deal with all of
this tremendous excitement at the same time. So I’ll throw that out. Anybody want to start with that? – I think it’s important
for patients to understand that specifically for CAR T-cell therapy you need a good target for
those CAR T-cells to go after. And whether or not we have good targets for that kind of depends on the type of leukemia or hematologic malignancy and so I think while it
has promise, great promise that is basically dependent on what kind of tumor a patient has. And I think the other thing
for patients to understand with CAR T-cell therapy patients can develop side effects and they can be quite pronounced. So they are typically transient but patients can develop something called cytokine release syndrome that resembles very much
kind of basically a super flu and can get very sick with that and they can also develop
neurologic complications where for a period of time
they may not speak very much they may not be able to interact
the way they do normally and this can be very scary
for patients and families. And so I think to know this
can be part of the therapy and that in the vast majority of cases we can support patients
through this successfully. I think that’s important
for patients to understand as they come to immunotherapy. – Yeah and along those lines as well those therapies have
had incredible impact but we’re also seeing now strategies where because the therapy is
dependent on the expression of the target and this exquisite
specificity for the target the cancer cells can adapt to that and they have, over the decades that we’ve been fighting cancer have evolved and developed strategies to become resistant to treatment and no longer be vulnerable. And unfortunately,
that’s also proving true for some immunotherapies and we know in particular
with the CAR T-cell therapies where we can see this incredible response of a tumor where nothing else has worked unfortunately, some of the cells can adapt and become resistant and no
longer express the target. So they can eliminate that target the immune system is still focused on it and still on patrol and
still trying to attack it but the cancer cells, when the target if they don’t have it anymore that’s one strategy where they can avoid and overcome this
effective immune response and that certainly is happening where we’ve seen in a subset. Fortunately, it’s a fairly small subset of tumors when they’ve come back but I think the next strategy
as I’m learning and hearing about is to try to develop
these cellular therapies that can hit more than
one target to be able to try to stay a step
ahead of the potential of the cancer from adapting like that. – Yes, if I could just respond to that. Yeah, so yeah, so there’s
definitely mechanisms for the leukemia to escape and then some cases the leukemia
can come back after that and that’s definitely
anactive area investigation both with developing CARS that can go after two different
targets at the same time or having a different
CAR therapy available if the leukemia comes back
when the CAR T-cells target that first epitope and
the leukemia can learn how to down regulate that or
basically put on camouflage. The other is for us to
understand those T-cells that we give patients,
they go in very active and can definitely recognize
some leukemia cells but there’s also cases where
the leukemia still continues to have this protein on their surface but somehow the T-cells
either don’t expand and kind of divide up to provide this army of T-cells to go after the tumor or they just sort of become,
after a period of time not reactive and don’t
stick around long enough. And so those are two active
areas of investigation for the CD19 directed CAR T-cell therapy to try to understand, how can we improve on the T-cell function and what can we do if the leukemia camouflages and
down regulates that protein? – And that’s been a
big challenge with many of the solid cancers as apposed to the leukemias and lymph node cancers the cancers that arise in
the solid organs of our body the lung cancers and the colon cancers and the brain cancers and the
breast cancers, and prostate. When these cellular
therapies have been developed and given back to patients,
it’s trying to figure out how to keep them around,
keep them proliferating because otherwise they’ll just die off and not be able to maintain
that persistence of the attack. I want to leave some time for we have opportunity for patient questions and comments here at this point before moving into one of
our patient presentations. So we’ve got some time here if we could open up for questions. Our staff will be
circulating with microphones if you wouldn’t mind, so that
we could hear your question. Could you talk a little
bit about mutations. I have esophageal cancer, metastatic and it seems to be mutating differently if I understand my oncologist correctly and how that impacts
immunotherapy if that’s relevant? I think it’s important to
distinguish the cellular therapies from the checkpoint
inhibitors in the sense that with the cellular therapies,
we know the target we know what we’re going after. By contrast, the immune
checkpoint inhibitors I would say while we know
a lot about the biology they’re still a blunt tool, right? We’re trying to remove a
break on the immune system but we don’t know in an
individual patient’s cancer what the immune cells
are actually recognizing. We don’t know the target and the target for one patient may be very different
than another patient and I think it goes to
the fundamental premise of cancer immunotherapy, which
is that cancer cells have to be sufficiently different
from the rest of your cells in order for your immune
system to recognize them. That’s the premise. And commonly the way that
they become different is they accumulate mutations. So mutations are just
misspellings in the DNA. So the more misspellings in the DNA the more and more a cancer begins to look foreign to the immune system and so what we’ve learned is that if you actually put all
cancers next to one another it’s really the cancers
that have the most mutations are the ones that seem to be driving the most benefit from immunotherapy. So if you think about, where these drugs were really pioneer and
things like melanoma. Melanoma commonly arises from UV exposure which induces lots of DNA
damage, lots of misspellings and so we are seeing that
it’s really those cancers that are the most immunogenic and so having more mutations
increases the probability. It’s not a perfect science,
but increases the probability that there is going to be one misspelling that your immune system
is able to recognize. So that’s where we
think about this concept of counting mutations. You may come across in
your reading or online this concept of TMB or
tumor mutation burden where we’re really just
trying to quantitate in a given tumor how
many mutations are there as some surrogate for
how foreign it may look to the immune system. – Thank you–
– The other. – Oh go ahead.
– I’m sorry. The other thing to add to that is just that especially
in esophageal cancer we now know that not all
cancers are the same so one esophageal cancer is not the same as another esophageal cancer and particularly for this type we now know that not every
site of esophageal cancer in the same patient may be the same. And so I think this just points and highlights the importance of really genetically understanding
every patient’s tumors and we do routinely
profile everybody’s cancer who’s seen here. And we need to actually
profile each individual site of cancer in a single
patient separately as well. Obviously, that’s difficult. You can’t biopsy everything and so trying to find a blood-based marker where we can get an overall sense of what the overall
tumor mutation burden is or what the overall genetic predominate genetic
signature is in a patient is important and may lead to
different ways to treat you. – [David] I think there’s a
question in the back here. – [Male Audience Member] Thank you. I’m coming from the
perspective of a patient with a rare and difficult
to identify sarcoma. My understanding was that Keytruda was approved two years ago
for use based on MSI-high and mismatched repair deficiency testing. My question is do hospitals or does any hospital
automatically run this test for all sarcomas in anyone else whose long-term survival is in doubt and are there any other test
available other than MSI-high in mismatched repair deficiency to determine if a checkpoint
blocker will work. – So microsatellite
instability or MSI-high cancers are most likely to be colon,
found in colon cancers as well as endometrial cancers but with the approval of
Keytruda and pembrolizumab after all types of cancers with MSI-high I think it has changed our practice at least here at Dana-Farber where most of the solid tumors now are being checked for whether
or not they are MSI-high. So it’s just that the percentages
of other cancers other than colon and endometrial having MSI-high is very low, probably
in the single digits. But I do think it’s something that is now routinely being implemented because there is such a good therapy for that type of cancer now. – But I think you bring
up a very good point and at many places, that
testing is not done routinely. For the MSI-high ones it should be but many of these less common cancers it’s certainly not being done. So in that situation, I
think it is very important to get an opinion or to get input from a center that has a
fair amount of experience in doing a lot of work
with cancer immunotherapy or at least to ask your
doctor, to ask your oncologist and say, “Can we find
out if my tumor has this “so that I might be a
possible candidate for this?” And there are commercially
available tests that can be done. If they don’t have it at their hospital they can get it done. Every patient who walks through the door at the Dana-Farber here and we’ve been doing this for many years we do an analysis of the genetic blueprint of their cancer cells. That’s just a standard
we do for everybody and it has been done for
over eight years now but it does include the MSI the testing of the mutational burden here. But you won’t get that done routinely it’s something you need to ask about and if they tell you it’s not possible then I wouldn’t settle for that. There’s opportunities to go
beyond and get an opinion go to a place where that’s done or get it commercially done. Other questions, I want to
make sure we cover this side of the room as well. – [Female Audience Member]
General chemotherapy has lots of side effects even the oral medication. Does the immunotherapy
have less side effect? – So for those who
couldn’t hear the question let me just repeat it. Chemotherapy has a lot, typically
has a lot of side effects and that’s true. How ‘about the side
effects of immunotherapy and are they less than chemotherapy? And maybe we’ll have
some commentary from some of our colleagues with direct
experience on that question. – So I can start by saying, first with respect to the checkpoint inhibitors which is where they get
in the solid tumors those are the drugs
most commonly being used as you’ve already heard more
than 15 different indications. On the whole, they have less
side effects than chemotherapy when they’ve generally
been compared head-to-head. But at the same time we also know that the side
effects are different. So and many of the side
effects actually stem from you’re stimulating the immune system and we’ve used the analogy of your blocking a break
on the immune system and as Dr. Reardon mentioned earlier Mother Nature put those
breaks there for a reason. And so sometimes, when you’re
stimulating the immune system it can begin to recognize normal parts of yourself as foreign and generate these immune side effects and so those are the big
side effects that we’ve seen. Now, thankfully, the most common ones are things like rash or an
underactive thyroid gland are things that are
easier for us to treat but there are certain adverse events that are quite challenging to treat and can be quite severe. Thankfully, they’re rare but really, the immune
system can affect anything from the top of the head down to the toes really any organ system has
the potential to be affected. And one of the things we came
to recognize at Mass General was that because these
side effects are different we actually created our own
immunotherapy toxicity service. This is in the hospital
to really recognize that these are unique side effects. They’re different from
typical standard chemotherapy and we need to understand them better and so built into that service
is not just oncologists it’s really subspecialists so we have 15 different
services that are apart of it but also trying to understand
and collect samples along the way to try to get a better sense of what’s causing one person
to have an immune side effect and not the next person. So in trying to understand that better. – And I think very importantly this, I think, brings up
a very important point. Because the side effects can be different the patients who have
gotten into serious trouble with these side effects primarily
are when they’re ignored. Because if you think about it if your immune system is starting to react against something
normal in the body and you ignore it, you
don’t pay attention and we keep giving the treatment the immune system is
going to keep activating and that can cause more
and more of a reaction. So it’s very important if
you’re getting these treatments if you’re having a little diarrhea or you’re having a little
cramping and bellyache if you’re having a little cough or a little shortness of breath even if it doesn’t feel
like much of a thing we routinely go through lots of questions when our patients are on these drugs and we’ve learned over the
years that that’s very important in order to pickup on very early before something escalates
and becomes more serious in order to nip it in the bud and prevent it from becoming a problem If you ignore it, that’s
when it can amplify and become more of a problem. And some of my patients are concerned they don’t want to talk
about any side effects ’cause they’re worried
they’re going to have to come off the trial
or they’re going to have to stop the treatment and that’s not necessarily true at all. The side effects, if
they’re picked up on early we can treat them, we
can adjust the treatment and keep things going along. It’s very important to
have that conversation and talk about things early and frequently if anybody’s noticing any side effects before they become more serious. Any other comments on side effects?
– Yeah, maybe just from a perspective of childhood cancer and CAR T-cell therapy. As I mentioned previously,
the CAR T-cell side effects can be quite dramatic but
are usually transient and so I think that’s important
for our pediatric patients. Some of the therapies
that would have otherwise been offered involve very
intensive chemotherapy and especially for a young child’s body that can have lasting effects
for the rest of their life. It can affect their fertility and the health of their
heart and other organs. So I think if we can learn how
to use immunotherapy safely more upfront in therapy,
we can spare them some of these chemotherapy side effects that can potentially affect
the rest of their lives. So I think that’s an important difference in the side effect profile. – So there’ll be a lot of
opportunity through the day here for more discussion and
questions going forward here but at this point, let’s
move on to the next phase of the program and I’ll
have Brian come back up for introducing us or moving that forward. Thank you everybody. (audience applauds)

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