Sep 10, 2020
In this episode, we hear from Jason Luke, MD, FACP, a medical oncologist and director of the Cancer Immunotherapeutics Center at the UPMC Hillman Cancer Center. His clinical focus is on immunotherapy for advanced solid tumors as well as cutaneous malignancies and melanoma. Dr. Luke discusses a range of issues in immunotherapy, including clinical trials, toxicities, and next-generation therapies that will likely shape the future of the field.
Transcript
ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carol, a reporter for the ASCO Daily News. Joining me today is Dr. Jason Luke, associate professor and Director of the Cancer Therapeutic Center at UPMC Hillman Cancer Center.
Dr. Luke's clinical focus is on immunotherapy for advanced solid
tumors, as well as cutaneous malignancies and melanoma. He joins me
to discuss a range of issues in cancer immunotherapy. Dr. Luke,
it's great to have you back on the podcast, and before we begin, do
you have any disclosures to report that are relevant to our
discussion today?
Dr. Jason Luke: Well, thanks for the invitation to
speak today, Geraldine. I would note that I work broadly in the
field of cancer immunotherapy and drug development, which means
that I have interactions with all levels of pharma. So certainly I
do have conflicts of interest in terms of consulting agreements or
advisory roles with many of the drug companies that are developing
new agents. So I would certainly suggest that anyone who's
interested in those, definitely follow them up.
ASCO Daily News: Thank you, Dr. Luke. Well, I'd
like to start with a question about COVID-19, which has radically
altered care for many patients with cancer. How has it impacted
your patients and the critical research you're doing to advance the
next generation of therapies?
Dr. Jason Luke: Well, thanks for that question. I
think that's a very important one to think about in this current
time. You know, firstly, for how we've done in western Pennsylvania
and the Pittsburgh area, we really missed the first wave. And I
think people were kind of on their high horse a little bit about
how we had done such a good job.
And, unfortunately, you know, as things kind of ricocheted around
the country, eventually it did catch up here. Now, I'll say that
we've been fortunate to not be nearly as impacted as some other
areas, but just like everyone else, we've seen a major decrease in
our volumes coming through the clinics, and then a slowdown in
clinical trials.
Now, that being said, we have now mostly returned back to full
capacity. And I would sort of use that as a bridge, then, to go
into thinking about how has COVID-19 impacted our patients getting
immunotherapy treatments, and the clinical trials, on the other
side, that want to advance the next generation of therapies.
So obviously, for individual patients, this experience with
COVID-19 has just radically altered their treatment. And, you know,
I think everyone knows how difficult this has been for patients
coming in and having to be treated without their family members.
You know, earlier on in the pandemic, potentially, having to make
treatment decisions kind of on their own in the room, and/or face
difficult news without the amount of support we would normally want
them to have. That's improved more recently, I think, with all the
testing.
I think like many places, UPMC tests people-- at least, you know,
temperature checks them before they come in and gives them a
survey. We're not testing everybody immediately that's come into
the clinic, but, you know, trying to screen out anyone who's high
risk. So I think that part of it has really impacted individual
people, and that's translated, then, into the research space.
Where earlier on in the pandemic I think there was a big movement
to try to limit the number of patients coming through the cancer
center just given the uncertainty, and the initial clinical trials
that that impacted a lot, I think, were some of the adjuvant, or
post surgical, clinical trials.
So in the field of melanoma, we have two stage II, or adjuvant
trials, meaning after surgery trials. And I think it was hard to
justify bringing people in to start those therapies for a treatment
that we normally wouldn't give. So those were therapies that were
exploring a new space in medical oncology in the stage II
post-surgical setting.
But I think that's now lightened up a little bit as people have
learned how to be safer. And I think we've been doing a pretty good
job at our cancer center, and I think most places have, to try to
avoid high risk. So that's sort of gone down and then come back
up.
On the earlier side clinical trials, we never really slowed down a
lot for phase I clinical trials. And I felt very much that it was
the case that we needed to continue to push forward for novel
treatment options for our patients because for someone who's facing
advanced disease, who has progressed through standard therapies,
you know, they were sort of faced with, 'Well, do I not go in
because of COVID, and knowing that that means can't get on a
clinical trial. Or do I take that risk as sort of an added element
to the uncertainty of a clinical trial?'
And so in that regard, we've continued to push forward. We've been
very fortunate that we haven't had any patients yet on our clinical
trials test positive for SARS-CoV-2. I know that has happened in
some other places, and it's probably just a matter of time, but I
think, like all other areas of medicine, we're starting to come to
grips with that fact that we're going to be dealing with this for a
long time.
ASCO Daily News: Can you tell us about the cancer
immunotherapy trials that you're excited about these days? And do
you think that the use of telemedicine that was adopted during the
pandemic will continue to play a role in some aspects of clinical
trials in the future?
Dr. Jason Luke: So there's a lot that's going on
that's very exciting in immunotherapy, specifically, for cancer.
And this question about telemedicine is a very important one, and
I'll come back to it a little bit later.
When I think about immunotherapy clinical trials, I might think
about them in a couple of different ways. One would be trials that
are sort of at the tip of the spear, meaning closest to clinical
practice. And there, I'm really thinking about combination regimens
that build on the standard of care, or explore immunotherapy in
sort of new settings, but that aren't very far from the standard of
care.
So for example, you know, people are all aware of giving
chemotherapy with immunotherapy in lung cancer, and a number of
clinical trials have started to read out with similar concepts,
building on standard of care with immunotherapy across a number of
diseases. So I continue to find those to be particularly of
interest.
And further to that, I would note that some of the post-surgical,
or even pre-surgical, immunotherapy clinical trials are really
starting to look exciting. So for example, in melanoma cancer,
there's a lot of evidence now from early clinical trials in the
neoadjuvant, or pre-surgical setting, to state that for patients
who have a major pathologic response prior to surgery to
immunotherapy that those people-- we don't want to call them cured
because we don't feel quite that certain, but essentially none of
them have recurred after surgery.
And those clinical trials are really, really exciting. And I
mentioned melanoma, but these kinds of clinical trials are now
coming into investigation across a number of different diseases, so
lung cancer and bladder cancer and kidney cancer. And I think we're
going to see, as we move into the future, that immunotherapy
clinical trials are really going to be expanding the use of these
systemic therapies much more broadly than we previously had used
chemotherapy.
So that's one part of immunotherapy clinical trials that I think is
really exciting that likely will impact on the standard of care
over the next couple of years. And mostly that immunotherapy is
going to be PD-1 or PD-L1 based immunotherapy.
The other side of the excitement in immunotherapy, obviously, is
the great unknown, meaning what kind of novel therapeutics, or new
treatment options, could be developed to bring forward for our
patients? You know, here we have to have some modesty to realize
that, well, immunotherapy has been a very exciting, even maybe game
changer, as some might state, for the field of oncology.
The vast majority of patients, and for the big diseases, they don't
really benefit from immunotherapy. So think colon cancer, think
breast cancer, and prostate cancer. And yet, we're seeing that
there are a number of exciting things going on that might be able
to expand this.
So one of the areas more recently has been the combination of PD-1
antibodies, or PD-L1 antibodies, with VEGF TKIs has looked exciting
in a number of these different diseases. But for me, personally,
who's really interested in novel therapeutics, I think it's really
trying to either integrate new biomarkers, or come up with new
immunotherapy, say engineering approaches, to think about expanding
the benefit.
So for example, we saw at the ASCO meeting this year a study of a
PD-L1 antibody with an anti-TIGIT antibody in the PD-L1 high
non-small cell lung cancer space. And so the biomarker here was the
PD-L1, and some might think, like, oh, well that's old hat. Don't
we already know about PD-L1? But some might be surprised to know
that we really haven't been optimally using that in our clinical
trials so far, and that's only one marker.
So say we start to integrate other markers like tumor mutational
burden, or even novel markers like LAG-3 status for LAG-3 trials,
or myeloid signatures for myeloid-directed, or the adenosine
pathway, and these kinds of approaches. If we started to stratify
patients more for these clinical trials, we might find that some of
the other novel therapeutics look exciting in subpopulations of
patients, honestly, very similar to how we do with targeted
therapy.
You know, obviously no one would think it's a reasonable idea to
use an end track fusion inhibitor if there's no end track fusion,
and yet in immunotherapy we've kind of been doing that for a while.
And then the other place that I would note is there are a number of
approaches now trying to overcome some of the earlier generations
of immunotherapy-- their problems-- by sort of reengineering
them.
And so in this regard, I mean multi-specific antibodies or
molecules. In other words, molecules that can block multiple angles
of the immune system at once. So one of the things that I would be
aware of is that the whole field of T cell agonist checkpoints- and
they have names like OX40 and 4-1BB and ICOS. The first generation
of these antibodies really didn't look very exciting.
There's a second generation of multi-specific antibodies that's now
combining those molecules with, say, PD-L1, or another molecule,
and I'm very excited to see, kind of, what those kinds of data are
going to look like. And similarly, trying to combine therapeutic
approaches that might sort of work on the other side of the immune
system.
So PD-1 really blocks the effector phage, or reactivates it, and
I'm very excited to see what some of these innate immune modifiers,
like toll-like receptors or sting agonists and some of these
molecules might do to potentiate immunotherapy in populations of
patients that we really haven't benefited with immunotherapy so
far.
So all of these to say that I think there's still a lot going on in
immunotherapy from enhancing the current benefit of PD-1 blocking
antibodies and adjuvant and neoadjuvant settings, combining with
standard of care-- say VEGF inhibitors or chemotherapy-- and then
more novel technologies like multi-specific molecules, innate
immune modifiers, and even cellular therapies that I didn't touch
on which are now starting to come into clinical trials for solid
tumors like TCR transduce T cells and chimeric antigen receptor T
cells, and even NK cells, and I heard about macrophage cars
recently, as well. So all of that is pretty exciting.
Just to finish up on this point, you asked about telemedicine, and
I think this is a big wild card, and I'm not sure about this. So
you know, due to COVID, we were able to take a lot more flexibility
in clinical trials for patients owing to the obvious danger that
people might experience by coming in. And the FDA allowed for that
with multiple guidances that said it was OK to do some of this
remotely. It'll be very interesting to see if and when that changes
back.
I am really hopeful for a COVID-19 vaccine around the turn of the
year, but I'm not holding my breath either, and it may very well be
that the first generation isn't what we're hoping for. So I don't
know whether or not we're going to be going back to normal, in air
quotes, you know, anytime especially soon. So I don't know.
I think telemedicine is definitely here to stay over the near-term.
Over the longer term, it's probably going to be some combination of
guidance from FDA, as well as potentially reimbursement from payers
as to whether or not that's going to be an approach that medical
centers thinks is viable to support clinical practice into the
future.
ASCO Daily News: Well, let's talk about
toxicities, which are a huge challenge for patients receiving
immunotherapy treatments. Are you concerned about this, and do you
think that the field is doing enough to address toxicities?
Dr. Jason Luke: So thanks for asking that
question. And maybe paradoxically, I'm going to give you two
answers, which is, obviously, we need to do more because even
individual patients experiencing severe toxicity is a problem. And
yet, I also would like to raise the concept that maybe we should be
pushing the envelope a little harder as well.
So let me take the first one first. You know, in standard clinical
practice, the toxicity profile of immunotherapy-- these
immune-related adverse events, as we've classically described
them-- they can be a major challenge. And they do require having a
pre-test probability in your mind about your patient, thinking that
they might be experiencing one of these things.
And so education with the patient and their family is just
essential so that they're aware of what these things are. From
experience, I had one of these today at clinic, honestly. A patient
who had had a little bit of diarrhea on an immune checkpoint
inhibitor, and we gave him a short course of steroids and it went
right away. And we challenged him with cycle two. For reasons
unclear to me, he just didn't tell me that these exact same
symptoms came back, despite my asking him, and he ended up getting
hospitalized.
And so that emphasizes on my part that I didn't educate him and his
wife enough for them to know, and we didn't stay close enough to
them. So really, the major thing that I would really remind people
is communication, communication. Tell the patients to let us know.
Because obviously we can take care of these toxicities and we can
head them off if we know about them. But when they kind of get to a
tougher place, then it becomes more of a problem.
So I think continuing to educate our community about these
toxicities, and continuing to engage with patients and stakeholders
around this is going to be really, really important. I do want to
shift, though, quickly as we think about novel drug development and
sort of moving the needle with immunotherapy as well, though, that
I do worry a little bit that in the research space we might be too
beholden to sort of our current paradigms around immunotherapy.
And so two examples to this point, which is if you look at the
combination of PD-1 and CTLA-4 blockade in melanoma, it's clearly
the case that the patients who have more toxicity for a short term
period of time have at least as good, and maybe better outcomes,
than the people who don't. And for the first generation of CAR T
cells, this was similar. If you didn't develop cytokine release
syndrome, essentially patients didn't benefit.
And so what I worry a little bit is that we're actually not trying
hard enough to generate toxicity. And that might sound kind of
strange to some people, but I worry that if we have not broken
immune tolerance that manifests as some sort of autoimmune-like
phenomenon in our patients, especially in early phase trials, that
maybe we haven't adequately explored the therapeutic window that
might be possible with these agents.
As almost everybody listening will realize, you know, with PD-1
it's been an amazing transformational shift in our field. And yet,
what's after PD-1? It's been five years now, and we kind of haven't
hit that next thing. And certainly we're making lots of progress
with various approaches that we've already talked about, but we
haven't continued to see that transformational shift.
And like I mentioned, multiple big tumor types with lots of
patients don't benefit. So I wonder whether or not we should
actually be pushing the envelope a little harder for some of our
combination regiments to be trying to generate greater levels of
immune-related adverse events. Obviously, we can always dial the
dose back, but if we don't explore the dose all the way up, we
never even really know whether or not the possibility was there for
some drug that we think maybe wasn't effective. Do we know that we
really tried it all the way through?
So I think that's more of a research question, and that's something
that we're trying to engage with the FDA around. What would be a
safe way to do this for patients? So that we could know better
whether or not we're really pushing the envelope. Because if we
stop too early, I think we may not be kind of adequately giving a
chance, and we might not fully benefit from the therapies that we
think could be the next, kind of, anti PD-1.
ASCO Daily News: Well, that's a very interesting
take on the issue of toxicities. Thank you for sharing that. Before
we wrap up, I'd love to ask you about your vision of immunotherapy
in, let's say, five years from now. What does the future hold for
immunotherapy?
Dr. Jason Luke: So as a prognosticator, I mean, I
think-- obviously, as somebody who drank the Kool-Aid on
immunotherapy, and I'm very excited about it, I think, for all the
right reasons. If we can get people's immune responses to kick in,
we can help them to avoid treatments like chemotherapy and
potentially morbid surgeries.
So I think about immunotherapy, again, sort of short and long term.
There are certain disease types where I think immunotherapy will
have an increasing role that might further, sort of, get rid of
some of the classic approaches that we've taken.
And so for example, in melanoma. You know, it's currently the case
that melanoma is sort of a-- immunotherapy to melanoma is a
backbone for metastatic disease and for stage III disease. And I
mentioned earlier that the neoadjuvant, pre-surgical studies are
starting to look really good.
There are also stage II clinical trials-- adjuvant clinical trials,
meaning after surgery-- for melanoma that did not involve the lymph
node where this treatment is starting to look really exciting as
well. So if all those trials were to be positive-- and we should
have those results within just a few years-- that would really only
leave stage one melanoma-- the kind that is usually removed by the
dermatologist-- as the kind that would need really substantial
surgical approaches.
And I don't think people realize how close to realization we are
there. It's not to say we wouldn't do any surgery, but the days of
doing these large, morbid lymph node dissections will be gone if
those trials come to pass in the way that we hope that they will.
And, you know, melanoma is really just kind of the most advanced
immunotherapy space. Such a paradigm could come into effect for
other tumor types-- bladder, kidney, et cetera, and maybe even lung
cancer-- in the future as well.
But moreover, in the advanced disease setting, what I really hope
we see by the year 2025 is much more strict stratification of
patients' tumors and the overarching-- sort of overall description
of their immune status for biomarker stratification. And so we have
advocated that studying the tumor is very important for PD-L1
status and interferon gene expression and tumor rotational burden--
all these things-- but there are other components of the patient's
body and their immune response. And I think we're only starting to
understand, but I think we can harness, in a hypothesis-driven way,
to improve patients' outcomes into the future.
So for example, we're learning more and more that germline
polymorphisms in certain immune regulatory genes can actually
impact on patients' likelihood of developing cancer and likelihood
of developing an appropriate treatment response to immunotherapy.
So can we profile that ahead of time and combine that with
information that we know about the tumor, like PD-L1 status?
Additionally, what about the fecal microbiome, or the patient's
overall commensal microbiome? So a number of high profile papers
have suggested that which bacteria are resident in our body might
change our immune system in a way that makes us more or less likely
to get cancer and respond to different treatments.
And so all of these factors-- the tumor, the host genome, the
microbiome components-- all of these are measurable now with next
generation sequencing approaches, and it's my hope that in the
future, maybe by 2025, a multi-dimensional analysis of
immunotherapy biomarkers could be applied to individual patients to
really try to choose for them the optimal approach that might allow
them to benefit the most from harnessing their immune system
against cancer.
ASCO Daily News: Excellent. Well, thank you Dr.
Luke for sharing your incredible insights with us today on the ASCO
Daily News podcast.
Dr. Jason Luke: Thank you for the opportunity to
speak.
ASCO Daily News: And thank you to our listeners
for joining us today. If you like what you're hearing on the
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