Good evening. Welcome. I'm Gina Vild. I'm the Associate Dean for
Communications and External Relations from Harvard
Medical School. And welcome to our grand finale
of the 2017 Longwood Seminars. As you know, we had a snow
date for the first one. So we're thrilled that all
of you decided to come back. May I ask if there is anyone
here who has attended all four of the Longwood
Seminars Wow, fabulous. Thrilled. Before we actually begin
our program tonight, I'd like to ask Belinda
Davis to come forward. Belinda, this is her first
year organizing the Longwood Seminars And I believe she's
done an extraordinary job. And it's an awful lot of
work that goes into this. And so just please join
me in thanking her. [APPLAUSE] And it's her birthday. So if you see her
on the way out-- Thank you. [APPLAUSE] The Longwood Seminars,
we initiated them about 16 years ago. And the concept behind
them was to share the knowledge of
Harvard Medical School and our extraordinary faculty
with the Boston neighborhoods. But we soon grew
far beyond that. And in the last few years,
we've been Livestreaming. And tonight, again, we are
Livestreaming around the world. And I want to welcome
all of our visitors who are joining us from afar. In fact, I thought you'd
be interested to know that, in the first
three seminars, they were viewed in 93
countries and watched by more than 638,000 people. So those in the room tonight
represent just a small number of who are enjoying these
seminars around the world. Some of the top
viewing countries are India, Taiwan, South Korea,
Mexico, Singapore, and the UK. In addition, we stream
live on Facebook. And the first
three seminars were viewed by 33,400 on Facebook,
and another 5,000 on YouTube. So to all of you, welcome. And thank you for being a part
of this very special program. Before we get started with our
program, An Answer to Cancer, I just have a few announcements. If you've earned a
certificate of completion or professional
development points, you can pick up your certificate
in the lobby following the Q&A. If you've earned the certificate
and are not here tonight, you can contact us via email. We also invite you to
complete an evaluation form. We have those in the lobby. And your ideas are
really an important way of how we can infuse some
really good, new ideas into these programs
so that we keep them vital and interesting. So please take some
time and do that. We also will be
collecting your questions. You all know this
because you're veterans. And we will have people
strolling up and down the aisles, so please turn
your questions over to them. If you're part of our audience
watching through Livestreaming, you, too, can send us questions. Join us and send your
questions by using the hashtag #HMSMiniMed. So this evening, we have
four of the world's leading authorities. And they truly are four of the
world's leading authorities, both scientists and clinicians,
here to talk with you. They'll share with
you the strategy of using the body's own
defenses to combat cancer. First, we have our
moderator, Dr. Arlene Sharpe. Dr. Sharpe is the
George Fabyan Professor of Comparative Pathology. She is the Interim
Co-Chair of the Department of Microbiology and Immunology
at Harvard Medical School. And she's a member of the
Department of Pathology at Brigham and Women's
Hospital, an Associate Member of the Broad Institute
of Harvard and MIT, a leader of the
Cancer Immunology Program at the Dana-Farber
Harvard Cancer Center, and Co-Director
of the Evergrande Center for Immunologic
Diseases at HMS and Brigham and Women's Hospital. Dr. Sharpe's lab
focuses on new therapies for autoimmune
diseases and cancer. And she'll be our moderator. Dr. David McDermott is the
Director of the Melanoma Skin Cancer Program and the Biologic
Therapy Program at Beth Israel Deaconess Medical Center. As a medical oncologist
and clinical investigator, he has a particular interest
in therapies that enhance the immune response to cancer. Dr. McDermott is an Associate
Professor of Medicine at HMS and a member of the editorial
board for the Journal of Clinical Oncology. Dr. Jerry Ritz is the
Executive Director of the Connell-O'Reilly Cell
Manipulation Core Facility at the Dana-Farber Harvard
Cancer Center and an HMS professor of medicine. He's a recipient of the
prestigious Stahlman Scholar Award given by the Leukemia and
Lymphoma Society of America. Dr. Ritz is an expert
whose lab focuses on hematologic malignancies,
bone marrow transplantation, and cancer immunology. Dr. Catherine Wu is an HMS
Associate professor of medicine and a staff physician at
Dana-Farber and Brigham and Women's Hospital. She's a member of the
American Society of Clinical Investigation, a
recipient of a 2011 Stand Up to Cancer
Innovative Research Grant from the American Association
of Cancer Research, and a scholar of the
Leukemia and Lymphoma Society of America. Her laboratory focuses on
dissecting the underlying mechanisms of pathobiology of
chronic lymphocytic leukemia, which is a common
adult leukemia, as a means to generate
more effective therapies. Particularly
immune-based treatments. This is truly an
illustrious panel that we bring to our
final Longwood Seminars. So thank you, Dr. Sharpe. [APPLAUSE] Well, thank you very much for
that very kind introduction. In my talk this
evening, I'm going to be introducing the topic of
cancer immunology and cancer immunotherapy. We all think of the immune
system as a way that defends us against infections. For example, the immune system
exists to defend us against the diversity of
the microbial world, viruses which we cannot
see with the naked eye. This is an electron
micrograph of influenza virus, which causes the flu, as
well as bacteria, shown here. Cancer immunotherapy
is designed to boost the body's own immune defenses. In this case, to fight cancer. Now, white blood
cells in the body are cells that are important
in the immune system. And a particular type
of white blood cell, called a T cell is able to kill
microbes that cause infection and also cancer cells. We have-- whoops. Is it possible to
go back one slide? We have a very limited
number of cells that can recognize a
particular microbe or cancer. But once these cells are
activated, they can expand. And one can get large
numbers of these cells that then can function to help us
fight infection or cancer. Now, a key function
of the immune system is to distinguish normal cells
in the body from foreign cells, such as infected
cells or cancer cells. And the immune
system uses proteins that are on the surface
of, for example, T cells shown here, that need
to be either activated to promote an immune
response or inhibited to prevent an immune response
at certain checkpoints. These checkpoints are important
for proper functioning of the immune response. And one needs to distinguish
infected cells, for example, or cancer cells
from normal cells. And these immune
checkpoints lead to responses against
infected cells, but not to our own
bodies or self. Now, cancer cells
are very clever. And they've figured
out many different ways to block immune responses. And one of the ways
that cancers do this are to use these
inhibitory checkpoints that normally are used
to prevent responses against our own bodies. In this case, we have
an immune response, and the tumor has
put up a blockade against the immune system. And this system, called
checkpoint blockade, that you've heard
about, essentially blocks pathways that
the tumors are using to inhibit anti-tumor immunity. So the tumor prevents an
effective immune response. And one type of immunotherapy
called checkpoint blockade blocks pathways that
the tumors are using to inhibit the immune response. Now, the tumor
cells themselves can make a variety of
substances that can prevent immune responses. And essentially,
they're able to use many of these
inhibitory checkpoints to their own devices. Two of these checkpoints
that are important and have been translated into therapy
are cell surface receptors called PD-1 and CTLA-4. These cell surface
receptors can be expressed on T-lymphocytes,
these T-cells, as well as some
other cell types. And when they interact
with their ligands, or binding partners,
these cells then can deliver inhibitory
signals into the T-cells and prevent their responses. Cancer cells themselves can
send signals through PD-1 into a T-cell, essentially
tricking the immune system into seeing these cells
as healthy normal cells. And checkpoint inhibition
blocks these pathways that then can expose these
cells to immune attack. This is a picture showing you
two different types of tumors, A kidney tumor on the left
and the non-small cell lung cancer on the right. And we've used an antibody to
PD-L1, one of the molecules that combine to PD-1. And this brown staining
here is an antibody that can visualize PD-L1 on
the surface of the tumor cells, and showing you in
this brown stain here that tumor
cells can express high levels of the
ligand for PD-1. So simply put, then, in
a tumor microenvironment, we can have T-cells that
express high levels of PD-1, shown here. And these cells then
can interact with PD-L1 on a tumor cell. When this happens, the T-cell
cannot function and kill the tumor. But the drug that's
used in this case is an antibody either
to PD-1 or PD-L1. And when this is given,
this prevents PD-L1 from interacting with PD-1 and
blocks this inhibitory signal. So now the T-cell
can function and is able to kill tumor cells,
and make certain protein hormones called cytokines
that also can work together to boost anti-tumor immunity. There are now a number
of checkpoint inhibitors that are approved
by the FDA that are targeting these receptors. One is against CTLA-4, a
molecule called Yervoy. And there are several antibodies
to PD-1, one called Opdivo, and the other is Keytruda. And then antibodies
to PD-L1 as well. And there are, in
addition, about 20 agents that are present in
ongoing clinical trials. These antibodies have
been approved by the FDA for several tumors,
shown in green here. And one of the remarkable
things about the PD-1 pathway is that it's been
used over and over again by a variety of types of tumors
to inhibit anti-tumor immunity. And so antibodies that
inhibit the PD-1 pathway have been FDA-approved for
melanoma, for bladder cancer, non-small cell lung cancer, head
and neck tumors, kidney tumors, Hodgkin's disease, and
Merkel cell tumors. And what this is showing you is
overall response rates, showing you the overall response
rate ranges from 20% to 30% in many tumors. Up to 87% in Hodgkin's disease. Now, why is there such
enthusiasm for immunotherapy? This slide illustrates
one of the major reasons. If we first look at this
graph on the left, what we're looking at are
patients whose tumors have been treated with
blockers of CTLA-4 or PD-1. The experience is longer
with blockers of CTLA-4. And what you can see is
that there are about 20% of the patients who respond. But the benefit is durable,
lasting for at least a decade. The experience with
PD-1 is more recent. But in addition,
in this situation, blockers of the
PD-1 pathway, also can lead to durable benefit. So the enthusiasm
for immunotherapy is that it can lead to
a long-term benefit, but a moderate number
of patients respond. And I'll come back
to that point. In contrast, patients
who receive chemotherapy, or other types of therapies
such as kinase blockade, there is a higher percentage of
patients who initially respond. But, unfortunately, the
response is short-lived. So the great enthusiasm
for immunotherapy is the durability of
response that's seen. Now, what is it
the immune system sees in a tumor to attack? Tumors have a variety of changes
in protein coding regions. And these are
[INAUDIBLE] mutations. And as a result of
this, these changes that occur in the tumor
cell can be recognized by the immune system. And these protein coding changes
are called tumor neoantigens. And so, in cancer, there are two
types of evolutionary processes that are driving the tumor. The first are the mutations
that are occurring. And there are two
types of mutations. There are so-called
driver mutations that initiate the
tumor-forming process. And then there are these
protein coding changes called neoantigens that the
immune system can recognize. In addition, there are a number
of immune evasion pathways that we're learning
more and more about. The PD-1 pathway is one, and
there are many others as well. And one of the reasons
why the immune system is the perfect approach to
use against the tumor is that, as the tumor
continues to evolve, so can the immune system. So the immune system can
keep up with the tumor. We're just beginning
to understand how to identify those
groups of patients who benefit from PD-1 therapy. Understanding of immunology,
as well as cancer genetics, has identified several
groups who are responders. One are groups of people who
have highly mutated tumors, where there's defects
in DNA repair. These patients have a high
response rate to PD-1. In addition, there
are certain tumors, such as Hodgkin's disease,
where the tumors have many, many copies of
the ligands for PD-1. And so when you then
block this pathway, there is a very
high response rate to PD-1 pathway inhibitors. In addition, certain
tumors of viral origin, such as those caused
by papilloma viruses, this can lead to head
neck tumors, for example, or Merkel cell tumors, one
can see in those settings that there also is a
high response rate. But we're really just beginning
to understand these responses, and further work is needed
to identify biomarkers that we can correlate
broadly with responses to PD-1 immunotherapy. But this is really
just the beginning. And really, we're
at the beginning of a revolution
in cancer therapy because there are many more
cancer immunotherapy targets than PD-1 and CTLA-4. This is a diagram showing you
here that these T-lymphocytes can express many of these
inhibitory receptors. And all of these receptors
have become druggable targets for cancer immunotherapy. And so while we
now have therapies to CTLA-4 and the PD-1 pathway,
many of these other targets are also now, molecules are
being made for therapies. And there are clinical
trials that are ongoing. And so the PD-1
pathway is really becoming a foundational
building block to combine with other
types of therapies. And right now, there
is great interest in combination therapy. How to increase the benefit
to PD-1 pathway blockade. And there are a
number of approaches that are being undertaken. The first is to
combine PD-1 blockade with blocking other inhibitory
pathways to release the brakes on the immune system. The other is to block
PD-1, and then stimulate the immune system in some way. Another is to block PD-1,
and then give chemotherapies or certain types of kinase
inhibitors or radiation therapy. Or give PD-1 blockade,
along with a cancer vaccine, a cellular or engineered T-cell. And you'll be hearing
much more about these in the subsequent talks. And so hopefully
over the next decade, we're going to have tremendous
progress because there's so much work ongoing now. So the future of cancer
therapy and decisions may look something like this. One will have sequencing
of the genome. So one can identify what
genes are causing the tumor, and these can be drug targets. In addition, one can identify
those protein coding mutations and identify neoantigens,
which also can service targets for therapy. In addition, one can develop a
so-called tumor immunoevasion score, identify which
ways the tumor is using what pathways to
evade the immune system, and then target these. So this would lead to choosing
the best immunotherapy, and how to combine immunotherapy
with the best targeted therapy or vaccine. So to summarize, then, the
success of checkpoint blockade therapy has led to
incredible change in the strategy
for cancer therapy. We're beginning to appreciate
that tumor immunity is limited by natural
regulatory mechanisms that the immune system is using. And by boosting the
body's immune defenses, we can fight cancer. The future is in
combination therapy to extend the benefit
of cancer immunotherapy, to build on the success we
have with checkpoint blockade and combine it with a
variety of other approaches. And in the next talks,
you'll be hearing about some of these other approaches,
taking basic discoveries in immunology and
translating them to therapy. The appreciation that there
are many pathways that inhibit tumor immunity
has translated to checkpoint blockade. And you're going to hear from
Cathy Wu about approaches that are leading to t-cell
vaccines, from Dr. Jerry Ritz about T-cell engineering
and stem cell approaches, and from Dr. David McDermott
about clinical trials in combination therapies. Thank you very much
for your attention. [APPLAUSE] And I'll turn it over to Dr. Wu. Great. So great, happy to be here. And just to follow
Arlene's talk, as she said, we have a very complex number
of different types of cells that comprise the immune system. There are specialized organs. They have the ability to
travel and go and survey the whole entire body to
make sure that we're safe. And just to remind ourselves
that as hardwiring, the immune system is
hardwired to recognize these external
pathogens, so protect us from these external evaders. They're really a mixed and
motley group of different types of organisms. Bacteria, fungi,
viruses and parasites. But also to reiterate
that, as a system, the immunity
responses, the function to survey all the interfaces
that our body interfaces with the environment,
detect whether or not these pathogens are present. If so, mount an immune response. For example,
traffic to the lymph node, where robust
responses can be generated. And there's another
very important function that happens which, is
memory is developed. So there may be, first,
the initial encounter with a pathogen. And
once an immune response is developed, if there
is a secondary encounter, there is a very swift and
high amplitude response. And again, this serves to
protect us in the long term. Now, the Danish physiologist
Peter Panum, back in the 1800s, was called to the Faroe
Islands to investigate a measles outbreak, and was
able to study this phenomena of immunologic memory. Because certainly
what he found was there had been already a measles
outbreak many years before, some several decades before. No measles for 65 years. And when there was this
new outbreak that came out, those that were infected earlier
were not affected again, back in 1846. So this really demonstrated this
long-lived immune protection that exposure to this
infectious agent had caused. Now, one question you
might ask, all of us are well-acquainted
with the flu. So why, for example, do
we get flu pandemics? And it gets back to the idea of
antigen and antigen exposure. Because influenza,
as a wily organism, it can avoid immunologic memory
by changing its molecules every so often. So mechanistically,
this is how we can understand why these
outcroppings of flu pandemics come from time to time. Now, what about cancer? We all know that cancer arises
because of DNA mutations that can lead to altered proteins. And there is quite a bit of
different types of mutations per different cancer. Many of you know that there's
been a technological revolution that's happened over the
last couple of years, with the availability
of broad sequencing that allows us to
systematically sequence the coding genomes of cancers. And many of these
large-scale studies have had the goal of
understanding the mutation spectrum of tumor cells,
putting that all together with other layers
of information so that we can come
to understand what are prognostic markers
related to that cancer. And also, can we
think better how to develop novel therapeutics? And certainly in the disease
that I study, but certainly, this could have been
any cancer, we've come a long way ever since
these sequencing technologies have been upon us, which has
been a mere seven or so years. So at least in chronic
lymphocytic leukemia, where a long-standing
question has been, can we understand why certain
patients progress more rapidly? Why do some patients have
a more indolent course? Can we understand what are
the clinical or the protein features? Well, I would say
that since the advent of next-generation
sequencing, there's been this explosive increase in
our knowledge of the genetics, the transcriptomics,
and the epigenomics that allow us to understand that. And just to give you a flavor
of what we've been able to find, through the mining of all
this high-dimensional data, is that we certainly
have been able to find, for example, again,
this is the example of chronic lymphocytic leukemia. But it certainly could
have been true for any of the many other tumors
that have been characterized in a similar fashion. We can identify those
type of molecular events that statistically
appear to be present at a higher-than-expected
frequency that suggests that there was
positive selection, and was involved in the genesis
of these tumors or leukemias. Each column here is
an individual patient. And what I want to
point out to you is that, although there are
some recurrent events that are common amongst patients
who have this type of leukemia, for the most, part
each patient has a different genetic profile. And that really speaks to not
only the immense heterogeneity in the genetics of individuals
that have the same disease, but also the differing
evolutionary trajectories that each patient takes as
all of these alterations are acquired. And altogether,
again, in the example of chronic lymphocytic
leukemia, but I think this is extendable
across the different cancers, we have come to a
picture such as this. Which is we understand each
tumor as not monolithically all the same type of cells that
are one block of population, but rather many sub-populations
within each cancer. So there's maybe one clone
that has three mutations that define this sub-clone. There's another group
that has another five mutations, and this one
with another two mutations, and so on and so forth. So within individual
patients' cells, there may be different
sub-populations. What that means
therapeutically is that, as we try to
start to treat patients with different
types of therapies, be it chemotherapy
or targeted therapy, if not all the cells are
eradicated, because there is such diversity in
the population already, there are evolutionary
pressures that lead small populations
then to expand and be the cause of
subsequent relapses. So too often in cancer, we
see remissions that are short, that come back. And we go through successive
rounds of therapy. So this really provides us
with a tremendous challenge as we think about how
to eradicate cancer. And so I would say that if we
acknowledge that not only is each individual's cancer
different from the next individual, but also within
each individual's cancer, there are many different
sub-populations, and that each of those
as in aggregate, that means that per
individual, there's a unique set of antigens
per tumor per patient. Then perhaps the solution
to this conundrum is we need to have
an army of T-cells. Because the immune
system is actually, again, hardwired to be
able to have a capacity to generate diverse T-cells that
can recognize diverse antigens and eradicate them. So in that respect, again,
along the same lines of what Arlene mentioned,
cancer vaccines actually have perhaps a very
complementary role to play. So Arlene already
talked about how blocking immune
checkpoints that have the brakes on the immune
system can now be overcome with some therapeutics. Perhaps we can use
cancer vaccines to help steer that response,
focus the response, raise T-cells that have
the right specificity, and guide the immune response
in the anti-tumor direction. So that together with
strong adjuvants, which are going to add strength
and speed to the process, and if we put this together
with checkpoint blockade, perhaps this is a
nice, effective way to generate highly-specific
anti-tumor immunity with fewer side effects. So how do we generate
cancer vaccine? So I've tried to bring it down
to the essential ingredients. And I think that
we would all agree that, for a vaccine to
work, we need at least these four complements. You need antigen, so
something to target against. You need adjuvants, so something
to kickstart the system. You need to figure out how
to deliver the vaccine. And of course, again, as Arlene
mentioned, decrease that shield around the tumor that's
immunosuppressive and inhibits the activity
of cytotoxic T-lymphocytes. So we need to block
that suppression. Do we have any evidence
already that vaccines can work? Well, it turns out
this is not a new idea. People have been
kicking around the idea of vaccines for a long time. This is from back
in the late 1890s. There was a very
renowned New York surgeon who created what he
called, his name was Dr. Coley, he created Coley's toxin. And he had this
one patient who had this awful tumor on his face. And he created this
toxin, which was really mushed up bacterial components,
and injected it in the site. And this gentleman received
at least [INAUDIBLE] or so rounds of these injections. And it did lead to
regression, and this man continued to live for
several more years than would have expected
for this type of tumor. And I think we now recognize
that this was probably the first adjuvant. So with all the biological
and molecular understanding that we've gained,
a very effective way to jumpstart the
immune system is to remind the immune system
of those external pathogens. So these were
microbial components that were mushed up
and injected onsite. So perhaps he was able to
awaken those T-cells that happened to already
be there and get them to work, at least for
this person, effectively for a number of years. Since that time, we've
come up with a list of so many different
ways to think about antigens or adjuvants and
formulations and deliveries. And it can be quite bewildering. But I will say that, in between
all of this mixing and matching of complements, there have
been some notable responses that we've seen in patients. So I will remind you that, for
early stage bladder cancer, we are using a microbial
complement to treat that. This has been in
use for decades now. There have been, in another
virally-mediated early type of carcinoma, there have
been peptide vaccines that have been able to
generate clinical responses in this setting. And some of you will know
about the first FDA-approved immunotherapy,
which is Provenge, a vaccine for prostate cancer. So there are a few examples
of where vaccines have worked. But what's especially
exciting to me right now is that we have an
ever-growing toolkit that seems quite clinically
efficacious, that makes the possibility of
vaccines seem like a reality now. So one is, in
terms of adjuvants, I'll just mention as an example. This Poly ICLC is, again,
a microbial component that has been distilled down
to its active ingredient and has been already
tested in clinical trials. There's been a number
of different studies that have used long peptides. So this is peptides
that can be synthesized and given in a syringe, and used
as a way to deliver antigens. And then Arlene already
mentioned the antibodies that we have to block
immunosuppression. So what we need is
actually a good target. So what are we
going to go after? And there, I would say
that we are in a time where we can identify neoantigens. I already talked about how each
tumor has its own specific set of mutations. Well, at least some
of those mutations will generate peptides that
have altered amino acid. So it can be translated. It can generate these
altered peptides. Some of them have
the potential to bind to the patient's
own HLA molecules. And it is this coupling that
allows these peptides to be displayed on a tumor
surface, where t-cells can come and recognize them. So neoantigens
are those antigens that are born out
of mutation and are present on the tumor
specifically, but not on normal cells. And so this has always
been conceptualized to be a really ideal
type of antigen. But what was missing for
so long was the ability to systematically identify them. What we have now
is new technologies that allow us to use
DNA and RNA sequencing so that we can readily
identify these new antigens. We can confirm that
their expression is present on the tumor cells. We also have very well-vetted
out prediction algorithms that allow us to rapidly identify
whether those peptides that we're identifying
from our DNA and RNA analysis would bind
to that person's own HLA molecules. And these are what we call
candidate neoantigens. And really, conceptualized
as hitting the sweet spot. Because by virtue of arising
from tumor mutations, they have exquisite specificity
in terms of expression on tumor cells, and
akin to pathogens, they are highly immunogenic. Because we do not
automatically have a way of deleting out T-cells
that might react to them. And this is really different
than where we've historically been, in terms of
the type of antigens that we have tried to use for
vaccines or immunotherapy. And these are what
we call the shared overexpressed self-antigens
that are variable in terms of their specificity
for expression on the tumor, and variable in the degree
to which they're immunogenic. Now, if you've been
following this, what's been very gratifying is that,
aside from conception and idea that these would
be ideal antigens, there is now lots
of exciting data that has cropped up
in the last three to four years that
have really supported the idea that neoantigens truly
appear to be effective tumor rejection antigens. Some of that data
comes from studies that have looked at hundreds
and thousands of tumors and try to identify
those antigens, and look at clinical outcome
and compare whether those tumor samples that had higher
numbers of neoantigen seem to do better in
terms of survival, compared to those that
had lower neoantigen load. These types of studies
have also tried to look at specific diseases
or specific treatment settings. Other studies have asked,
well, if neoantigens are such great antigens,
are they actually expanded? Can I see whether or not they're
expanded in those settings where patients demonstrably
have clinical responses? And the answer is yes. After stem cell transplant,
after cellular therapy, after checkpoint
blockade therapy, in fact, there have been a
number of interesting studies that have shown that
these T-cells seem to expand out and have
specificity for neoantigens. And finally, both in model
systems and in patients, it's been demonstrated that
neoantigen-specific T-cells can directly kill tumor cells. So really, with
all this data, it's been very supportive of
the idea that these are in fact immunogenic antigens. And then maybe the
next logical step is, well, if that's
the case, can we not generate individualized
personalized vaccines? If we know what the mutations
are in the individual's tumors, can we not actually
generate a vaccine that would be specific for
that individual person? And so the concept that we had
already quite some time ago was, could we not take a tumor,
have normal cells sequence the DNA from these in parallel? And then use the HLA
typing information and predict what are
those peptides that are personal for that
specific individual, come up with a
synthesis strategy that we could make peptides,
for example, that were reactive, that would be predicted
to be individualized for that individual's tumor,
and get it in a syringe where we could give
it as a vaccine? And already, at the
Dana-Farber, we've conducted and recently completed
two proof of concept studies. One in high-risk
melanoma, as well as previously untreated
glioblastoma, that have in fact demonstrated
safety, feasibility, and immunologic activity. And so I think we're really
here now at a time of a paradigm shift in terms of, at least
in the field of vaccinology, where we have the ability
to find these neoantigens and conceive of ways
of targeting not one, but multiple antigens that
are specific for a person's individual tumor
in a tumor-specific in immunogenic fashion. And so I had to put this up,
because I often think about, well, I like Star Wars. But also, I think one
of the opportunities that we've been afforded by
checkpoint blocking antibodies is that we do have a
Obi-Wan Kenobi that has been able to bring down the
shields from the Death Star. And so I think part
of our challenge is how to use that opportunity
and put this opportunity together, so that we can
actually get in there and actually ultimately
destroy the enemy. And so I would say that,
again, coming together with what Arlene
said, combinations. I think that's really
where our future is. She's talked about overcoming
the immunosuppression. But can we also
add another step, which is potent/specific,
anti-tumor, immunosensitization? That is certainly
where vaccines come in. But also, cellular therapy also
has a really important role. So I'm going to pass the podium
to my colleague, Dr. Jerome Ritz, who will tell
us more about that. Thank you. [APPLAUSE] Thank you, Cathy. So I'm here to talk
about cellular therapy. So we've heard a lot
about the immune system. And the immune system
works, in large part, through the generation
of cells that are part of this immune
system, that can then actually do the work. They either make the antibodies
that fight infections, or they actually attack
these invaders themselves. And the question is, can we use
cells as the treatment itself? And this gets us to
the idea of thinking about cells as a living drug. Now, that's not a
totally new concept because we've been involved
in stem cell transplantation for 40 or 50 years. So if we think about a
stem cell transplant, this is for a patient, often
with leukemia or lymphoma, or for a patient who has an
abnormal immune system that is not able to make
their own immune system, not make their own blood cells. Well, we know that if we can
find an HLA-matched brother, sister, or an unrelated
donor, and if we transfer those stem cells
into the individual, that we can actually
get rid of the leukemia. And that can last
for a long time. There's a single transplant,
and that single transplant of a relatively small
number of stem cells actually lasts for the
lifetime of the recipient and continues to make blood
for the rest of their time. Well, it turns out that we
can do that with immune cells, and with T-cells, too. T-cells are long-lived cells. We can generate those T-cells. It's been done primarily
here in the past for virus-specific T-cells. Or it's been done from taking
T-cells from actual tumors, growing them up, activating
them, and giving them back as a T-cell therapy. So these are actually
long-lived, if you will, living drugs. Unlike an antibody
or a chemical that is going to be great
degraded over time, these cells can live. They can multiply
in the recipient. And I'm not going to
talk about it today, but I'll mention
it at the very end, there's actually a new
way of generating cells, long-lived cells,
through reprogramming. And that's the ability to
start with a mature cell and reprogram that cell so that
it may become an immature stem cell. And then once you have
that immature stem cell, that cell can then be programmed
to make other mature cells in the body, often
the same individual. So that's an exciting,
very, very new technology for cell therapy that
is yet in the future. But I think it's
going to be coming. So another way of
thinking about this is, if you think about the
evolution of cell therapies, what I mentioned to you
initially about stem cell therapy. Well, we've been doing stem cell
transplants for over 40 years. It's a common procedure. There are over 20,000
done in the United States, over 50,000 worldwide,
in each year. But what we're doing
is we're taking a mixed cellular product,
we're taking where we can get, and infusing that
into the recipient. And that's where the
whole field started. We're now at a
point where we can begin to identify specific
cells within a larger context. We can purify those cells. We can activate them. We can expand them. And we can then give them
some more defined therapy. What's coming now in
the future, and I'm going to talk a lot about
chimeric antigen receptor, CAR, T-cells, we can now
actually start with a cell, and we can genetically
engineer it to do what we want it to
do for that individual. So all of this is really
the evolution of cells, starting with a mixed cellular
product 30, 40 years ago, then being able to identify
the cells that we really want. And now actually being able
to engineer the cells that we want for individual patients. So how is that done? So here's an
example that has had an awful lot of
interest and excitement over the last few years. It's called-- can
we go back a step? It's the ability to generate
chimeric antigen receptor T-cells. So you heard from
Arlene and from Cathy that T-cells have specific
receptors that can be used to identify cancer cells. Well, in this approach,
we start with a patient. This would be a patient
with leukemia or lymphoma. We do a leukapheresis
procedure that allows us to get out large
numbers of the patient's own T-cells. Those T-cells are then
activated in the laboratory. And then they're
genetically engineered through various viral
vectors to now express a new receptor, a
receptor that is now going to be able to allow those
T-cells to actually recognize the patient's own cancer cells. Those cells are generated
in the laboratory, and they're expanded for a week
or two weeks or three weeks until we get enough
of those cells. And then they're infused
back into the patient, where they now become a living drug. Those cells, now
our immune cells, derive from that patient. They now can go because they
now have a new receptor. They can now go target and find
the patient's own tumor cells. This has been done
most successfully using CD19 as a tumor
antigen. And this is an antigen that is
expressed by normal B-cells, but also all of the cancers that
come from the B-cell lineage. So that would include
acute lymphocytic leukemia, chronic lymphocytic leukemia,
and B-cell lymphoma. So these are actually
a relatively large, different kinds of
cancers that now can be treated using CD19 CAR T-cells. That's just the first target. There have now recently
been several papers that have shown that another
antigen called BCMA, stands for B-cell maturation
antigen, it's another antigen and that is
expressed by myeloma tumor cells. And that also can be
generated into a CAR T cell, again, specifically for
patients with myeloma. So just to show you how
this field has evolved, the whole genetic
engineering field, starting over 20
years ago, people tried to generate these
chimeric receptors, that they could put
them into cells. And they started out by
taking a signaling domain. This is a receptor that
is now synthetically put into a cell that has
one binding domain. It has one signaling domain. People use different
kinds of binding domains, actually, to take an antibody. The binding domain, the
specificity of an antibody, hook it up to a
signaling domain. And these actually worked
in some animal models, but actually were not very
effective in patients. The trick was to enhance
the signaling capacity of these receptors. And when you begin to
add signaling domains and costimulatory domains, that
Arlene Sharpe talked about, you can begin to add those
together into a receptor. You get a much more powerful
signal that is transmitted. And these are now the receptors,
the CAR receptors, that are now being very effective. Of course, you can
go even further. You can add multiple
different signaling domains. These are called
second-generation CARs. We now have
third-generation CARs. We have armored CARs. We have all kinds
of different CARs that people are beginning
to use in clinical trials. This actually is a diagram,
that I borrowed from a paper from Michel Sadelain, that
actually shows the CD19 CAR T-cells, the vectors,
that are actually being used in clinical trials. And they all have many
features in common. They're all a little
bit different. But the ones that are effective
have two signaling domains. These have CD28 as a signaling
domain, in addition to CD3 zeta. These have 4-1BB, in
addition to CD3 zeta. They all have very
similar receptors, all against the
specific CD19 antigen. And these are the ones
that are currently being tested in clinical
trials that are showing really very dramatic efficacy. Now, Cathy, in her talk, talked
about having specific T-cells, with T-cell
receptors to generate those cells expressing receptors
for specific tumor antigens. Well, those can also be
genetically engineered and put into cells that may
not express them already. So you can generate
both an antibody CAR that's called a
surface antigen CAR, or a transgenic TCR CAR. So both of these are now
being developed for patients for different treatments. The advantage to this
is that it really attacks a target,
an engine that is expressed on the surface of the
tumor cell, of the cancer cell. The advantage of this approach
is, as Cathy identified, these are actually specific
for internal proteins, internal mutation,
so that you can see different kinds
of tumor targets using these two
different approaches. So CD19 CAR T-cells have really
hit the hype, as it were. And the reason is
because they've been very effective
in patients with relapsed B-cell malignancies
that have actually failed all other treatments. And in that setting,
anywhere from 50% to 90% of patients with these
various diseases, pre-B-cell ALL, CLL, B-cell
lymphoma, Hodgkins disease, actually can now respond to
these chimeric antigen receptor T-cells. And as I said, these are
effective in patients, both pediatric and
adult patients, that have failed other treatments. And everyone is expecting
that the FDA will actually approve these as living drug
therapies sometime later this year or next year. However, there is
a price to pay, in that there are some
significant toxicities with these treatments. First of all, these antigens
may not be expressed only on the tumor cells. Certainly the ones
that are expressed on the surface of
the tumor cell, but also some normal cells. So those cells can
also be eliminated. When these T-cells
get activated, and actually, they can expand
1,000 fold within a week, you get the release of various
growth factors and cytokines that can be very
toxic in itself. And then there's also very
poorly-explained neurotoxicity. And then, even
though these patients have very dramatic responses,
some of those patients actually do relapse, even after
they've had this treatment. This is data from the
University of Pennsylvania. Really, one of the
leaders in developing this type of treatment. This is for patients
with relapsed ALL. Their response
rate is very high. And about a year afterwards,
still, 50% of the patients are doing very well. And these are patients where you
would expect very few, if any, of these patients to survive
this long after treatment. So it's really very
dramatic therapy in patients who have
failed other treatments. So this is now an area of
intensive investigation. This, again, from
another review paper that came out earlier
this year, just looking at the various types of
trials that have either been completed or ongoing. And there are 20
different CAR T-cell targets that are being
evaluated in clinical trials. And for each one
of these targets, there may be five or six
different clinical trials. These are the trials that are
actually looking at the TCR targets that I mentioned. There's a little bit
less activity for these. But these also are, I think,
going to be very promising. So this is an area of very,
very active investigation. So as I said, I think the
challenges in this treatment is that there are
some toxicities. And so people are
really looking at how to manage these toxicities. And as more people get treated,
as people more become better at understanding what's
working and what's not working, these toxicities
are being managed. There is a relapse. And sometimes, these patients
relapse because the cells actually stop persisting. And so sometimes, you
may need to actually give a second dose of those cells. But sometimes, the tumors
actually figure out a way of deleting that target
antigen. So even though it's something that is expressed very
commonly, and at high level, cancers are very smart
and they figure out how to protect themselves. And then, I think
solid tumors, so we've talked about leukemias and
lymphomas and myelomas. The big challenge is, how do you
get these CAR T-cells to really infiltrate a solid
tumor where you have problems of what is
the right antigen, what is the right target? How do you get the T-cells
to target into the tumor microenvironment? And once the T-cells get there,
even though they're genetically engineered to get there, how
are they going to protect themselves from the
immunosuppressive environment that the cancer has generated? And so again,
combination therapies, trying to figure out how
to pull all this together, they're going to
be very important. And then, in the
last few minutes that I have, I want to
spend a few minutes talking about what's actually also
needed in this type of therapy, is you actually need a
place to make these cells. And that's what we call
the cell manufacturing for the early phase trials. And because these are
very complex therapies, require a lot of work to
generate one dose of cells, the cost of these is, I
think, going to be very high. So one of my hats
at the Dana-Farber is as the head of what we call
the Cell Manipulation Core Facility. So this is a
laboratory that we've developed to actually do this
under controlled situations. And the mission
of our laboratory is to provide safe and effective
cellular products for use in clinical trials. These are for patients who are
getting stem cell transplant, but also for
patients with cancer who are getting these
innovative cell therapies. Unlike a drug or an
antibody that you can get from a
pharmaceutical company, or you can actually
have made for a lot of different patients,
these individual therapies, we're talking about
making one cell product that's actually going
to go for only one patient. That's the ultimate
personalized therapy. So this is the people that
work in our laboratory, just to show that these are
all clean room environments. To actually get into the
facility, you have to gown up. There's constant monitoring
of the environment and the procedures that
are ongoing to make sure that there is no contamination,
that these products are safe and sterile. Because of the increased
interest in this, we're actually building
a new facility. It's going to be located on
the 12th floor of the Smith Building at the Dana-Farber
Cancer Institute. It's going to be completed
in about a year from now. And this is just a design,
looking at this facility. All of these light
blue rooms here, that are shown in
magnification here, are all clean room
suites designed to make products for
individual patients. But you need to have
the place to do it. You also need to have the
well-trained people that can they can manufacture the cells. But then, you need to have
quality control systems. You need to have
quality assurance. You have to deal with all
the regulatory issues. You have to keep
track of everything in the data that's
generated in the facility. And then you have to have
an inventory system for all the different bits and
pieces that go into actually making these things. So it's a complex
environment, and we already have about 50 people who
are working full time in this facility. So just to end here, I think
the points I've tried to make is that I think it is actually
feasible to make these living drugs not just for a
stem cell transplant, but for patients as
a cancer therapy. It's likely that the CD19 CAR
T-cells are actually going to be FDA-approved sometime
later this year or early next year. But they have toxicities. And so it's important
to think about that, and to develop even better
generations of these CAR T-cells that have
the same efficacy, but avoid some of
the toxicities. Now we know this is effective
for some blood cancers. Leukemias and lymphomas,
solid tumors, I think, will also be an important
target for these. And so there's an
awful lot that's going on to be able to engineer
these cells and how to do this. There's a lot of work
going on, so stay tuned. I think there'll be
a lot of progress to be made in this area. Thank you. [APPLAUSE] David. Yes, sir. There you are. You're next. All right. Good. [INAUDIBLE] Thanks. Thank you. Thanks to the organizers
for inviting me here. It's really an honor to
speak in front of you today. It's also an honor to
follow Jerry Ritz, who's been a pioneer in the field
that I started in 20 years ago, focusing on bone
marrow transplant and cellular therapies. I didn't really last
very long in that field. I wasn't very successful. About five years in,
someone pulled me aside and said something about not
earning all of my salary. And I was given the
opportunity to move from hematologic malignancies,
like leukemia and lymphoma, over to what Jerry
was describing. What we call solid tumors. Tumors that start in major
organs, like the kidney. Melanoma, lung cancer. And that's what I've
been focusing on for the last 20 years. But in the first
15 of those years, it wasn't exactly a
great career move. And I'll describe a little
of my history, the history of solid tumor
immunotherapy, and how some of the basic science that's
been done by some of the folks here at Harvard has
changed not just my career, but the outcomes for our
patients with solid tumors. So you've heard a lot
about different approaches to immunotherapy. I'm going to focus
on a few of these. The first one I'm
going to talk about is one that was actually
developed over 30 years ago, the so-called cytokine therapy. You can think of cytokines
as protein messengers of the immune system. They communicate between
different cell types and tell them to
turn on or turn off. And some of the most
important cytokines, when it comes to
fighting cancer, are agents like
interleukin-2, or interferon. And they're actually
natural substances, meaning we all have them
in our bodies at all times. We think they're there to
help us fight off infections, like viral infections. But they can be
synthesized in the lab and made into large volumes,
and given back to patients to essentially act
like an accelerator on the immune system. To put it into overdrive. And what impact did that have? Well, 30 years ago, this
is looking at an x-ray. This is before the
advent of CT technology. You can look at the
scan on the right as a young patient with
metastatic melanoma. You see all those
blotches in the lung. That's all disease. Those are all individual
melanoma metastases, Stage IV solid tumors. And after a short course
of immune therapy, you can see the x-ray
two years later. No cancer. That patient is
still in remission. That patient outlived
their cancer. And that was a truly
exciting development in the field of immunotherapy. But we can talk a
little bit about why this had a limited application. One of the reasons why is IL-2
when given in large amounts, creates significant
side effects. But that wasn't
the only reason why IL-2 had a limited application. But needless to say, this
is one of the pioneers in the field of IL-2. This is Dr. Steven
Rosenberg, who's still at the NCI surgery branch. I remember reading this
article that was in Newsweek. I don't even know if
Newsweek still exists. But at the time, I was in
college reading this article. And after reading
it, I decided I wanted to go to medical school. It sounded like a
really great idea. And this is some of
the early outcomes data from some of those
original trials. This is a trial that
my mentor, Mike Atkins, presented about 10 years
after some of Dr. Rosenberg's initial discoveries. And what this essentially
shows is, in the patients who had a major shrinkage
of their disease after getting interleukin-2,
if you had a response, if your cancer got smaller, the
benefit could last for years. You see 120 months here, these
patients staying in response. So what did the IL-2
experience teach us? It taught us that
remission was possible. That we could take a person
with normally a lethal disease, and put them into remission
that could last decades. And some of these
patients are still coming to see us in clinic. But what else did we
learn during this process? Well, it turns out your immune
system, as you've heard, is not very well-designed
to fight cancer. It's actually designed
to fight infection. And it's designed to
turn on when you're dealing with a viral infection. If you've ever had a bad virus,
you felt fever, chills, sweats, those kind of things,
that's your body revving up to try to fight the infection. Once it's contained,
though, the immune system is designed to shut off. And it turns out that the
brakes on the immune system, as Dr. Sharpe was talking
about, are actually more potent than the accelerator. But now, we understand
some of these breaks. And we can actually,
while the immune system is designed to shut it
off, it can be reactivated. And this is just a cartoon
of just releasing the brakes on the immune system. And one of the most
important breaks on the immune cell, the T-cell,
is a substance called CTLA-4. Now, what happens when
you release the brakes, or you release the
pressure on CTLA-4? Well, this is from one of
our first large studies, Phase III randomized
studies in 2010, that was published in
the New England Journal. These are patients, again,
with metastatic melanoma, who had advanced cancer,
Stage IV disease. They were given a
blocking antibody intravenously that
treated their disease and improved their
overall survival. But more important is
this was the first drug to show an improvement
in survival. But more important, this is
what's called a survival curve. You can see these patients still
alive two, three, four years afterwards. And their treatment
is stopping here. So once again, this is the
ability of your immune system, you're releasing the brakes
on the immune system. You're not treating
the cancer directly. You're treating
the immune cells. You're creating a
benefit in some patients that's lasting years
after the treatment stops. And this was the first
time this was ever shown in a solid tumor. And it was outpatient treatment. So unlike interleukin-2,
which has so many side effects it has to be
given in the hospital, CTLA-4 blockade could
be given outpatient. And patients could come in
for treatment, get a benefit, stop the treatment. And the benefit,
in some patients, could last for a long time. But the benefit doesn't
come without some cost. When you rev up the
body's immune system, sometimes the
T-cells will actually go after healthy cells. And that's what you're
seeing here on these slides. So for example, you hope that
when you activate the T-cells, it's going to fight the cancer. But sometimes, it
can attack the skin. You can see this patient here
with red dermatitis, skin rash. This is a brain MRI. This is before CTLA-4
for blockade is given. And after, you can
see, what we're looking at here in the circle
is the pituitary gland. This is the pituitary
gland essentially being attacked by the
immune cells, which can cause the pituitary
gland to not function, which is not good. But it can be treated
with supplements, with hormones given. This is also one of the
more serious side effects. This is looking at a CAT scan. This white area here
is an enlarged colon. I'll show you a
better picture here. This is a picture of inside
a patient's colon, who's received CTLA-4 blockade. If you've ever seen
one of these before, if you've ever seen
your own colonoscopy, this is a pretty swollen colon. And that's because
of the effects of the immune activation. Now, if detected early,
these side effects can be treated with immune
suppression medications. But they can be serious. So this story is
not just positive. There are some side
effects that we have to manage on a regular basis. One of the other
concepts, and Arlene didn't really go into this. But she is so important in this
part of the story, which we'll talk about in a little bit,
which is not only are there breaks on your immune cells. The cancer can actually create
a braking system of its own. It can actually create, I like
to think of it as barbed wire. Cathy described it as
almost like a force field in Star Wars. The tumors can actually
create a resistance to T-cells that
have detected them as a threat, found their
way into the tumor, are about to kill the tumor. And the tumor puts
up this barbed wire, or this so-called
PD-L1, on the surface of the tumor that takes
active t-cell and says, you're not going to kill me. I'm going to stop
you in your tracks. Now it turns out, once this once
these discoveries were made, you can actually
create antibodies to block the activity
of either PD-1 T-cells, as Arlene was describing,
or this PD-L1 defense that's often on many tumor cells. This was the first large
trial from just five years ago in the New England
Journal of Medicine, which looked at one
of the first PD-1 blocking antibodies in humans. The reason this study
was so important is the patients on this study could
have had one of five cancers. They could have had melanoma or
kidney cancer, the two cancers that I treat. But they also could have had
colon cancer, prostate cancer, or lung cancer. And one of the exciting
parts of this story is, for the first
time, we started seeing activity outside of
kidney cancer and melanoma with these drugs. We started seeing
activity in lung cancer. And when we saw that, we knew
this was going to be big. Because if you could get
lung cancer to respond, if you get the immune system to
wake up and kill a lung cancer, there was going to be a large
list of cancers that would also be sensitive to the treatment. And that story has played out. What did we see early on? Well, this is a patient here
with metastatic melanoma. You can see a very
large mass here that I'm circling in the neck. After treatment, with this
outpatient immune therapy, the mass gets much smaller. You're seeing a
picture of the side of the neck of this patient. And what you notice
here, I don't know if you can notice
it, it's a little hard, the woman is actually
losing pigment in her skin. And why is she doing that? Well, because the
T-cells are detecting the malignant melanocytes,
the malignant melanoma, but also the
healthy melanocytes. So she's losing skin pigment. So this is an immune
reaction, which is dramatic. You can see it on the
microscope as well. But for the first time, we're
seeing this in other diseases, similarly to this one case. What else did we see
in that initial trial? Well, this is one of our
patients with advanced kidney cancer. You see this very large mass
here in the left upper quadrant of the abdomen. The mass is so
big, it's actually growing through the
abdominal wall here. With treatment, once again,
outpatient [INAUDIBLE] treatment, you can see the mass
getting much, much smaller. And most importantly,
this response lasted, meaning this
patient is still having benefit from
treatment several years after finishing the therapy. This is a little bit dramatic. And I apologize to
those people who may be a little bit squeamish. But I wanted to show this,
because this drives home the power of PD-1 blockade. This is a woman who
is 78 years old, who actually had a cancer
of the tongue that spread, unfortunately, to her breast. You can see the mass here. This big, bright,
angry-looking red thing here. This person got an
outpatient PD-L1 blockade. You can see, just
after two weeks, you can already see it
less angry, less red. Within three weeks,
you can see it's almost like it's drying up
here, and essentially dying. And almost back to normal
within six weeks of treatment. Why am I showing this
sort of graphic story? Well, it points to several
important parts of this story. The reason why this
tumor is so angry is the immune system
is already there. The immune system is creating
an inflammatory reaction at the tumor that's causing,
probably, the redness, and probably pain
and discomfort. So the T-cells are there. And what do you do when
you give the antibody? Essentially, those T-cells
can now kill the tumor. And that's why the killing
of the tumor is so quick. Because the T-cells have
already detected it as a threat. And now, the barbed wire
around the tumor is blocked, and they can kill. And that's one of the reasons
why this class of drugs is not just more active,
but is also less toxic. Because the T-cells
you're activating are sitting, for the most
part, at the tumor. They're already there. They're ready to do some damage. But they can't. You're not activating
every T-cell in the body. With some of these older
treatments, like I mentioned IL-2, for example, you're
activating a much larger number of T-cells. So you're creating
much more side effects. And the other interesting
part of this story, which I also wanted to
mention, is this woman's 78. These drugs are not more
toxic as you give them to older patients. In fact, older patients tend
to tolerate these treatments very well and have often
dramatic improvements. This woman had failed multiple
rounds of chemotherapy, which is something we also see, is
these treatments can work, even after chemotherapy fails. So Arlene showed something
similar early on. This is just a list of cancers
where we're seeing activity. And the list is long and growing
all the time, which is good. And in red are the
places where we've seen FDA approvals, where these
treatments are now available. So far, we've had 18
randomized trials. And 16 have been positive. So we're on a roll,
although that's probably not going to continue. One important question
I get a lot is, do these work in
some other cancers? Well, so far, we're not
seeing a lot of activity in some very common cancers. Like the most common
form of breast cancer, for example, and a lot
of prostate cancer. And you might ask why that is. And we're still trying
to figure that out. But it may be because the
typical breast cancer does not generate as dramatic
and immune response. So we don't have the potential
of activating those T-cells at the tumor, like in
the last case I showed. But we're still trying
to figure that out. But I don't want to leave
the impression that these treatments work for most
cancers, because they don't. And they don't work
for most patients with cancers on this list. So just following
up, I was asked to talk a little bit
about combinations. Oncologists are
notorious for thinking, if one drug is good, well, two
drugs has got to be better. And that's not always the
case, because it can sometimes lead to more side effects. But there is a long list. Because PD-1 blockade
is relatively tolerable, you can combine it with Dr.
Wu's vaccines or Dr. Ritz's cellular therapy, or
chemotherapy and radiation, without making those approaches
too much more difficult. And those are being
done right now. There are literally
hundreds of clinical trials ongoing around the world. I just wanted to focus on
one in the last few seconds that I have. This is combining
the two approaches that I mentioned, once
again in melanoma. This is combining
CTLA-4 blockade, releasing the brakes
on the immune system, and also adding PD-1
blockade on top. So covering the barbed
wire on melanoma. And what does that produce? Well, if you just release
the breaks, about 16% of patients with
CTLA-4 blockade will have a lasting
benefit, a lasting remission of their disease. But if you do both
at the same time and you look two years
later, at least in this trial that we did, half of the
patients hadn't progressed. Meaning, essentially,
their cancer hadn't grown in over two years. And some of these patients are
in remission of their disease. So whether we can do better
than this, we'll have to see. But it's truly exciting that,
potentially, combinations might take us a step beyond what
we get with just PD-1 alone. So we're in the era
of immunotherapy. And it certainly
made a big splash in our scientific journals. Because of the impact
across a variety of cancers, it's also made an
impact in the lay press. But I just wanted to say
two important things. One, this would not
have been possible, this story, without the
taxes that you folks pay, that fund places like the NIH. A lot of the money
early on they'd funded that led to
these discoveries was actually money that
went not to study cancer, but went to study things like
autoimmunity and allergies and all that sort of stuff. A lot of that money
went to people like Arlene Sharpe, who is
one of the three or four most important people in this story. She won't tell you that,
because she's very humble. But a lot of this wouldn't
have been possible without her work and her
husband's work, Gordon Freeman. So keep the support
for research. And hopefully, we can do
better work in the next decade. Thank you very much. [APPLAUSE] I'd like to invite all
of our speakers to sit. And we have a number of
questions from the audience and from Facebook that
have been shared with me. And so we'll have time
to discuss a few of them. The first question,
several people have asked how will the cost
to patients of immune therapy or vaccines compare
with chemotherapy? And will this be
covered by insurance? Do you want to take that? So, go ahead. Well, so I think-- well, David can speak
to this as well. I think the immune therapies
that have been approved, the anti-PD-1
antibodies and CTLA-4. So these are now
FDA-approved drugs. And they are new treatments
for lung cancer, for bladder cancer, for [INAUDIBLE] cancer. Those are being
covered by insurance. I'm sorry, so those are
being covered by insurers. They are expensive. But I think almost
any new therapy, whether it's for autoimmune
disease or for asthma or for cancer, these are
now very expensive agents. The cellular therapies
that I've talked about have not yet been approved. We do expect that they will be
approved sometime this year. We don't yet know how much
they're going to cost. We think they're going
to be very expensive. And we really don't
know how expensive. We don't know how insurers
are going to deal with this. It is a big challenge
for the field. Because just the cost
of one of these drugs can be tens of
thousands of dollars. Because it can be given
month after month. The good news is it can
be given chronically. The side effects don't build up. But if you can stay on the drug,
the costs continue to rise. When you talk about adding
expensive drugs together, that will be a major issue. And as a field, it's
up to us to make sure we're only giving these
drugs to the patients most likely to benefit, as
opposed to giving them to everyone, which is a
pharmaceutical approach to these things. We also shouldn't be giving
them longer than need be, which is part of the reason
why I focus a lot on creating remissions of the disease. If you can create a
remission of a cancer, well, then you can
stop the treatment. And also, that means
the side effects stop. That means the cost stops. So as a field, I think we need
to be pushing for treatments that move us in that direction. We generate that
occasionally with patients. But not enough yet. And I think when you
go think about that in terms of the
cellular therapies, they're expensive because you're
making a drug, a cell for one individual patient. And it's a lot of work. It could be three
weeks or three months to actually do that
work to generate for that individual patient. That builds up the expense. But on the other hand, it
is a one-time treatment. It's a living drug
that you really expect to last for a long time. And so that is going to be
one of the mitigating factors. I also think it's
hard to know, I think Jerry talked about
saying that it's hard to know. And I think when treatments are
in their infancy, when they're being tested, when they're
in clinical trials, they are expensive. In the beginning,
it is expensive because there's a lot to
test and a lot to optimize and a lot to figure out. If they do hit the
mainstream, it's hard to know how those costs
will come down over time. OK, maybe we should move on. Another question
that several people have asked, how are people
looking at genetic differences in the treatment of cancer? Cathy. So, yes. Very much worth
thinking about how to use the genetic information,
on one hand to individualize. I talked about the
new antigen vaccines. So that is one way to
individualize our care. Another way, another
aspect that has been really touted, and there's a lot
of thought going into this, is there a way that we can
genetically test and figure out, out of all the
different menu of options that we presented, what is
the most efficacious way to proceed? So for one individual
with one type of cancer, it may be a vaccine. For another person, it
may be cellular therapy. For another person, it may
be a combination, together with checkpoint blockade. So I think we're at a
time where we're all thinking about all of that. So we have, on one hand,
lots of genetic data. On the other hand, we
have lots of developments in immunotherapy. And I think a major thrust is
how to bring that all together. You hear a lot about generically
what are termed biomarkers. And a lot of the thrust
of biomarker research is to identify a marker of
an individual patient that will tell you what the
best treatment would be. Should it be this drug
because the cancer has this specific genetic mutation? Should it be an immune
therapy because there are T-cell infiltrates
that are already there, like David talked about? So I think being able to
predict in a better way who will respond to which
treatment will also help with the cost issue. Because it is very
expensive to give drugs. It's even more expensive to
give drugs that don't work. Another question that
we had is, do you see CRISPR playing a role in
future treatment of cancer in immune approaches,
or other approaches? So CRISPR gene editing,
I think, will play a role in being able to genetically
engineer the cells that we're going to use for treatment. So I think that's already
being used and being applied. Gene editing is going
to be effective. But you need to have a cell
in which to edit genes, and to work through. And you need to
have a laboratory, like the one I showed
you that we're building, that will allow you to
do that in a safe way. So I think gene
editing will really facilitate the
engineering of cells that you really want to
target to a specific cancer. Agreed. Yes. Another question. Do patients have to fail other
therapies before receiving CAR T-cell therapy? Right now, yes. I think right now, it's still
an experimental treatment. And it's really, before you
know that something's working, you really need to
know the patient that you have has exhausted
other known treatments that you know work. So it's really only
in patients who have failed other treatments
that these cells have been generated. In the future, I think
if they get approved and if they're shown
effective for patients who fail treatment, then
it makes sense to say, well, is it is it
possible to use it earlier on in the course of disease? We do a lot of stem
cell transplants. And initially, stem cell
transplant was exclusively for patients with
leukemia or lymphoma, who had failed all other
treatments, as a last resort. It turns out the results are
much better if you actually treat patients
before they failed all the various treatments. So I think it may well move into
an earlier phase of treatment in the future. So another question. Vaccines are used often
before illness occurs. Do you think we can have
personalized cancer vaccines when an individual
is a 100% healthy? Yes. I mean, I agree. In infectious disease, we
always think about vaccines to prevent illness. In cancer, that's
not where we've been. But along the same lines
as what Jerry mentioned, which is vaccines are
going to work the best when your immune system is more
competent and ready to do some work. One thing in the near-term
that we can think about is how to bring vaccines earlier
in the course of disease, not way toward the end
when it's so hard to mount any sort of immune response. In terms of prevention,
I think we're still really far from that time. But I do know that
there's a lot of interest out there about thinking
and conceptualizing how we can find those
premalignant lesions, for example, and trying to find
specific genetic determinants of the premalignant lesion. And maybe we could
vaccinate against that. All concepts and things to test. But certainly, it would
be a promising approach. Cathy did have this
on one of her slides, but HPV vaccine is
actually a cancer vaccine. And probably, it's
really not used enough. Cervical cancer can really be
prevented over 90% of the time by immunizing young
people to the virus that causes that cancer. Another question. Have there been extensive
studies of healthy people with no cancer to
identify immune system differences between them and
those with a cancer diagnosis? And how can those findings
help develop immune therapies for those who need them? You're pointing at me? I don't know that
anyone has done that. I don't think so. So I think there's been a lot
of work, on the genomic side, to look at variation
in cancer responses and degree of immune infiltrate
over hundreds and thousands of samples across many,
many different cancers that have been sampled. In terms of
comparison to normals, I do know that, with respect
for example to neoantigens, it is true that if you take
[INAUDIBLE] neoantigens and you test them
in normal donors, there will be very,
very robust responses. There will also be responses
in cancer patients. But they are less
strong and less broad. But with something
like a vaccine, our hope is that we can
put a little fuel into it and generate those
broad responses that we see in normal donors. I mean, it is
known that patients who are very immune deficient
are more susceptible to cancer. But it's not necessarily
just one type cancer. And their immune system has
a lot of redundancies in it and overlapping functions. And so often,
someone who might be immune deficient in one area,
other cells can compensate. So you don't actually
notice it very much. It's really only in
patients who have very profound immune
deficiency that you see this very high risk of cancer. So we'll have one last question. How is the polio virus
being used to combat cancer? So I think that there are-- I'm not sure how much of
it is polio virus, or only polio virus. But there are what are
called oncolytic viruses that are now being used. So these are
genetically-modified polio virus, or other herpes viruses,
that are genetically engineered to allow them to
infect the cancer cells and kill cancer cells, but
not allow them to spread. And what that does
at the cancer itself is it releases all
the other antigens. And so there's an
immune response that's generated against the virus. And then also, the
immune response against the dead
cancer cells, that is now one form of a
vaccine, if you will. Right. We're using that
approach in melanoma. There's an actual
FDA-approved drug that's actually a herpes virus
that's injected into a tumor on the skin, or under
the skin, to create that local immune response that
hopefully will generate a more systemic response
throughout the body. Most of the patients who
benefit from that injection have relatively
localized disease. And one of the things
folks are trying to do is to take that modified
virus, and combine it with the checkpoint
blockade, in hopes of expanding the benefit
that we see beyond to more critical organs in the body. As far as the
polio story goes, I know it's been looked
at at Duke with patients with brain tumors. And there, they've
seen mixed results. And they made it all
the way to 60 Minutes, helping a couple of people. But also, several people didn't
do so well on that trial. I don't know whether it's
been expanded beyond that. But the concept
is the same idea, which is to take a tumor
that's not being recognized by the immune system, create a
localized immune response that will then lead to
more recognition, more killing of the tumor
by the immune system. Well, I think, unfortunately,
we've run out of time. So I'd like to thank the
audience for their attention and thoughtful questions,
and the speakers once again. [APPLAUSE]
