Is this working? Can you hear? Can you hear me? No? There we go. Good afternoon. Thank you for being here. We clearly have
tremendous interest in this talk on Immunotherapy-- An Answer To Cancer. And we are really
privileged to have two very special
presenters here today. I'm Gina Vild. I'm the Chief
Communications Officer for Harvard Medical School. And in addition to all
of you here with us, we are live-streaming
this around the globe. And so I want to
welcome all of you who are here watching us from afar. After the discussion, we
will be taking questions. We will have a microphone
circulating here in the auditorium, but if
you are watching from outside of Harvard Medical School,
please post your question on the Facebook page,
or if you are watching, you can also post on
Twitter at Talks at 12. T-A-L-K-S A-T 1-2. Talks at 12. And we're really hoping we
have time for discussion. So immunotherapy
is the treatment that uses the body's own
defense to combat cancer. Although treatments of
this type were first attempted more
than a century ago, it's only recently that
immunotherapy has shown promise as a means of treating cancer
and other autoimmune diseases. Ralph Waldo Emerson said, "Do
not go where the path may lead. Go instead where there is
no path and leave a trail." And we are really privileged to
have two trailblazers with us today Arlene Sharpe
is the George Fabyan Professor of Comparative
Pathology and Head of the Division of Immunology
and interim co-chair, as you may know, of the
Department of Microbiology and Immunobiology at
Harvard Medical School. Gordon Freeman is Professor
of Medicine at the Dana-Farber Cancer Institute in HMS. You may know that they
run separate labs, but not everyone knows
they also are married. And so there is collaboration
at many different levels. Dr. Sharpe and Dr.
Freeman's discoveries have yielded key
insights into how cancer evades the
immune surveillance and thwarts the body's
immune defenses. Their insights helped launch
a generation of new drugs that unleashed the immune
system to attack tumors and halt the spread of cancer. These discoveries have
made immunotherapy an exciting new
strategy for improving cancer treatment,
and importantly, for extending lives. In partnership with Harvard
Medical School, the Warren Alpert Foundation
each year recognizes the world's foremost scientists
for their seminal discoveries-- discoveries that hold the
promise to change understanding of disease and our
ability to treat it. And I'm really
privileged to tell you that Dr. Sharpe and
Dr. Freeman were among the five recipients
of the 2017 Warren Alpert prize awarded last month. We're honored you
can both join us. Thank you for being here. [APPLAUSE] Can you hear me? A little louder. How's that? Well thank you, Gina, for
that wonderful introduction. And in our talk this
afternoon, Dr. Freeman and I are going to give a brief
introduction to Cancer Immunology and
then discuss cancer and immunotherapy
focusing on our work on PD-1 that has been
translated to therapy for cancer and is beginning to lead to a
paradigm shift for cancer care. These are our disclosures. So as Gina already
mentioned, immunology has offered hope for curing
cancer for over 100 years but now is just beginning
to deliver on this promise. What is different
now is the strategy. We're beginning to
appreciate that the tumor micro-environment has many
layers of immunosuppression. Tumors evolve to
evade immune attack. The immune system can
survey our bodies for tumors and can eliminate
many early tumors. Elegant studies of
Dr. Robert Schreiber. But as tumors grow, they evolve
and evade the immune system. This new strategy for
cancer immunotherapy blocks pathways that are used by tumors
to inhibit anti-tumor immunity. And this strategy is
called checkpoint blockade. Since this audience has
a variety of backgrounds, I'm going to start
by telling you a little bit about what we know
how the immune system fights cancer. The immune system has
the remarkable ability to recognize a
diversity of substances. It's been estimated that the
immune system of a person can recognize somewhere
between 10 million to 100 million
different substances. This enables the immune
system to defend us against the diversity
of the microbial world-- from the smallest
virus to worms, which can be many
meters in length. Immunologists call these
substances antigens. And these antigens are
recognized by white blood cells that are called lymphocytes. And lymphocytes have,
on their cell surface, receptors that can
recognize these antigens. Now we all have a limited
number of lymphocytes that can recognize a particular
antigen. But upon activation, these lymphocytes
can expand many fold. For example, it's been estimated
that T lymphocytes can expand over 50,000 fold
within one week, and such a rapid response
is needed to defend us against infections. The same mechanisms
that are used to defend us against
microbes also can defend us against tumors. There are certain
types of T lymphocytes that can kill cancer cells,
as well as infected cells, and these can expand rapidly
following activation, so this activation process
needs to be carefully regulated. For T cells to become
activated, they need to receive two
signals that are delivered by antigen presenting
cells, such as dendritic cells. The first signal
confers specificity to an immune response
and involves recognition of antigen. The
antigen is presented by a cell such as the
dendritic cell to the T cell. But in order for optimal
and complete activation, the T cell also needs to
receive a second signal known as a co-signal or
co-stimulatory signal. And when the T cell receives
both Signal 1 and Signal 2, it can become
optimally activated. However, we now know
that in addition to these co-stimulatory
signals, there are also negative
second signals that can inhibit T cell activation. Our early work in the
1990s, early 1990s, identified that the
B7-2 CD28 pathway is the major positive
second signal, providing critical signals
for T cell activation. We identified B7-2 as an
early activator of T cells. B7-2 engages CD28, and
together this signal with CD28 together with a T
cell receptor signal promotes T cell activation. The signal through B7
CD28 leads to an increase in growth factors so
the T cells can grow, survival factors, as well
as the bio-energetics. So T cells are able to
proliferate and then differentiate into effector
cells, such as cells that can kill tumor cells. Our discovery of B7-2 lead us
to look for other molecules that looked like B7. This work in the early
1990s was before we had the entire
human genome, so we conducted high homology
searches and looked for cousins of these B7 molecules. Two molecules that we
discovered were PD-L1 and PD-L2. And we discovered that
these were ligands for PD-1. Let me use this cartoon
to introduce the players. The PD-1 receptor is
up regulated on T cells upon their activation. And when PD-1 is engaged
by either PD-L1 or PD-L2, it becomes phosphorylated
on tyrosine motifs and it's cytoplasmic domain. This leads to the association of
protein tyrosine phosphatases, such as SHP-2, which
then can dephosphorylate kinases downstream of the
T cell receptor or CD28. As a result, there
is reduced signaling through the T cell receptor
and reduced T cell responses. Now PD-1 is an acronym
for Program Death 1. The PD-1 receptor
was cloned in 1992 by the laboratory of
Dr. Honjo in Japan from a CD3-activated
T cell hybridoma that was undergoing cell death. But despite its name, PD-1 does
not directly cause cell death, or apoptosis. It doesn't directly
activate caspases. So it's not like a
molecule such as Fas that can cause cell death. The effect of PD-1 on
cell death is indirect because PD-1 can reduce
cytokine production and survival factors that T cells
need for their activation and responsiveness. Ever since the discovery
of PD-L1 and PD-L2, we've been fascinated
by their expression. What we learned is that PD-L1
was very broadly expressed on a wide variety of
hematopoietic cells and non-hematopoietic cells,
whereas PD-L2 was much more restricted in its expression. PD-L1 could be expressed on
dendritic cells, macrophages, B cells and T cells,
and on a variety of non-hematopoietic cells,
including vascular epithelial cells, epithelium, muscle
cells, liver cells, islets in the pancreas, and it's
sights of immune privilege, including the
placenta and the eye. The expression of PD-L1
on a variety of tissues suggested to us that PD-L1 may
control responses locally, T cell responses, within tissues. PD-L2, in contrast, is more
restricted in its expression. It's expressed mainly
on dendritic cells and macrophages. However, it can be
expressed on several types of non-hematopoietic cells, in
particular, cells in the lung on airway epithelial. The PD-L2 molecule
has an important role in controlling responses in
the lung micro-environment. Interferons, alpha,
beta, and gamma, are potent stimuli for up
regulating expression of PD-L1. And interferons can
also up regulate PD-L2, but 1L-4 and GM-CSF
are more potent stimuli for up regulating PD-L2. To So different types
of inflammatory stimuli up regulate this pathway. To understand the functions
of the PD-1 pathway, we developed tools to
probe its function. Gordon's lab made
antibodies to PD-1 and it's ligands to block
functional interactions. My lab made knockout
mice lacking PD-1 or it's ligands
to understand how elimination of these molecules
from the immune system would impact immune responses. Using these
complementary approaches, we learned that the PD-1
pathway has an important role in controlling tolerance to self
and preventing auto immunity. We also learned
that this pathway has an important
role in controlling resolution of inflammation. Sometimes you can have
too much of a good thing and inflammatory responses
can damage tissues. And the PD-1 pathway
has an important role in preventing tissue damage in
response to an immune stimulus, as well as tuning down
the immune response after elimination of disease. We also learned that this
pathway is a key mediator of T cell dysfunction. This pathway has been
exploited over and over again by tumors and microbes, who
I think are the smartest immunologists, and
they've used this pathway to evade eradication
by the immune system. PD-1 contributes to T cell
dysfunction during cancer and chronic infections. During T cell dysfunction,
there are T cells that highly express PD-1 and
PD-1 inhibits their function. Another special
feature of this pathway is that the tumors themselves
can express the ligands for PD-1, PD-L1, and PD-L2. This is from a paper
that we published in 2001 where we showed that PD-L1 was
expressed on breast cancer cell lines. There was an article in the
Dana-Farber Cancer Newsletter that named this discovery
as cancer's shield against the immune
system, recognizing that PD-L1 expression on a tumor
may be a means for the tumor to evade the immune response. Indeed, using antibodies
that we developed and working together with
colleague Scott Rodig at Sabina Signoretti
and David McDermott we determined that
PD-L1 can be expressed on a variety of tumors. We now know that
PD-L1 can be expressed on the surface of about
30% of solid tumors and certain hematologic
malignancies, and that PD-L1 on tumor cells
can inhibit T cell responses. This is just one example
of a human kidney tumor and a human non-small cell lung
tumor showing PD-L1 expression. PD-L1 expression
here is visualized using an anti-PD-L1 antibody. And this brown staining
here is showing expression of PD-L1 on the rim
of the tumor cells, bringing here brown
in the kidney tumor, as well as you can
see there is very high expression on the tumor cells in
the non-small cell lung cancer. So in the setting of
cancer then, we have-- in the tumor micro-environment-- CT8 T cells that
highly expressed PD-1. And these are dysfunctional. PD-L1 can be expressed on
tumor cells themselves, or hematopoietic cells, or
stromal cells in the tumor micro-environment. And the antibody
that's used as a drug blocks anti-PD-1 using
anti-PD-1 or anti-PD-L1 to block the interactions
between PD-1 and PD-L1, and as the results
of this can unleash a potent anti-tumor immune
response, increasing killing by these CD8
cytolytic T cells, as well as cytokine production. As a scientist, you always hope
that something you discover will make a difference,
never really knowing whether that will be the case. And it turns out
that the PD-1 pathway is a major way that cancer
turns off the immune response. And this has been
translated to therapy using PD-1 pathway blockade to
block the inhibitory functions of this pathway. And I'll turn it over to Gordon. [APPLAUSE] Thank you for the invitation
to come and talk to you. If the people on the back
row, if I'm not loud enough, just wave your hands and wave
a little if you can't hear me. So I wanted to show you now how
the basic scientific research at Harvard Medical
School developed into the effective
cancer therapies that have come from this work. This basic science was
taken up by scientists at [INAUDIBLE] Alan Korman and
Nils Lonberg, who developed antibodies against PD-1. And there are now five
FDA approved antibodies which have progressed
through clinical trials to FDA approval. These have names like Nivolumab,
Pembrolizumab, Atezolimumab, Durvalumab, and Avelumab. Now I'm a PhD immunologist,
but some very good clinicians have provided me
some clinical slides. And this is how patients
progress on a PD-1 therapy trial. So this is in kidney cancer. And there are 34 patients. Now the drug is
generally tolerable. The side effects include
fatigue, rash, and pruritus. Now each line on
this graph indicates the progression of one patient
and the change in the tumor size in that patient. So clearly you can see here that
the tumor increases in size. This patient hasn't had
a successful response and goes on to a
different therapy. About 29% of the
patients had what's called an objective response,
which means that the tumor has shrunk more than 30% in size. So here you can see these
objective responses. Now what was remarkable
in this trial is that after about two
years, all the patients stopped the drug. And that after the
drug was stopped, there wasn't rapid
regrowth of the tumor. There is off treatment survival. PD-1 antibody can lead
to durable responses. Now the PD-1 and
PD-L1 drugs have been used in a large
variety of clinical trials, leading to FDA approval in each
of the cancer types indicated in dark blue. So for instance, at the
Dana-Farber, Margaret Ship and Philip Armand, have
shown that Hodgkin's lymphoma can have an 87%
objective response rate. The first FDA approval
came with melanoma in 2014 with about a 35% to
40% response rate. Lung cancer accounts for
21% of cancer deaths. And the PD-1 drugs have
been approved there. Now in the lighter
blue is clinical trials which have not yet
led to FDA approval, but it probably will
be approved in some. Now clearly the PD-1 antibodies
don't work in all tumor types. At the bottom, you can see
that there's very low responses to colon cancer or pancreatic. That doesn't mean that
there's absolutely no hope. For instance Ira
Mehlman's group has shown that if you combine
a MEK inhibitor with PD-1 in colorectal cancer, you
can get a 17% response rate. So even though discoveries
over the last year, 20 years, have emphasized that cancer
is many different diseases, to the immune response, cancer
is much more one disease. This can lead to
some very notable , successes such as a 90-year-old
with metastatic melanoma and four brain metastases. The brain metastases were
treated with radiation. He also received
a PD-1 antibody, and is now self-reported
as to be doing well. Now I wanted to emphasize that
PD-1 immunotherapy is really different from chemotherapy. It's not a poison. You're not trying to
directly kill the tumor cell. Instead, you're trying to let
the immune system activate and attack the tumor cell. So with PD-1 therapy,
there's just a little nausea, no hair loss, no neutropenia
or blood cell count declines, has a reasonably
good safety profile. The PD-1 drug is delivered by a
half hour intravenous infusion. This is fairly
simple, and I think can become community
hospital medicine. Now the adverse events
seen with immunotherapy are very different than
those seen with chemotherapy. They all end with
names like itis. They're basically on target side
effects of the immune system going somewhat awry and
attacking self organs. So these have names
like pneumonitis, basically immune
attack in the lung, or myocarditis,
attack on the heart, which can be very serious. The serious grade three or
four events occur in about 12% of patients. Now clearly physicians
are-- there's an education process going on. And physicians are
going to have to learn to handle a very different
range of adverse events than seen in chemotherapy. The other thing that's
notable about PD-1 immunotherapy is, when it
works, the quality of life can really be good. So for instance, this is a
graph of the quality of life in lung cancer patients. You can see, if treated
with chemotherapy, the quality of life
of a cancer patient who's responding to chemo
is still the quality of life of a lung cancer patient. In contrast, if PD-1
works in lung cancer, the quality of life can actually
return to approximately normal. And I know some patients
at the Dana-Farber who've been off their PD-1 drugs and
are now riding their bicycles into checkups. It certainly doesn't
happen for every patient. The tremendous challenge
now is that responses are seen in about
20% of patients, and the tremendous challenge
is to bring benefit to the remaining
approximately 80% of patients. Now one of the reasons
we have this enthusiasm for immunotherapy is
shown in this slide. The first checkpoint
blockade was CTLA-4. And these show results
in melanoma patients, from Steve Hodi and
Schadendorf's work. Now historically, melanoma
is a terrible disease. Most patients died
within two years, as shown in the red line. Now in the green
line is the response to the Ipilimumab,
a CTLA-4 antibody. About 20% of the
patients respond at approximately two years. But what's remarkable is
that if you follow survival across many years, these
patients who have responded are alive at years three,
four, five, out to the 10 years tracked here. And they only received the
drug in the first year. Now the PD-1 drugs have
not been around as long, and this graph follows them
out for about six years. What's impressive
is that the curve does flatten at about two
years at about 35% survival. The other-- in
contrast on the right, is the response to a targeted
kinase inhibitor, Vemurafenib, which hits Braf mutants. Now the wonderful thing about
this targeted kinase inhibitors is, if you have the
mutation, you're almost 100% likely to respond. But the problem is, because
this hits just one target, the tremendous mutational
heterogeneity of cancer learns a way to get
around it and evade it. So after a year or
so, patients become unresponsive to this
targeted kinase inhibitor. Some more recent targeted kinase
inhibitors last more years. But if you target
just one thing, cancer will find a way around. Instead, what I'd emphasize is
cancer is an evolving system. It has hundreds of pattern
recognition molecules, billions of T cell receptors
and antibodies, and it can evolve and
change as the tumor changes. It can attack many points,
so evasion of just one doesn't lose you
the effectiveness. The immune system
also has a memory. So T cells that have expanded
remember what they've seen. Now here, the CTLA-4
antibody works in melanoma, but unfortunately as
a single agent, hasn't worked in well enough in other
tumors to receive FDA approval. In contrast, the PD-1 antibody
works about twice as well in melanoma with about
half the side effects, and has been extended to
many other tumor types. Now critical
questions for us now are how do we identify who
will respond to PD-1 blockade. What are the mechanisms
of failure to respond, and how do we bring
benefit to the patients who aren't responding? What are the mechanisms
of resistance? And how do we develop
combination therapies for non-responders to PD-1? So this can begin with
what does the immune system see to attack in a tumor? And what it sees is changes. Indeed, what the immune
system sees is changes. Now if you're a
micro-organism or a virus, those are totally foreign. And the immune system
sees them as foreign. Now a tumor has many mutations. Some of these, such as pictured
in the bull's eye here, are the driver mutations,
such as in Ras or Raf, which drive proliferation
of the tumor. But there are many other
passenger mutations, some of which contribute to the
tumor, many of which do not. And these can change the
protein coding information. And these changes are seen as
foreign by the immune system. And they're called
neoantigens for new antigens. So one realization from this is
that the tumor is an evolving thing and that there's also an
evolution of immune evasion. The tumor is learning
to evolve and evade the immune system by
expression of PD-1, IDO, and other mechanisms. The other thing this
emphasizes is that every tumor to the immune
system is different, because each person's tumor has
different mutational changes than another person's. Now the response
rates to PD-1 therapy appear to correlate with
the mutational frequency. Work at the Broad
Institute and Farber has shown us that
different tumor types have different levels of mutations. The tumors with the
highest mutation rates are things like
melanoma from sunlight, or lung cancer from
tobacco mutagens. And this graph shows you how
mutated each tumor type is. And over on the far right,
you can see melanoma or lung cancer, also bladder cancer. And these are the tumor
types that respond very well to PD-1 immunotherapy. The tumor types over on the
left have lower mutations, fewer changes for the
immune system to see, historically are not
as good responders. Now Rizvi has shown that
the higher mutation burden rate in some tumors
can be associated with better responses
to PD-1 immunotherapy. And indeed, understanding the
immunology and the genetics has identified groups that
respond particularly well to PD-1 or PD-L1 immunotherapy. Work by Louis Diaz
at the Johns Hopkins has shown that certain
tumor types have deficits in mismatch repair. And these tumors have
many more mutations than the average run
of the mill tumor. And immunotherapy turns these
mutations on their head. All these mutations
let the tumor advance, but they give much more
targets for the immune system, once you block the tumor from
evading the immune system. So these mismatch repair
defense deficit tumors have about a 62%
overall response rate. At the Dana-Farber,
Margaret Shipp has pioneered and
shown that there are genetic amplifications
in PD-L1 and PD-L2 in literally every
Hodgkin's lymphoma. Now in all, about 4% of
tumors have mismatch repair, particularly those about 15% of
colorectal, 20% of endometrial, a range of other tumors. The Hodgkin's have
amplifications, but 1% or 2% of broad range of tumors
have genetic amplifications of PD-L1. So one of the
things that I think there's enthusiasm
developing for is for any cancer patient
who walks in the door to be analyzed to see whether
they have these deficits, which make them particularly
amenable to PD-1 immunotherapy. Now other things I'd emphasize
is that the immune system sees differences. So tumors caused by viral
antigens, such as Merkel cell polyoma or HPV in
head and neck can be particularly well-recognized
and have good response rates. Now how do we identify who
will respond to PD-1 blockade? And these are
predictive biomarkers. Now the first biomarker
examined was PD-L1 expression. It does suggest who is likely
to respond to PD-1 therapy, but it's not a highly
confident prediction. Some patients who don't
express PD-L1 on their tumor still respond. Definitely every tumor
with PD-L1 on their tumor does not respond. So we need better biomarkers. And different studies have
shown that the CD8 infiltration and proliferation or
an interferon gamma signature, neoantigen burden,
all can suggest higher response rates to PD-1 immunotherapy. But there's a lot of work
that remains to be done. And we may need
combinations of markers to confidently predict response. So the failures of response can
include no good neoantigens, or the expression of other
immunoinhibitors, like Tim 3. And there are clearly many more
cancer immunotherapy targets than just PD-1. These include all of
the molecules shown here on this slide, including CTLA-4,
TIM-3, TIGIT, and many others. And indeed, academic
labs and pharma are developing agents
to test each of these. So other failures
of response can include the failure
of immune cells to infiltrate into the tumor. And this slide basically
illustrates this idea. Over on the left here
is a tumor with a lot of infiltrating lymphocytes
and PD-L1 expression. And these have a good response
to PD-1 immunotherapy. And over on the
far right is what's characterized as
an immune desert-- a tumor that doesn't
have any infiltrating T cells or lymphocytes. And this doesn't respond well. So what this does say is
that where PD-1 is working, we're taking a smoldering immune
response and releasing it. And the big challenge is
to find ways to get T cells into these immune deserts. Now the future is clearly
combination therapy. And indeed, this list
is just a small list of the possibilities. There are publications of
over 300 different agents that can be combined with PD-1
CTLA-4 to get improved results. So CTLA-4 and PD-1 combination
has been approved in melanoma and is showing promising results
in lung and kidney cancer, though it's more toxic
than either agent alone. Other agents in
advanced clinical trials include IDO, TIM-3 and LAG3. TIGIT is coming. Other possibilities
include combining PD-1 with immunostimulators. And immunology's first
approach to treating cancer was to try to stimulate the
immune response with vaccines or adjuvants. And that didn't work. But once you block
tumor immunivation, a lot of these tumors
stimulation strategies are enabled and can work. So you can combine PD-1 with
anti-Ox40, IL-2, TLR ligands, or STING. Now chemotherapy in
its simplest form is basically designed to
kill proliferating cells. And the basics of the immune
system is proliferating cells. So a lot of chemotherapy
you might expect would knock out the
immune response. But not all. So academics and
scientists have carefully looked at which targeted
therapies and chemotherapies can combine with
PD-1 immunotherapy. And ones that can work
include Braf inhibitors, MEK inhibitors, cisplatins. So certain chemotherapies
can be combined with PD-1 immunotherapies
and work better. Others possibilities include
angiogenesis blockade. Five years ago, if you asked
me how radiation worked, I would have said it
just kills tumor cells. It does do that. But when you kill
a tumor cell, it's taken up and presented
by the immune system. So you can get the
immune system engaged. HDAC inhibitors, affecting
epigenetic changes, can also enhance the immune
response against tumors. Other possibilities include PD-1
blockade plus cancer vaccines, such as being pioneered by
Kathy Wu at the Dana-Farber, or oncolytic viruses,
such as being pioneered by Sean Lawler,
Martuza, and Nino Chioza at the Brigham. Or PD-1 therapy can also enhance
the activity of CAR-T cells. There are other more nonstandard
possibilities, such as PD-1 plus certain nutrients. For instance, vitamin
D is not good. It can actually increase
PD-L1 expression. So you don't want to just take
a simple-minded mega vitamin. Now recent papers are also
emphasizing the importance of your microbiome. The presence of certain
microbes in your gut can enhance anti-tumor
immune responses. So I hate to say it, but
you may go to your drugstore and get a probiotic which
is purported to increase anti-cancer immunity. And careful studies
are needed there to find the right, real ones. So the goal is basically
illustrated in this slide. We want to take PD-1 therapy
and combine it with some of these combinations. Many of these
combinations have been shown to work better in mice. Many of them are progressing
to human clinical trials. And we'll see how they do. So we hope to increase
the response rate and to increase the durability
of these combination immunotherapies. I think the future of
cancer immunotherapies is going to start with
cancer genome sequencing. If a cancer is identified to
have mismatch repair or PD-L1 amplification or viral
genomes, that patient is a good candidate to progress
directly to PD-1 therapy. It will also identify what
oncogenes are drug targets. And so what tumors
are good targets for a Braf targeted kinase
inhibitor, plus PD-1. It will tell us what
tumor, what mutations, are immunogenic and can be
developed into a vaccine. The pathologist is going
to look at the tumor and show us how it's evading. So it'll show us how much
PD-L1 expression, how much IDO, what's the right
strategy to take. And this will allow us to
choose the best immunotherapy and combine it with the best
vaccine or targeted therapy. So it's really an
exciting time to be a researcher or an
oncologist, because it's a better time for patients. And there's tremendous
opportunity for all of you to do additional research
and improve these therapies. The PD-1 is a good
foundation to work with because it has a moderate
percentage of responders and is reasonably safe. It gives us a
foundation to build on. And with this success,
a tremendous amount of human creativity has been
unleashed on the problem. So as of October
last year, there were five FDA approved drugs. 15 more are in clinical trials. I think now over
1,000 clinical trials ongoing, with over
166,000 patients slots. Clearly, there's a
tsunami of data coming. And bioinformaticians
are badly needed. We'll learn what works,
what safe, how it works, and who it'll work for. And I think this will really
change cancer therapy. So I'd like to
acknowledge over the years the collaboration between Arlene
and myself, and all the members of the Freeman and
Sharpe labs who have contributed to this work,
particularly Ivette Latchman and Julia Brown in
the early stages. Many others thereafter. All the patients,
nurses, and physicians who have participated in
these clinical trials, and all our collaborators
over the years, including David Reardon,
Peter Hammerman, Tony Chuari, Kwok Wong, Nick Haning, Glen
Dranoff and Margaret Shipp. At the Brigham and
Women's, wonderful pathology by David
Dorfman, Sabina Signoretti, and Scott Rodig. Great work on TIM-3
by Vijay Kutru. Really critical early
biological studies, as well as tremendous signaling and
metabolic studies by Vicki Bouceiatis at the Beth
Israel and the Dana-Farber. Kidney cancer collaboration
with David McDermott and Michael Atkins. Wonderful collaborations
on the idea of T cell exhaustion with
Rathi Ahmed and John Whery, and really the
early discovery work that opened the door on
the PD-1, PD-L1 pathway, with Tusuko Honjo and Clive
Wood at Genetics Institute. Thanks for coming. We're happy to take questions. [APPLAUSE] So we have some
time for questions, but Gina just told
me that we have a number of people watching. So I want to thank the many
people who are watching. And it's truly amazing. We have people
participating, many people from India, Algeria,
Brazil, Moscow, Vietnam, Peru, the UK, Dominican
Republic, Cambodia, Spain, Mexico, and Tanzania. Truly amazing. You can take those question
or we can ask questions from the audience. Anybody have a question? Here are two of the questions. Could you have given
this talk four years ago, or how much of it? Could you hear him? No. Could you have given
this talk four years ago? How much has changed
in four years? So some of the principles-- could we have given this
talk four years ago? Some of the principles were
known, but what's amazing is the astonishing rate at which
the clinical translational is occurring. The advances in the
clinical trials, the FDA approvals of PD-1-- this year alone, there have been
four or five new FDA approvals for therapy. As more clinical
trials are occurring, more types of questions
arise in terms of how we want to answer them,
going back from the bench to the bedside,
trying to understand mechanisms of response and
mechanisms of resistance. PD-1 therapy really was
approved only in 2014. So in the past
three years, there's been a tremendous change. We're going to take one of
the questions from the thing. It's said tumors
evolve for survival. Does this also increase
the immune resistance of cancer cells? Well, they're
evolving for survival by changing survival factors,
like BCL-2 and evolving mutated oncogenes. But at the same time,
the immune system is trying to attack
and destroy the tumor. The genome of
tumors are unstable and pattern
recognition molecules can also recognize the tumor. So the tumor has to evolve
to evade the immune system by expression of PD-L1,
IDO, and other mechanisms. So they're parallel
pathways of evolution. But in addition, there
are some patients who do initially respond to
PD-1 and then become resistant. And we're beginning to learn
about those types of mechanisms that tumors no longer
express PD-L1, for example, or have mutations and MHC
molecules or processing pathways. And so this has also
led to great interest in combination therapies. So you're combining
several different types of targets at the same time. Hello. So I'd like to ask, since this
therapy PD, PD-L1, has showed such a high success in
primary tumors such as lung or melanoma, what's
your thoughts about how successful do you think this
therapy could be, for example, in brain metastases? Since, you know, the
majority of brain metastases are precisely from the
lung or melanoma tumors. Would you repeat the last-- the disease type you
said at the last? Do you think that
this therapy will be-- could be successful
in brain metastases, since it's showing
such promising results in the primary tumor,
such as lung and melanoma? There are publications
that the immunotherapy can work on brain metastases. Certainly not every
brain metastasis. Many of the brain
metastases are treated with focused radiation, in
addition to the immunotherapy. So there may be some
synergy between the two. Beautiful work. Congratulations. I wonder if it could be
a numbers game, though, that there might not
be enough T cells to kill all the tumor cells. How many tumor cells
can one T cell kill? Any information on that? [LAUGHTER] That's a very good question. I don't know how
many tumor cells one T cell can kill in vivo. In a tissue culture dish, we
probably can estimate that. But in vivo, I think we focused
on talking about T cells, but in addition, there's
other types of cells. There are different
types of T cells that can participate
in killing tumor cells. In addition, there are
natural killer cells. So there's a whole armamentarium
of cells that can be unleashed and really T cells
are the first ones. Thank you very much for
the very inspiring work. So my question is, do you
think for the future we can, instead of going to the
direction of blocking, all the checkpoint
blockades, can we engineer the immune
system not to express the checkpoint
blockades, for example. I don't know. It can be used SIRA 2 shot
down, CTLA-4 expression, PD-L1 expression. Can we engineer
the immune system? Do you think that would be a
promising future direction? Well, these inhibitory
signals that are expressed by
these checkpoints have important physiologic
roles in regulating our immune responses. I think the PD-1 pathway
is the paradigm for how inhibitory signals are
used for proper functioning of the immune response. Signals through PD-1 and
CTLA-4 are important. So we have tolerance. We don't have
autoimmune disease. In addition, if you
eliminate these-- so if you eliminate
these, you could get increased autoimmune disease. You also could get
increased tissue damage with inflammation. So these pathways have very
important physiologic roles. So you wouldn't want to
eliminate them completely. Though in strategies where there
are engineering of T cells, such as car T
cells, there is work ongoing to think about how you
might eliminate these cells completely or temporally. Now one of the
questions on the card was, is immunotherapy good
for glioblastoma, which is a serious brain cancer? And the answer there
is, as a monotherapy, the response rate was about
4%, which isn't very high. So the initial answer is no. Glioblastoma is going to need
combination immunotherapies. Some of the complicating factors
there are edema in the brain, and swelling is
clearly a serious side effect in glioblastoma. And that's often treated
with corticosteroids, which can reduce immune responses. So probably finding ways both
to use less immunosuppressants and to also alleviate brain
edema, such as research we're doing with
Rakesh Jain are needed to make immunotherapy safe
and effective in the brain. Thank you very much
for both the talks. It was a very inspiring
and very informing as well. I have a question about, if
I take a look at the bigger picture, ideally it
would move towards a form of cancer therapy where
you have [INAUDIBLE].. So you have destruction
of tumor cells. You alleviate the micro
environment immunosuppression, such as the PD-1 therapy. And you would like to
stimulate the immune system and make it stronger to have a
stronger response to a tumor. So first of all, am I
missing something there in terms of the bigger picture? And the second
question would be, are there other mechanisms
in the microenvironment of the tumor that
can be targeted to avoid immunosuppression? So I think you summed
up accurately the good take home messages from our
talk in terms of the tumor using checkpoint blockade as
one means to inhibit these suppressive mechanisms
that are in the tumor microenvironment. But as was mentioned,
the PD-1 pathway is only one type of
immune suppression. There are many other
inhibitory receptors that can be expressed
locally within a tissue microenvironment. In addition, there
are stromal cells. There are different types
of myeloid suppressor cells, adenosine, many
different elements that we're learning about
that can be suppressive. And all of these different
types of suppressive mechanisms can become targets
for immunotherapy. And in fact, they are targets. They're being analyzed
now individually and in combination. I also wanted to expand on
the glioblastoma answer. And in mouse models
of glioblastoma, we and others have shown
that the immune response can get into the brain, attack
glioblastoma, and eradicate it. So it is susceptible
to immunotherapy. There are also a number of
combination therapies being advanced, such as
oncololytic viruses, viruses that rather specifically
attack, kill tumors, and bring in the immune response. These are being pioneered at
the Mass General and Brigham and Women's. And so there are
combination therapies relevant for glioblastoma. Thank you very
much for the talk. It was a beautiful love
story between the industry and academia. I don't know how
much of the profit the academia will see from
that, but my point question is whether the T
cells or the system develops a memory
after the treatment, because it seems the
treatment is rather brief. And then the effect
is prolonged. If you have any data on
that or any insight on it. So you raise a very good point. And I think one of the special
features of immunotherapy for cancer is the
durability that can be seen. And so from the earliest days,
the work that Steve Hodi did using anti-CTLA-4
ipilimumab, it was beginning to see
a tail on a curve where you could
see that there was long-lived durability in a
subset of patients, about 20% of patients. And now these patients who have
shown benefit are over a decade out. With PD-1, it's a
shorter experience, but they're also a group
of patients, about 30%, who also are showing
durable responses. So the excitement here
is much the same way when we see responses to infections
where we can see immune memory, that are we generating immune
memory to these cancers? And that may explain
some of the durability. Hi. Thank you for the
beautiful talk. During the talk, you have
described these PD-1 inhibitors as a means to unleash
T cell responses. So since T cells are
involved in many growing inflammatory
diseases, my question will be whether by
using this therapy, are you risking to
actually trigger an inflammatory [INAUDIBLE]
in these patients? If that makes sense. I don't know. Yes. The adverse events seen in
PD-1 immunotherapy are indeed increased immune activation,
attacking self tissues-- something like pneumonitis is
the immune system attacking lung. And again, this is serious
in about 12% of patients. The other-- as you said,
this PD-1 expression is broadly seen in other
chronic viral and infections. So for instance, in, AIDS,
tuberculosis, malaria, hepatitis C, all of
these are diseases where the immune system
has tried to attack, not succeeded, and then
reached a compromise to muddle along, not destroy the
liver of a hepatitis patient, but not let the
virus go wild either. And PD-1 is a major regulator
of this attenuated dysfunctional immune response. So the PD-1
immunotherapies may be relevant in chronic
viral diseases, such as AIDS and hepatitis. In addition, there
is at least one paper saying that PD-1 therapy in a
mouse model of Alzheimer's was therapeutic, as long as you kept
giving it the PD-1 antibody. This, perhaps, could be through
enhanced macrophage activation and clean up of brain garbage. But that's an intriguing
area of future work. In addition, when we
first got into this field, we were very interested
in autoimmunity. And if you could-- all the PD-1 agents that
are drugs now are blockers. But what if you could
engage the pathway and increase its activation? That could be therapeutic
in multiple sclerosis or rheumatoid
arthritis, and is really an open, but challenging,
area to develop agents that increase the activity. So there's a lot of work
remaining to be done. So I think, as Gordon mentioned,
that developing agonists to trigger these inhibitory
signals to shut down immune responses in type
1 diabetes or multiple sclerosis-- and because these pathways
can control responses locally within the target
tissue, these are areas of active investigation. And hopefully soon we'll see
some agents that can deliver. Since the PD-1 therapy work
in many type of tumors, it looks like [INAUDIBLE]
or antigen tumor [INAUDIBLE] antigen. So I'm curious what
are your comments for antigen specific therapy for
[INAUDIBLE] a tumor independent of this PD-1 therapy. Well, I think the big idea
of the last four years is the realization of the
importance of neoantigens, the new antigens in the
tumor caused by mutations in the protein coding regions. So the immune system recognizes
those neoantigens and attacks the tumor. But each person's tumor
has a different spectrum of neoantigens than
every other patient. Each patient is really-- has an individual spectrum of
changes which are recognized. Is there any actual
success at all in the dendritic
basic immunotherapy? Could you repeat? Is there any success at
all in the dendritic basic immunotherapy? I'm just curious
because there are plenty of studies describing T
cells and all other cell types, but dendritic cells are
kind of interesting. People are not-- I think there are clear, small
clinical trials successes with dendritic therapies. I think the-- they're just
more complicated than not. I think the Cardiff therapies,
I think, are very exciting. They work well in some of
the hematologic malignancies. And the tremendous
challenge now is to make the Cardiff therapies
relevant and effective for solid tumors,
where they haven't yet shown significant success. Hi. So in your slide,
you showed that there are a higher response
rate to PD-1 than CTLA-4. So why is that so, when
both CTLA-4 and PD-L1 was in a similar manner to
directly immuno response? I think part of it is timing,
that both of these pathways can control initial
T cell activation. But the PD-1 pathway can control
effector T cell responses and responses in target organs. And it's a key mediator of
this T cell dysfunction. And because it's
expressed locally and many tumors can express
the ligands, that when you block this pathway
within a tissue, you can stimulate
an immune response. So I think it's partly timing. CTLA-4 acts early. PD-1 can act early, but
it also can act later during an immune response. One last question [INAUDIBLE]. So the question is, which
anti-PD-1 immunotherapy drug has shown the most success
for adenocarcinoma? [LAUGHTER] I don't think I'm going to get
into the business of trying to choose between there. Last question. When you talked about
T cell infiltration, you talked about immune
deserts or some term like, that meant that T cells,
areas the T cells cannot get in at all. How common is
this, and it should be a hot area of research. Do we know anything
about the mechanisms of blocking T cells
from completely getting into an area of
tumors, or how does this work? So there are a variety of
different types of tumor microenvironments, some that
are inflamed called hot tumors, and others that are
called cold tumors that are these immune deserts. And these types of
environments are more common than
the ones where you have an inflamed environment. And there can be many
reasons why you may have this type of environment. And so there are a number
of strategies underway to try to stimulate T cell
activation and migration into these tumor environments. So the strategies for
success for cancer immunotherapy may be
different for a cold tumor or an immune desert than
for an immunogenic tumor. And with the
realization that there are different
requirements, then we can begin to tailor strategies
to these different types of tumor microenvironments. Thank you very much. [APPLAUSE]
