>> Ashley Cuffia: Thank you
for joining today's Library
of Congress Cancer
Moonshot webinar
on Immunotherapy and Beyond.
Throughout today's session, we
invite you to submit questions
for our presenters using the
Q&A panel on your screen.
We will address these at
the dedicated question
and answer segment at
the end of the webinar.
If we're not able to
get to your question,
or if you have further
questions after today's event,
please send them to Ask
a Librarian on loc.gov.
Today's webinar is
being recorded
and a captioned version
will be made available
on the Library's website
in the coming weeks.
We will share this information
again before we wrap up today.
So with that, to get us started,
please welcome the
Chief Medical Officer
at the Library of Congress.
Dr. Sandra Charles.
>> Sandra M. Charles:
Good afternoon, everyone.
It is a pleasure to welcome
you to the Library of Congress
for this sixth panel discussion
in our annual Cancer
Moonshot series, co-sponsored
by the Library's Health Services
Division, and the Science,
Technology and Business
division.
This panel comes at
the five-year mark
from our inaugural discussion
held just after the passage
of the groundbreaking bipartisan
21st Century Cures Act proposed
by then Vice President
Joseph Biden.
That act authorized
seven years of funding
for the Cancer Moonshot
Initiative,
aiming to improve
access to therapies
and through collaborative
efforts and sharing of data
in research and innovation,
facilitate progress.
Today's discussion will focus
on cancer immunotherapy,
and bring to us several leading
scientists, patient advocate,
and clinicians in the field.
In the US and globally,
cancer is a second
leading cause of death.
Few people on the seminar can
say they have not been touched
personally by cancer.
Immunotherapy is an exciting
and ever-expanding approach
to treating cancer and this
discovery and development came
about rather serendipitously
as curious minds were trying
to better understand
the immune system.
We look forward to hearing from
our distinguished researchers
and clinicians to hear
how the attributes
of the immune system
are being harnessed
to provide life-changing
therapists.
One of our key objectives here
at the Library is connecting
ordinary people and patients
to experts, scientists
and clinicians,
who can further the
understanding
of cancer diagnoses, diagnostics
and treatment choices.
The Library is indeed fortunate
to have access to researchers
and health experts who are
willing to share their knowledge
and cutting-edge
information with us in order
to promote health literacy.
I now turn the podium over to
my colleague and co-sponsor,
Dr. Tomoko Steen to
introduce our first
distinguished panelist.
Dr. Steen.
>> Tomoko Y. Steen: Thank you.
Actually, next slide, please.
So we have five different
speakers
and they are all top experts
in our field, and especially,
we are looking at the
most recent advancement
in immunotherapy, so we are
very excited about this.
First speaker is Dr. Danielle
Carnival from White House.
She was the initiator
for this important bill,
and also we have two original
2016 Cancer Moonshot the Library
of Congress Cancer Moonshot
speakers, Dr. Weiner,
who is the winner
from Georgetown.
He was one of the speakers
and he is going to talk
about the basics of the
immunotherapy and also
as a clinician, he can
share lots of information.
And we have a Nobel Laureate
and the discoverer of this,
you know, important
therapy, Dr. James Allison
from the Houston UT Medical
School is joining us,
and we also have another expert
from the National
Cancer Institute,
Dr. Giorgio Trinchieri.
He's going to talk about some
fine tuning of this therapy
and how we can make it
more effective, you know,
even better treatment
for this immunotherapy.
And then we have
a cancer advocate
and the original speaker
also from 2016, Dr. Sigel,
and then Sigal is going to
conclude the set of speakers
and she is going to
share with us, you know,
how we just connect this
wonderful, you know,
new therapy to the patients.
So can you send me
next slide, please?
So first speaker is
Dr. Danielle Carnival.
She worked from original
development of this theory,
as I said, working under
Dr. Biden, administer Biden,
and she was the main, you know,
architects of this important
bill and but she also worked
on not only many years at the
White House, but also she worked
at the ALS, I Am ALS,
organization, you know,
looking at patient and doctor
and the scientists just reaching
among them, so I was told not
to give too much details.
We have a handout coming
out, in a virtual handout,
so everyone attended
this meeting,
you can get the virtual
handout, so before further ado,
I'd like to give the floor
to Dr. Carnival, please.
>> Danielle Carnival: Thank
you, and thank you so much
for that introduction.
I will amend just not
to offend the people
who were the architects of
the 21st Century Cures Act,
I will take credit for helping
to frame the Cancer Moonshot
here from the White House,
but leave it to those
in Congress
who worked long before we
had started on the Cures Act,
but we were really excited
that we were able to, you know,
be there at the finish line
and to make a big impact
on that bill for people
living with cancer,
and I'll talk a little bit
about that, but thank you
for having me, and thank you
to the Library of Congress
for bringing together the
knowledge and speakers
on this agenda this
afternoon so we can all learn
about the amazing impact
that immunotherapy is having
in the treatment of some
cancers, the difference it is
and can make for
millions of patients.
The framing for today as
have been mentioned is cancer
moonshot, and I want to spend
a few minutes just setting the
stage for that conversation.
To step back a little further,
50 years ago this month,
in December of 1971, Congress
passed the National Cancer Act,
creating the cancer
research system we have today
in the United States led by
the National Cancer Institute.
The researchers and clinicians
on this call can tell you more,
but we learned a great
deal over those 50 years.
First, that cancer isn't a
single disease, but in effect,
we have already identified
hundreds of distinct types
of cancer, that cancer is
influenced by our genes,
and usually involves a gene
changing or mutating in a way
that allows the cell to
replicate out of control.
Because of this, we now know
that we aren't going to develop,
identify a cure for
all cancer, but we have
and will develop
effective treatments
for many types of cancer.
Dr. Allison and the
panel will go into that
in further detail later.
I mention this to provide
a glimpse into the history
of how we got here today, and
to go to five years ago when,
as others have started to
mention, President Biden
when he was Vice President,
I lead a national focus
to make progress against cancer
called the Cancer Moonshot.
The goals were to inject urgency
to our collective approach
to end cancer as we know it,
to bring all possible solutions
and partners to the table
with ideas and action,
to provide an avenue to hear
and prioritize what patients
and caregivers and
survivors identify
as being the most important,
change to change the systems
and cultures to culture
to meet this moment.
It wasn't the situation
of 50 years ago.
We had learned so much
and we needed to build
on that knowledge we had gained
and to really have a 21st
century approach to how we deal
with cancer of we had gained
all this knowledge over decades
of research and treating
patients, and all of this
to deliver on the
hope felt by millions
of families facing
a cancer diagnosis.
We brought a national
focus on cancer, you know,
gathering together all parts
of government to do their part
from new studies on cancer
disparities, new trial networks
to drive drug discovery, and new
projects on childhood cancer,
to addressing prevention
and early detection
and making sure everyone
has access
to the resources they need.
As part of the Cancer Moonshot,
Democrats and Republicans
in Congress came together
and passed the 21st Century
Cures Act in December of 2016,
which delivered $1.8
billion over seven years.
This enabled the National
Cancer Institute to invest
in new priority areas of
research that hundreds
of researchers, clinicians,
patients and other members
of the ecology community,
identified as having
the most promise
and it streamlined
cancer-related decision making
at the FDA.
A line can speak to this
through the Oncology Center
of Excellence so that cancer
drugs can be approved faster
and patients can
have direct input
into understanding how the
process is moving forward.
In addition, as part of the
Cancer Moonshot, companies,
patient groups, universities
and foundations launched more
than 70 new programs
and collaborations,
all to make progress to prevent,
detect and treat
cancer more effectively.
As the oncology community spends
this year commemorating the 50th
anniversary of the signing
of the National Cancer Act,
and five years since the signing
of the 21st Century Cures Act,
it has been a year of
reflection in many ways.
Cancer mortality rates
have been declining
over the past 25
years, and the rate
of that decline has
been accelerating.
We have more understanding
of the underlying mechanisms
of cancer, as I mentioned, and
will go into further later,
including genetics, cancer
genomics and the interaction
with the immune system.
We have more tools to
prevent and detect cancer.
We have increased outreach
to medically underserved
communities, rural, urban,
tribal, to address
gaps in access to care,
and although many factors
contribute to this trend,
more effective treatments are
definitely a driving force
in recent years, led by
many immunotherapies.
However, as we all know, there's
so much still to be done.
We have remaining issues with
how we know cancer today.
President Biden has said
his strong commitment
to making progress towards
any cancer as we know it,
and to be able to do that,
we want to make it very
clear how we think we know
cancer today.
It's a disease for which
we don't have enough tools
to prevent it and don't
effectively use all the ones we
already have.
As a disease for which we don't
routinely detect it early enough
when it is most treatable,
and often with less
invasive treatment.
We have inequities in time to
diagnosis, access to treatment,
trial, care and outcomes based
on who you are and
where you live.
We know more about the genetics
of cancer than ever before,
and yet we are not fully
at acting on familial
or hereditary risk,
and providing people
with the tools they
need to live as long
and healthy a life as possible.
We lack some of the --
we still -- excuse me.
We still lack the solutions for
some of the toughest, deadliest
and rarest cancers,
and cancer is a disease
for which we don't have
the systems to learn
from every patient or the system
to share data and
knowledge widely.
The good news is that President
Biden knows cancer as well.
He knows it personally, and he
is taking it on as a national
and global leader in
making urgent progress
for people facing this disease.
As he has said, he's committed
to do everything in his power
to make progress toward
ending cancer as we know it.
He has already made a
down payment on that
by proposing strong funding for
NIH, the National Institutes
of Health, the National
Cancer Institute,
and in proposing a bold new
approach to taking on some
of the remaining issues
facing biomedical research
and those living with
a disease like cancer
in an ARPA for health, ARPA-H.
This administration has
supported more people getting
quality and affordable
health insurance,
and but we know we still need
to make strides to ensure
that everyone in the
United States has the best
in prevention, early
detection, treatments,
trials and care through
survivorship.
We all have a role to play
and as we organize the
administration's response
to this mission, we
will need your ideas,
your action and your change.
One area with some urgency is
in cancer screening
and early detection.
Nine million -- more
than 9 million --
we have a deficit of more
than 9 million screenings
over the course of the last few
years driven by the pandemic.
We can all do our part to
get those screenings back
on the books personally and
from our seats in foundations,
companies, health providers
and policymakers, we must stand
up to make sure that people
have the knowledge and access
to detect cancer early.
President Biden has a bold
vision for how to make progress
against this disease, progress
that can continue to bring hope
to every family facing
a cancer diagnosis.
We will drive a new
understanding that we can lead
to ways to prevent detecting
treat cancer, and we, as I said,
must deliver more equitable
access to quality care,
bring more personalized and less
harmful effective treatments.
We must take on cancers today
for which we don't
have an answer,
including some childhood
cancers, and we must all learn
from the perspectives and
experiences of patients
and caregivers, looking to
them as the experts they are.
As we look at the five-year
anniversary of the signing
of the 21st Century Cures Act,
I just want to reiterate this
administration's commitment
to this mission.
We will take on each of the ways
in which we know cancer today
and make concerted
progress toward any cancer
as we know it together, so
thank you for the opportunity.
>> Tomoko Y. Steen: Thank
you so much, Dr. Carnival.
That's very wonderful outlines
of some administration's
efforts.
Next slide, please.
So next speaker is Dr. Louis
Weiner from Georgetown.
He is a Francis L. and
Charlotte G. Gragnan -- sorry --
Gragnani Chair, and
he's Director
of Lombardi Comprehensive
Cancer Center, and he's Chair
and a professor at the
Department of Oncology
at the Georgetown
Medical School.
And he's also director
of the MedStar Georgetown
Cancer Institute, and he's --
he was, as I mentioned,
the first speaker
2016's Cancer Moonshot,
and he is really making
an effort to, you know,
pass on this information
to the public,
and we can distribute his
detailed bio after this event,
so before further ado, Dr.
Weiner, floor is yours.
>> Louis Weiner:
Thank you, Dr. Steen.
It's a pleasure to be back here
again to speak with everybody,
to be on a panel with so
many friends and colleagues,
and to share with you some
of the most important
foundational elements
of what has really become an
important way of treating cancer
and understanding cancer.
So I'm going to be talking
about immunity in cancer,
and with my good friend, Dr.
Allison following, I'm not going
to talk about immune
checkpoints in any great detail
in my presentation, leaving
him to share that information
with you, but rather to provide
you with a broader context
so you can understand what
the field is really about.
Next slide, please.
So traditionally, there
had been two ways to think
about how you can
kill a cancer cell.
In the 1940s, we began
developing chemotherapy drugs
that attack what you might think
of as the bricks and mortar
of cancer cells, such as
DNA, the cells' cytoskeleton,
the basically the girders
that are keeping cells going.
In the '90s and early 2000s,
we began developing
targeted therapies,
the so-called smart
bombs, the idea being
to attack the electrical
wiring system of cancer cells,
their receptors, their enzymes,
and their cell signaling
molecules, and the idea was
that this was going to be far
more selective, and much easier
for people to take, because
you wouldn't have some
of the same challenges
associated
with nonspecific
killing mechanisms.
Next. The problem is it's hard
to know what target to go after.
This is a 20 year old paper
from Hanahan and Weinberg,
which just takes a very,
very simplistic view
of the complex signaling that
goes on inside of a cell,
and these are all things
that can be disrupted
when people develop cancer, and
so it's a legitimate question
to ask what target is it that
you would want to go after?
And how could you be sure if
you went after that target,
would it be enough to
kill the cancer cell?
And in fact, we learned
over painful experience
with targeted therapies, that
resistance to the treatment
that you're going to use
is nearly inevitable,
because there are so many escape
hatches that cells can use
through these various
different signaling mechanisms,
that it's very difficult to use
a single drug that will be able
to control the cancer
for the natural lifetime
of the person receiving
the drug.
There's occasional
exceptions, and they're great
when they happen,
but unfortunately,
resistance is nearly inevitable.
Next slide.
So if that's not
complicated enough,
all these different
signaling pathways
that I was just showing
you are really part
of a larger ecosystem, and you
can see this follow up paper
that was written a decade
ago by the same authors.
They talk about sustaining
proliferative signaling,
evading growth suppressors, and
you can see this whole wheel
of fortune around here.
Note that in this particular
iteration, they finally began
to recognize the power and
importance of inflammation
in the immune system, and I
point out here that they talked
about avoiding immune
destruction, how inflammation
of tissues can promote cancers,
and finally, that the actual DNA
of cancer cells might be
unstable in certain ways,
and there might be mutations
that are driving many
of the malignant
events that we see.
Next slide.
Now, let's take a step back
a couple of hundred years
to the late 18th century, to
the beginning of immunotherapy
when a Dr. Edward Jenner, a
Scottish family practitioner,
observed that milkmaids who got
a very mild viral disease called
cowpox, which is caused
by the Vaccinia virus,
a commonly used virus in our
cancer therapy strategies,
did not get the deadly
disease smallpox,
and so he did something that you
couldn't do in the 21st century.
Without IRB approval, he
conducted a non-randomized,
non-controlled clinical
trial, and what he did,
he actually took the pustules
from a milkmaid who had cowpox,
and he inoculated himself,
and challenged himself to see
if he would get smallpox
and he didn't.
And emboldened by
that experience,
he began using these
cowpox sore contents
to basically vaccinate people
who did not get smallpox,
and that was the birth of the
smallpox vaccine, and the idea
that the immune system
itself might be able
to control the outgrowth
of certain diseases.
Next slide.
And this has led to
development of many vaccines.
I know some of this is
controversial for some,
but on the left, you can
see the impact on cases,
and by inference, survival, for
polio, measles, mumps, rubella,
diphtheria, and tetanus.
In each case, immunotherapy was
applied in the form of vaccines,
and lives were saved and
diseases were minimized,
and on the right, you see
one particular example
from the recent SARS-CoV-2
outbreak
that we're still experiencing,
demonstrating that individuals
who do get vaccinated
have far less in the way
of clinically symptomatic
virus infections than do people
who were vaccinated
with a placebo control.
Vaccines save lives.
Next. So vaccines usually
work in those contexts
by eliciting the production
of antibodies that can be used
to control these
various viruses.
It doesn't work as
well with cancers.
Antibodies have been used
and they are widely used
to treat human cancers, because
they're able to be designed now
through recombinant antibody
engineering techniques
to target very specific
molecules on the surface
of cancer cells, as
you can see here,
and this is an older slide, and
I've stopped trying to update it
because the approvals are
coming so fast and furious now,
that we can't keep
track of them all,
but about 25 different drugs
and antibodies were approved
in the last year
alone to treat cancer.
What you can see
here are cancers
such as non-Hodgkin's lymphoma,
breast cancer, certain kinds
of leukemia, colorectal
cancer, head and neck cancer,
kidney cancer, low grade
leukemias, and a variety
of breast cancer again.
Many different diseases
can be treated
by unconjugated antibodies.
These are just antibodies that
attach to the surface target
on the cancer cell,
and that does something
that makes the cancer
cell get killed.
Next slide.
And here, you can actually
attach toxic molecules,
so-called magic bullets to the
antibodies, fulfilling a vision
that was articulated
first by Paul Ehrlich,
a famous physician-scientist
in the late 19th century
and early 20th century,
who hypothesized
that you could create toxic
molecules that would be attached
by things like antibodies
to eliminate human disease.
And these drugs that I'm
showing you on this slide,
are actually the embodiment
of a century-old dream
that a brilliant
physician-scientist had.
And here you can see that there
are drugs that can be conjugated
to various toxins, antibodies
to treat acute leukemias,
lymphomas, and breast cancer,
and the breast cancer drug
and its derivatives have
had very important impacts
on the management of patients
with advanced metastatic
breast cancer.
And finally, I told you
I wasn't going to talk
about Dr. Allison's work, but
with all homage to the work
that he and many others have
done, there's a whole list
of checkpoint antibodies
that have been developed.
These are the ones
that target PD-1/PD-L1,
and you'll hear a
little bit more
about the CTLA-4
antibodies shortly.
Next slide.
So these antibodies, as I
just described, they can work
in a variety of different ways.
They can mess up the signaling,
the electrical wiring system
of the cancer cells
that they're targeting.
They can also target the cells
for destruction by elements
of the body's immune system,
so-called antibody-dependent
cell-mediated cytotoxicity,
or complement-dependent
cytotoxicity,
or they can simply
modulate the immune system
so the immune system
will know how
to attack the cancer
cells more effectively,
and they can deliver a
variety of different kinds
of toxic payloads, but
antibodies can also be used
to attack, not the cancer cells,
but the normal cells in the area
where the cancers are, in the so
called tumor microenvironment,
and they can block a whole
bunch of different functions
in the microenvironment so that
when cancer cells corrupt the
local area around them in order
to support their survival
and metastasis and invasion,
these things can be
selectively interrupted
by a variety of different drugs.
Next slide.
So there's a limit to what these
antibodies can do, and in fact,
most scientists would agree
that the most important
immune population of cells
that are responsible for the
control of cancer are T cells
of the immune system, the cell
population that is disrupted
when people have
immunodeficiency, such as those
that are caused by HIV.
And mutated proteins in
the cancer cells caused
by the genomic instability that
I was talking about earlier,
can represent potential tasty
tidbits that can be attacked
by the body's immune system.
They're known as
antigens, and on this slide,
which now is a an
eight year old paper
that has really become
a classic,
what you're seeing here are
the numbers of mutations
in each different kind
of cancer when you sort
of catalog them using
the Cancer Genome Atlas,
a National Cancer
Institute-initiated process
that allowed us to get
an extensive encyclopedia
of various cancers and mutations
and other abnormalities.
And you'll see here that
melanoma, on the far right,
has the largest number
of mutations,
so that becomes important when
we think about how certain kinds
of T cell activating
treatments might work.
Next slide.
So because of these mutations,
cancers possess innumerable
targets and decoy targets,
and have a capacity to survive
targeted attacks, and that led
to the question,
do cancers result
because our bodies aren't
able to see these things,
or are cancers actively
thwarting the development
of anti-cancer immunity,
or is there some kind
of combination of the two?
Next slide.
And in fact, we get
a hint from --
if you just look at a
cancer under the microscope.
It's chaotic.
All the normal organization
of the organ is destroyed
by the cancer.
You have disordered blood flow
and disordered vascular
distribution in the cancer.
You have a lot of fibrous
tissue, scar tissue,
that makes it hard for
cells to move around
and do what they want to do.
And in fact, it's become
quite clear that tumors go
to great lengths to evade or
subvert the immune response,
because as they're
developing, it's the only thing
that is attacking the cancer
is the body's immune system,
and so therefore,
the cancers have
to develop evasion strategies
and ways to defeat the cancer.
Next slide, and you can see
this in clinical samples.
This is I'm not going to go
through what the pictures mean
here, but this was a study done
by a French group about 15 years
ago now, where they were able
to demonstrate that if you
just take a look at the kinds
of killer cells of the
immune system, the T cells
and their various subsets,
and you characterize them
in different early stage
colon cancers, and ask,
so who did well, and who
didn't do well, more important
than the conventional
clinical staging that we do,
which is based on the
size of the tumor,
the number of lymph nodes
and other factors like that,
the immune infiltration
of the cancer was the most
important predictive variable.
The more immune infiltration
you had,
the better the cancer was
going to do, by and large.
It was a very powerful
independent predictor,
and that's really important.
Of course, I also will point
out that despite this
powerful immune reaction,
people were still
getting these cancers.
Next slide.
So the challenges are that
cancers look like self.
Even if you have a few
thousand mutations,
that's a few thousand mutations
out of literally billions
of different kinds of molecular
targets that might be present
in a given cell, so the
cancers look like self.
So the question becomes, is
there a way to effectively
and safely break what we call
immune tolerance to self?
In other words, if you
were to attack self,
you would actually hurt self,
and that would be normal organs
and normal tissues, and
you don't want to do that.
Next slide.
And that brings us to something
that Dr. Carnival
mentioned earlier,
which is the National
Cancer Act of 1971.
This is when the war
on cancer was declared
by President Richard
Nixon, but -- next slide --
we have been at war against
cancer throughout human history.
This is a photo of a grave
that was exhumed from somebody
who died in medieval times,
who was a male, and it looks
like that person had a
sarcoma, a bone tumor,
probably a young male who
died, and the battle was not
between -- next slide -- society
and cancer, doctors and cancer.
The primary combatants in the
war on cancer is one person
at a time and it's a
malignant cell population
against the host's
own immune system.
The host immune system is the
dominant active enemy that's
faced by a developing cancer,
and every successful cancer
must solve the challenges
of overcoming these defenses.
Next. And we can help.
As physicians and as scientists,
we have developed a suite
of tools that allow the body's
immune system to overcome some
of these defenses that
cancers have erected even
after they're established,
and you see here a list
of treatments and diseases.
The single asterisk then
are those situations
where treatment can be
curative as a single agent.
The double asterisk are where
you have a long-term remission,
maybe too soon to know
if there are cures.
And the triple asterisk is
when you combine these drugs
or these antibody
immunotherapies
with chemotherapy.
And the list of diseases that we
can now treat and sometimes cure
with immunotherapy is really
impressive and getting larger,
bladder cancer, kidney cancer,
melanoma, a form of skin cancer,
lung cancer of some
types, Hodgkin's disease,
bladder cancer, head and neck
cancer, cancers of the thymus,
and there are a variety of other
strategies that can be used,
but you'll note that the
checkpoint antibodies,
the PD-1 antibodies, and also
the anti-CTLA-4 antibodies
that are frequently combined
with PD-1 antibodies
have an expanding role,
and it transformed the
landscape of how we think
about immunotherapy
and treating cancer.
Next slide.
As we think about where we
go from here, because only
about 15% of the people we treat
with these immunotherapies
are going to have the kinds
of fabulous responses that
we all want them to have,
and when they happen,
they're dramatic,
and they're remarkable, and
I've had them in my clinic,
and it's just like nothing --
it's like nothing you can
imagine as a physician
to treat somebody and see
their cancer melt away,
because you basically didn't
treat the cancer by trying
to kill the cancer cells.
You treated the immune system
so that the immune system
could eliminate the cancer.
But as we move forward,
we're going to have to think
about the resistance
phenomenon even here
and how we begin developing
novel combinations,
and when we do that, we have to
think about how cancers get --
can overwhelm the
body's immune response
by out-proliferating it,
racing ahead too quickly.
That doesn't happen very often,
but cancers do know how to hide.
The things that are necessary
for the immune system
to recognize the cancer are
frequently eliminated or lost
or diminished in cancers
that are evading immune
recognition and response.
Sometimes cancers will
subvert the immune response
by elaborating molecules
that suppress the
body's immune functions,
so that the immune cells
can't do their jobs
and kill the cancer.
Other times, the immune system
will be shielded from access
to the cancer because the
cancer elaborates molecules
that don't necessarily turn the
immune system off, but rather,
they simply will make
it hard for the cells
to migrate into the cancer.
And finally, when
all else fails,
the cancer cells will erect
a molecular picket fence,
if you will, around
themselves to protect themselves
against the attack by the -- by
T cells of the immune system,
and those are those immune
checkpoint antibodies you'll be
hearing about shortly
from Dr. Allison.
Next. I would be remiss in
not recognizing the promise
of so called CAR T cell therapy
and other cellular therapies,
and again, a very complex slide
but what I want you to remember
from this is that you can
take cells out of the body,
you can manipulate
them genetically
so that they will now express
the ability to recognize
and attack a cancer, and
then you can use these cells
as drugs essentially, to go
in and invade into the cancer,
recognize the cancer
and destroy it.
This is a very powerful new
technology, and I think many
of us in the field,
myself included,
believe that cellular
therapy represents one
of the next great opportunities
for improving the ability
to control the development
or the sustenance
of cancers using the tools
of the immune system.
Next slide.
So finally, I used to have this
slide titled cancer immunology
is the next great frontier
of cancer research,
and I don't think that's true.
It's the current frontier.
It is the great frontier
of cancer research,
both to treat cancer, and
maybe as we understand how
to do this more safely and
in a more targeted way,
I think it may be possible
to prevent cancers this way,
using -- if we can identify
people at high risk,
and then basically
use the immune system
as a very specific probe in
order to essentially get rid
of the pre-malignant clones
as they're developing.
And with that, I'll stop and
I thank you for your attention
and look forward to the
rest of the presentations.
>> Sandra M. Charles:
Thank you so much,
Dr. Weiner for your clear
and thorough description
of how immunotherapy has been
harnessed to provide a variety
of cancer treatments, and how it
differs from other modalities.
We've always enjoyed
your presentations
and the hope it provides for so
many who have different cancers.
And I hope we will
have you back again.
Next, I would like to present
to us our next speaker,
Dr. James Allison.
Dr. Allison is the
Regental Chair and Professor
of the Department of Immunology,
the Olga Keith Weiss
Distinguished University Chair
of Cancer Research, Director
of the Parker Institute
for Cancer Research, and
the Executive Director
of the immunotherapy platform
at MD Anderson Cancer Center.
You will get a copy of his bio,
but I'd be remiss if I did not
at least say he has spent a
distinguished career studying
the regulation of
T cell responses
and developing strategies
for cancer immunotherapy.
He earned the 2018 Nobel Prize
in Physiology or Medicine,
which he shared with Dr. Tasuku
Honjo, for their discovery
of cancer therapy by inhibition
of negative immune regulation.
And one of his most notable
discoveries was how the T cell
receptor structure and another
structure were blocking the
activation of the killer T
cells, and through their work
and their -- in individual
labs, but certainly in his lab,
he paved the way for
the emerging field
of immune checkpoint
blockade therapy for cancer,
and that work led
to the development
of the drug ipilimumab, which
is the first immune checkpoint
blockade therapy
approved by the FDA
and is used among other things
in the treatment of melanoma.
So without further
ado, I will introduce
to you, Dr. James Allison.
Dr. Allison.
>> James Allison: Thank
you very much, Dr. Steen,
for that kind introduction.
Today, I'm going to give you
a little bit of a description
of how we came up with the idea
of blocking immune checkpoints
to treat cancer, and then sort
of show you what's going on now
and show some work that we've
been doing at MD Anderson
with Dr. Padmanee Sharma
to really discover how
to extend the therapies
to more kinds of cancer
and make them more effective.
I'll show my -- Go to
the next slide, please.
These are just disclosures
of myself and Dr. Sharma.
Next slide.
This work-up, it shows mostly
done by a number of people
over the years but as I said,
some of it more recently
and I'm going to show
us about with Dr. Sharma
and fellow Sumit
Subudhi at MD Anderson.
The next slide just
shows the story
of what we're talking about.
This is -- I've always
been interested in T cells
since I was in graduate school
and they were discovered,
particularly in the possibility
that we could use
them to treat cancer.
It was a daunting task because
we didn't really understand
that much about how -- what
regulated T cells at the time.
The left panel of his
shows the simple idea was
that T cells recognized
an antigen
on an antigen-presenting
cell or a tumor cell
and then would kill it,
but we realized by the --
and we worked out the
structure of the T cell receptor
in the early '80s, but quickly
a number of people realized
that it's the T cell
receptor signal
by itself was not enough
to activate a T cell.
It needed a second signal called
a co-stimulatory signal provided
by a molecule called CD-28
that we showed on T cells,
when combining with
a molecule called B-7
on very specialized
antigen presenting cells,
would provide all
the signals necessary
to tell a T cell to expand.
To put this in context, you've
got an enormous repertoire
of T cells, probably in the
order of 10 to the 10th, or so,
you know, tens of
billions, but the problem is
that you need an army of
them to attack a tumor
or attack a virus
infection, but you only got,
because of this high
diversity, you've only got a few
of any given clone, and so
you have to rapidly expand
that clone to get the army
generated to go out and,
you know, do whatever it has
to do to eliminate the virus
or kill the cancer cells,
and so that practice --
that regulation has to be --
the proliferation has
to be tightly regulated,
so that's why you have these
two signal requirements.
Now as it applies to cancer,
I'll get to in a moment,
but basically when a T cell
gets those two signals,
it makes a lot of stuff
and it makes growth factors
such as IL-2 that tell it to
proliferate almost as fast
as bacteria, so you go from
just a few dozen, perhaps,
T cells of any given specificity
to hundreds of thousands
within a matter of days to ward
off that problem, but you have
to stop that process,
and it used to be thought
that was just a passive process
to the T cells undergoing
a process called activation
induced cell death, but it
sort of ran out of steam,
but we discovered a molecule
along with that bit of molecule
which we previously discovered,
along with Jeff Bluestone
called CTLA-4, highly analogous
to CD28, very similar
in structure,
is turned on when the T
cells get that CD28 signal.
A way of looking at it is
that the T cell receptor
engages antigen along
with C28 given a
co-stimulatory signal,
you get this go program,
shown in green.
It's started by CD28, but when
the [inaudible] that also turns
on another program mediated
by CTLA-4 that accumulates
and turns off that
proliferative program
and stops those T cells are
proliferating, and we showed
that by showing that if you
eliminate the gene for CTLA-4,
the stop -- the T
cells lose that ability
to stop their immune responses,
and the T cells just keep
going and it's lethal.
Your immune system is killing
you, so that's the role
of CTLA-4 is to stop immune
responses, and this was shown
by [inaudible] as well as
ours, so you have to restrict
that proliferation eventually,
and as part of normal regulation
of the immune responses,
but what does this have
to do with cancers?
Well, when we discovered
this -- next slide --
and apply this to cancer,
because one of the things
that we learned very quickly,
which was that tumor cells,
solid tumor cells are basically
invisible to the immune system,
because they can't give that
second signal through CD28,
so they can grow for
substantial period of time
without being detected, until
as shown on the next slide,
there is the T cells get big
and or can't get enough oxygen
or enough nutrients, so
they begin to die a kind
of death called necrosis,
and that causes inflammation.
These professional
antigen presenting cells,
there have to be seven molecules
on them, pick up antigens
from the tumors, reprocess, then
put them on the cell surface,
and then that starts
the immune response,
but as with everything
else, that induces CTLA-4r,
which can come along then,
I show on the next slide,
and attenuate or even stop a
immune response to a tumor,
and so when we worked out
all these basic aspects --
and the early work had nothing
to do with cancer whatsoever.
It had to do with regulation
of T cell responses,
basic T cell biology
that was actually funded
by the National Cancer
Institute,
because the ultimate
relevance was, I think,
not necessarily obvious, but
was at least a possibility.
But anyway, this led to this
situation where it's kind
of a race, you know, if
you get enough T cells
to kill the tumor before CTLA-4
turns them off, then you win,
but if the tumor
get out grows them,
then the immune response gets
shut off and the tumor wins.
So we had the idea I
show on the next slide,
just to interrupt this
process, to interrupt CTLA-4
with an antibody that
keeps it from binding
to the B-7 molecules and let
the T cells just keep going long
enough to eliminate the tumor
and then they stop giving the
antibody and everything returns
to normal, and this
was compelling
for a couple of reasons.
As Dr. Weiner mentioned, this
does not attack the tumor
of these antibodies,
unlike the ones conceived
of by Dr. Ehrlich
in the early 1900s.
The target here is the
immune system itself,
not the tumor cell, so we're
treating the immune system
to allow it to kill cancer.
So since you're doing
that, the possibility is
that this could work
for all cancers,
because Dr. Peter told you all
cancers have mutations in them,
and they're going to
have foreign things
that can be detected
by the immune system,
and so potentially one
drug could be a universal
cancer treatment.
It doesn't work out that
way for several reasons,
some of which I'll get to later,
but the second compelling
reason was that shown
on the next slide, this
whole process is started
by cell death, and so one of
the things that you can --
that the immune therapies, the
T cells give you, you know,
is memory for example.
Once you've got T cells, some
of them stay around for the rest
of your life, and if
the tumor comes back,
they can easily be
reactivated to attack it,
and it can also change
as the tumors change,
and help continuous immunity.
And also the immune system does
not necessarily attack just
that mutation in
the target therapies
that Dr. Weiner told you about.
They cause the tumor, but it can
attack the passenger mutations
as well, that have nothing to
do with the cancer process,
but are there in the cell, and
if you can hit enough of them,
then you can eliminate the
tumor despite not doing anything
to the causal mechanism,
but anyway, you can combine
that with anything that kills
tumor cells potentially,
chemotherapy, radiation, hormone
therapy, anti-angiogenesis,
and those targeted therapies
themselves can also extend the
range of targets of vaccines,
so it was a nice idea,
but would it work?
And the next slide shows
an example of one of many,
many mouse experiments
that we did.
This just shows a mouse
tumor, a transplantable tumor
that can be passed
from mice to mice
that are genetically identical,
and it will grow
and kill the mice.
If we inject antibodies to CD28,
you can see the tumor
gets bigger, faster,
showing there is an attempt by
the immune system to get rid
of the tumor, but it's just not
able to completely eliminate it,
but in many animal models, when
we just injected antibodies
to CTLA-4, the tumor
would grow for a while,
and then the T cells
would reach them
to where they could
eliminate the tumor,
and the tumor would be rejected,
and the animals then would
reject that tumor for the rest
of their lives when we
tried to re-challenge them.
And, you know, this worked
for, we found out later, for --
it worked by itself with tumors
that were considered strongly
immunogenic, and we know now
by sequencing those,
those were tumors.
Typically that were
chemically induced,
and had a lot of mutations.
There were other tumors that had
very few mutations, and were not
by themselves immunogenic,
and that you could not
immunize a mouse, for example,
by giving them radiated
tumor cells, but we found
if we combined anti-CTLA-4 with
chemotherapy or a little bit
of radiation or with a vaccine,
we could even eliminate those
kinds of tumors, so we were able
to cure almost every single
mouse model that we went
for in our testing this.
So we show on the next
slide, after a time,
we found a company --
next slide, please.
-- that had a mouse, a company
called Medarex, that had a mouse
that didn't -- that they had
eliminated the mouse antibody
genes and replaced it
with human's, human genes,
so we could make a
fully human antibody
that was immediately ready
to go in the clinic and so
with Medarex, we made
this antibody which has,
Dr. Steen told you,
is called ipilimumab.
They are developed by
Bristol-Myers Squibb,
which was used initially
in many small trials
and in many tumor types and was
found to cause objective tumors,
objective responses in many
of these including melanoma,
prostate, kidney, bladder,
ovarian and lung, and prostate.
It was a combination
with a vaccine.
But there were adverse events.
In mice and monkeys, we never
saw -- in toxicity studies,
we never saw any
adverse events other
than some deep pigmentation
in melanoma models,
but when it went into
patients, we began to see a lot
of adverse events, colitis,
hepatitis, a lot of [inaudible].
These are inflammatory responses
that are not really
autoimmune diseases
when looked at carefully.
Now they are immune related
in that they represent
a dysregulation
of the immune response,
but they could be treated
with systemic steroids
typically, and they go away,
their symptoms go away, and
then you can stop giving it,
wean the patients off the
steroids and they do fine
and the tumors still respond,
but now we know that hundreds
of thousands of people have been
treated with this, that are,
pretty rare, 1% or so
of patients develop
type one diabetes,
or a T cell mediated
problem called myocarditis.
It's a very interesting thing
that we've developed an animal
model for and are studying now
and have developed a way, I
think, a way of treating it.
But overall, it's -- although
it has adverse events that have
to be paid attention to like
any cancer therapy it turns out,
they can generally be managed,
so the next slide
just shows a patient,
one of the early
patients treated.
This was a -- I like
to tell the story.
This is a personal friend, now.
She wasn't then.
But anyway, she was 22 years
old in 2004, had just graduated
from college and was
engaged to be married
when she was exhausted anyway.
She was diagnosed with
metastatic melanoma.
Most of the tumor metastases
were inside her body,
in her lungs, as shown here,
in the left panel circled.
She had 31 lung metastases.
She also had liver metastases
and she had a brain metastasis.
She went on an early trial
was treated, by Jed Wolchok
at Memorial Sloan Kettering.
She failed, actually, two
chemotherapies, high dose IL-2,
a dendritic cell-based
vaccine before she --
and radiation for her
brain tumor before she went
on ipilimumab.
She was hospice-bound
at that point in 2004,
so and then after the
treatment with ipilimumab,
her tumors completely
disappeared.
This shows -- CAT scan shows
the metastasis in the lung.
The next slide shows
that the metastasis there
in the lower right that was in
her brain, and it also resolved.
All of her tumors
completely resolved,
and she was a complete
responder in 2004.
The next slide just shows her --
she sent me this photo in 2016
with her two beautiful children,
and I actually saw her last,
two years ago, and she
is still doing fine
with two wonderful teenage
children now, with no sign
of disease, and able
to live without looking
over our shoulder after a time
now, so she's now, you know,
close to 14 years --
16 years actually out,
so I show on the next slide.
This went to a phase
three randomized trial
with a overall survival
standpoint,
which completed in 2010.
It was started about four
and a half years earlier.
Anyway, the lower curve here
shows a placebo control,
and the situation with melanoma
at that time was a median
survival of about seven months
after diagnosis with
fewer than 3%
of patients being
alive in five years.
The top line is the
ipilimumab line, and it's moved
over several months, which
moves the median survival,
50% survival over a few months
so that would have been
sufficient for FDA approval,
because no drug at
the time had ever done
that in a randomized
trial, but as you can see,
the other interesting thing is
that the survival curve flattens
out in about two and a half to
three years, and then stays flat
for the duration
of this treatment.
Anyway, this resulted in
approval by the FDA in 2011,
but as shown in the
next slide, by 2015,
there was a sufficient number
of patients as shown here,
that could do a meta-analysis
of survival, and it turns
out that the overall survival
at 10 years was about 20%,
a little over 20%, after
monotherapy, so which was,
you know, a remarkable
achievement at the time,
although it's only 20%, you
know, given the alternative,
but it was only 20%,
and why isn't it better?
But I can give you
a number of reasons,
a number of mechanistic
possibilities, but of course,
the more interesting one is
that maybe there were multiple
checkpoints, and sure enough,
we show the next slide, Tasuku
Honjo, this was mentioned,
in about the time that our
phase one data were coming out,
he found that, in
collaboration with Arlene Sharp
and Gordon Freeman at the
Dana Farber Cancer Center,
showed that a month molecule
Tasuku had been studying
for years, PD-1, was another
one of these checkpoints.
It had two ligands, PD-1 and L1
and L2, as shown in the bottom.
A difference though between
this and CTLA-4 is that one
of its ligands, PD-1, can
be expressed on tumor cells,
and this is different than
what goes on in the CTLA-4,
because PD-1 is induced in
response to gamma interferon,
a substance produced by T
cells to kill tumor cells,
which can kill tumor cells,
and so this is an
acquired defense mechanism.
You know, the specific T
cell that can detect antigens
on the tumor makes
gamma interferon.
The tumor responds by
up-regulating PDL-1
which turns off the T cell,
so this is an active
defense mechanism.
This mechanism has also
been shown to play a role
of protecting the
fetus from destruction
by the maternal T cells,
targeting paternally encoded
antigens, so this pathway seems
to be co-opted by tumors
to protect themselves much
that same way, so
different than CTLA-4.
The next slide just shows the
result of a phase one trial,
just a summary by Suzanne
Topalian, where like CTLA-4,
which responds to react -- many
tumors respond to it, including,
again, of course, melanoma,
non-small cell lung cancer
in this trial, renal cancer,
which also responds well
to CTLA-4, but colorectal
cancer did not respond.
Now that's since been shown
that there is a subset
of colorectal cancer
that has hypermutation,
has defects in DNA damage
repair, so it has a lot
of those neoantigens that
Dr. Weiner talked about,
so that subset of colorectal
cancer does respond to PD-1,
but there were no responders
to castrate-resistant prostate
cancer, and this is different
from CTLA-4, which did
respond in some early trials,
at least there were
some responses to it,
and I'll come back
to this in a while,
because there's certain several
lessons that we've learned
from studies of prostate cancer.
At any event, show the next
slide, and these quickly began
to be realized that these
pathways were indeed not only
purely mechanistically
independent,
but because of that they --
one drug could be
used after the other.
In other words, patients that
failed ipilimumab could go
on a PD-1 antibody nivolumab
and still have a good chance
responding in the reverse
which was also true
those that were treated
with PD-1 could respond,
sorry --
fail PD1 could respond
or subsequently treated
with anti-CTLA-4, so this plus
a lot of mechanistic studies
that were done could show that
they were different, in part,
lead to a trial combining
these two agents
as shown in the next slide.
Putting them together,
the actual data I show
in the next slide is a trial --
sorry, [inaudible]
or a little bit.
Anyway, this is an experiment
that we did in mice very early
on showing that these
two could be combined.
The next slide then finally
shows the results of a trial
where these were put together.
This shows that 52% of patients
here we're alive five years
after therapy, and
in a different --
this a phase three
randomized trial,
Jed Wolchok recently
published an update
where the response is
six and a half years
and another trial is
even slightly higher
than this, but anyway, over 50%.
So the lesson here is that by
combining these two checkpoints
now with melanoma, this drug --
this disease, which, you know,
no drug had ever treated before
this and now the majority
of patients are alive at
six and a half years now,
and then there's no reason why
they're not going to be alive
at 10 or whatever, just as
shown within our CTLA-4 alone,
so quite an advance,
especially with melanoma,
as shown in the next slide.
This isn't just melanoma though,
and this is as Dr. Weiner said,
a very classic slide
at this point,
but here I've just
marked it up a little bit.
Actually, this is with Bob
Schreiber and Tony Schumacher,
to show you that in the red
box, these are these tumors
that have hundreds to thousands
of mutations per cell and lots
and lots of new antigens,
and you notice again,
melanoma is at the high end
of that, and also other kinds
of diseases caused by mutation.
Like lung cancer, for example,
not caused by UV induced
mutations, but by carcinogens
in tobacco smoke along
with, you know, lung cancer,
but also bladder cancer,
head and neck cancer,
other things like that.
Those tumors all respond
very well to monotherapy,
so either CTLA-4 or
anti-PD-1 [inaudible] tested,
and now are being tested
with their combination.
But as you move to the left on
this slide, with other kinds
of cancers, they have much
lower frequencies of mutations,
and down here, kidney cancer,
although it's at a level
where you would not necessarily
expect it to respond,
responds very well again to
monotherapies, either PD-1
and CTLA-4 but even
better to the combination,
where the response rate is 40%
or so, and then when you go
to the left, though, you get
down to where pancreatic cancer,
glioblastoma, and prostate
cancer, there in the blue box,
which there are occasional
responses to,
but not regular responses.
Again, I'll mention
this in a moment,
but this is the challenge
now is to deal with the rest
of these kinds of tumors, but
as shown on the next slide,
this just shows the
approvals by the FDA
and different cancer
types, and there --
this is only a partial
list, as Dr. Weiner said,
with the antibodies with
the checkpoint antibodies.
I got tired about three
years ago keeping up
but there are 40-something
approvals now.
You can see here,
not just melanoma,
where if you're doing ipilimumab
was approved in 2011 and CTLA-4
and the Pd-1 antibodies, 2014,
and a combination in 2015,
but also lung cancer, renal
cancer, colorectal, on and on,
but the notable or what I
should point out, though,
where we're at is that it's
gradually moving towards
frontline use of checkpoints,
generally with a combination
of anti-CTLA-4 and anti-PD-1,
PD-1 which gives you
a higher response rate
and ipilimumab was thought
to provide perhaps better,
you know, sustained responses.
Together, they work quite
well, but not quite as well
as in melanoma and kidney
cancer, for example.
The combination is active, like
somewhere between 35 and 40%
of patients, so we've got a ways
to go in improving the rates
of responses there, and so
far, there's been no approvals
in prostate cancer, although
we have seen clinic --
some complete responses within
anti-CTLA-4 plus anti-PD-1
and also no responses so
far in two very well-known
and very lethal tumors,
pancreatic cancer
and glioblastoma, although
there's a lot of effort here,
and I think progress is being
made, although not much yet.
We just got a lot of work to do.
So in the next slide
that just again,
a summary because I don't have
time to show you the data,
but we did some studies along
with Pam Sharma in
prostate cancer.
Remember that I told you there
was no responses with PD-1
and we took biopsies
for patients before
and after therapy with
CTLA-4 monotherapy.
There was a phase three trial of
anti-CTLA-4 in prostate cancer
because there were
sufficient numbers of responses
to justify it, but the
phase three trial failed,
and so it led to Bristol-Myers
Squibb to completely shut
down their prostate
cancer program.
You know, we got biopsies from
a number of patients before
and after ipilimumab
therapy and what we found was
that before therapy, they
were as cold in terms
of immune cell infiltration as
pancreatic cancer, for example,
but after ipilimumab, they were
just as infiltrated as melanoma.
On the other hand, what we
found was that those cells
in the prostate cancer now
expressed a large number
of checkpoints including not
only PDL-1 which, you know,
involved in PD-1 blockade,
but also several others.
This led us to then look
at the combination of drugs
because PD-1 antibodies
do not drive T cells
and prostate cancer, and so we
went to Bristol-Myers Squibb
and said let's give CTLA-4
to get the T cells in PD-1
to take away that checkpoint,
and then we'll see some
responses, so Dr. Sharma
and Dr. Subudhi led a trial.
There were complete
responders in that trial,
meaning PSA became undetectable.
The tumors went away, including
primary prostate cancer,
but also soft tissue metastases,
and there were some patients
that are now two,
three years out,
but bone metastases
did not respond.
In any event, that trial
was being expanded now,
and there was a registration
trial.
There was some toxicity,
but the amount
of CTLA-4 is being cut back to
minimize that, and we'll see
if it's going to be effective,
but one of the other things
that we learned in the
course of this study was
that with CTLA-4 monotherapy,
we could get response
to neoantigens in this
tumor, even though as I --
as Dr. Weiner just showed,
and as I showed you earlier,
prostate has very low
levels of mutations.
In our sequencing, we found most
tumors had only a few dozen,
a dozen to a few dozen
mutations, but we found
in a smaller panel of patients
that we looked at, one patient
and we had 10 mutations.
Two of them, those mutations
were recognized by T cells
and induced after
CTLA-4 therapy.
Another one that had 12, only
12 mutations had one response,
so there is some
hope for patients
that have low mutational loads
that need not be a
total reason to not try.
So I show on the next slide
-- next slide, please.
Just to summarize
some differences
between these two checkpoints.
CTLA-4 is hardwired.
PD-1 is an induced resistance.
CTLA-4 seeks to target C28.
PD-1, the T cell
receptor pathway.
CTLA-4 works during
clonal diversity,
and because that has been
shown to work pretty slowly,
but also to move T
cells into cold tumors,
and to recruit new
T cells into tumors
and expand the clonal diversity.
Whereas PD-1 works very rapidly
and only expands the T cells
that were already there before
treatment, because it works
on fully differentiated T cells.
Main difference is
that adverse events
with PD-1 are much less
frequent, and adverse events
with CTLA-4 much more
frequent, but it's found
that disease recurrence after
PD-1 monotherapy at least,
is significant, but it's pretty
rare after a response to CTLA-4.
At any event, so a very
powerful pair checkpoints
that can be used, but the
story doesn't end there
because I showed you.
It was on this -- the
prostate cancer slide.
There was also a molecule called
VISTA that we detected there,
which is a very powerful
inhibitor of T cell responses.
It's not ever found on
tumors, but it is found
on a myeloid cell population
that we find after treatment
of prostate cancer, but
not melanoma, for example.
So there's some complexity
of these checkpoints,
as to the kinds of tumors that
they expressed in that needs
to be paid attention
to if we're going
to continue to combine these.
At any event, the next slide
just shows a partial list
of the molecules I talk about.
I've already talked about
the main two, PD-1 and CTLA-4
which I think are going
to be the combination
that can be built upon in
most therapies coming forward.
Antibodies to molecule called
TIGIT are looking pretty good
in the clinic now as
are antibodies to LAG-3,
but this other class
of molecules that are
on just myeloid cells
that I've mentioned
on the lower right here,
VISTA is one of them.
Another one that we're
looking at now is LILRB4.
Again, both inhibitors
of T cells
that are not expressed
on tumors.
The mechanisms aren't
completely elucidated yet,
but there are antibodies
to them, and for patients
that don't respond, for example,
to anti-PD-1 plus anti-CTLA-4,
I think in certain kinds of
tumors, we're going to be able
to add these if we see that
they're upregulated in response
to the other checkpoints.
And then the next slide just
shows what I think is going
to happen.
We're going to continue blending
antibodies to both positive
and negative checkpoints.
OX40 4-1BB are molecules
and ICOS molecules
that I talk about, that actually
increase T cell responses,
and those could be
combined, but I think,
going back to the
first part of the talk,
we're going to start
seeing more combinations
with conventional therapies and
target therapies, which again,
can prime T cell responses
by killing tumor cells,
and allow us to treat
exactly, you know,
when we know these
tumors are beginning,
these antigens are going to
be released by tumor cells
and prime a response,
which should make the
therapies much more efficient,
so any problems to
face, as I told you,
we're not that far along.
There are many kinds of
cancers, a long way to go,
but I think we know the basic
rules now, and we can get there
and show on the next slide is
something that I like to show
and this is something that
as Dr. Weiner told you,
beginning with chemotherapy,
in the '40s the goal
of oncology is largely
to take a --
do a clinical trial with a
fairly large number of patients,
treat them with the drug that
you're testing, compare and see
if you get an increase
in immediate survival.
And if you do, that's
obviously a good thing,
providing a longer life with
quality of life, but we know now
from ipilimumab, the
early studies there shown
on the next slide, you can
do that, but also get a tail
on the curve at about 20% or
so in melanoma, but the next --
the final slide is
not any data yet.
It's an aspirational line
showing you what we're trying
to do now, and that is to raise
that survival tail as high
as we can get it, not
just the response rate,
but the overall response,
the durable responses,
like we've seen in
melanoma that can last
for decades can finally be
considered cures of cancer,
and as I said, we've
got a lot of work to do,
but we're learning
the fundamentals
and we've learned
the fundamentals.
Now we can begin to
start kept combining them
in more productive ways to
try to achieve this goal,
so that I hope I haven't
gone too much over time,
and I'll stop and thank you
for inviting me and allowing me
to participate in this
conversation about progress
and moonshots, so
thank you very much.
>> Tomoko Y. Steen: Ah, thank
you so much, Dr. Allison.
It is really a very informative
presentation, and it's great
to know that, you know,
continuously improving,
and we have the combination
with targeted treatment,
it's available, and that brings
to a wonderful, you know,
introduction to next speaker,
Dr. Giorgio Trinchieri.
He is Chief at the Laboratory
of Integrated Cancer Immunology,
and he is the head of Cancer
Immunology Section in the Center
for Cancer Research,
and he is at NIH, NCI,
and he's also the
Distinguished NIH Investigator,
and now he's working on
fine tuning and, you know,
how we use this technology
therapy to even better level
and so that's Dr. Trinchieri
is going to share with us,
so before further ado,
the floor is yours.
>> Giogio Trinchieri:
Thank you, Dr. Steen.
Thank you for the introduction.
If I can have the first slide,
can you show the slide
from the beginning?
>> Tomoko Y. Steen: Yes, yes.
>> Giogio Trinchieri: This
is -- there is animation.
It's not showing the animation.
>> Tomoko Y. Steen:
Yeah, it's perfect.
>> Giogio Trinchieri: Okay,
it is supposed to be shown
with animation, show
only the center of box.
>> Tomoko Y. Steen:
Oh, animation.
I'm sorry.
>> Giogio Trinchieri: Yes.
>> Ashley Cuffia: The animation
is not coming up, Doctor.
>> Giogio Trinchieri: Okay,
can I show my slide myself?
>> Ashley Cuffia: Sure.
Give me one second.
>> Tomoko Y. Steen:
So then, meantime,
I like to tell audience,
please put in your question.
It's bottom center part.
It's the Q&A, so some people
were putting in the chat,
but please put in the Q&A,
and you can write in any time
so we'd like to have
the questions.
>> Giogio Trinchieri:
Can you see my slide?
>> Ashley Cuffia: Yes.
>> Giogio Trinchieri:
Yeah, perfect.
Thank you very much.
I'm sorry for this
inconvenience.
So I said it was --
>> Tomoko Y. Steen: Sorry,
it's in like a speaker's
mode, so you can switch.
>> Giogio Trinchieri:
Okay, sorry.
Okay. It's fine now?
>> Tomoko Y. Steen: Yes.
>> Giogio Trinchieri:
Okay, perfect.
Apologize again.
So it's been discussed by
Dr. Allison and Dr. Weiner,
even with a great
result with immunotherapy
and immuno-checkpoint
blockade, still unfortunately,
not all patient respond
to immunotherapy,
so the question really
come out, can we predict
and improve the response?
And we know that the
tumor cells was discussed.
The presence of a new antigen
mutation is a major role
as a tumor increasing factor,
but there are also tumor
experiencing factors, the cell,
they are present in the
tumor microenvironment,
circulating factor
like different inflammatory
factor present in the blood,
but also [inaudible]
present for example,
the number of granulocytes
neutrophils in the blood.
There is a correlation of the
response with adverse effect.
Adverse effects are always
a problem in the therapy,
but also are associate
normally with a good response,
and then in many different
host factor, metabolic factor,
what is I want to discuss today
is to generate quite a lot
of interest is the role
of the intestinal gap
for commensal microbiota means
the bacteria and other organisms
or microorganisms that
are present in our gut
that affect our physiology and
pathology, and it's been shown
to have an effect on
cancer immunotherapy.
Now, what are these
commensal microbiota?
We know that we have evolved
with microbial partners.
It means our body is formed
by our own human cells,
together with these
microorganisms, bacteria,
but also virus, protozoa,
fungi, and they are present
in all the [inaudible]
surface that divide our body
from the outside world, and
particularly are very abundant
in our lower intestinal tract,
lower small intestine
and in our colon.
And what is very important is
that the commensal microbiota
is known now to be indispensable
for health and survival of
the metaorganism, our organism
with our bacteria, and the
crosstalk between our cells,
the host cells, and the
microbiota regulate many
physiological function that
include many different one,
but particularly metabolism,
inflammation and immunity,
and in this way, also think
cancer, may cause cancer,
may favor the cancer
progression,
but they may also
regulate cancer there.
And our group and others about
eight years ago has shown
that the gut microbiota
is require
and determine the
efficacy of cancer therapy
by modulating the
anti-tumor immune response
and so naturally doing that
by educating one type of cells
in the tumor microenvironment,
the myeloid cells
and in this way regulate
immunity and the ability
of the immune cell to
regulate the tumor growth.
We originally described
that for a new type
of immunotherapy based
on CPG oligonucleotide,
as well as chemotherapy
based on platin compound,
but then many other group
and other paper has
been described the role
of this gut microbiota in
regulating cancer therapy,
and a lot of interest
was more recently,
when immune-checkpoint
inhibitor therapy has been shown
to be regulated by the
presence and composition
of the gut microbiota.
Now well just summarize
in this slide.
There are several
studies been published,
but they are mostly based on
animal model, on mouse model.
Therefore, really the
major interest in this type
of research was about
three years ago
and several papers
starting come out,
three in the journal
Science showing that the
in a clinical trial,
a patient treated
with immune-checkpoint
inhibitor,
particularly anti-PD-1
and anti-PDL-1,
the gut microbiota controlled
the response, and here we have,
for example, two studies
of [inaudible] in Chicago
on melanoma patient
and [inaudible] Paris
on lung and renal cancer.
Now, this patient
clearly established
with many different type
of data and also correlate
in animal model that
the composition
of gut microbiota is
important for the effectiveness
on the PD-1 cancer therapy..
What there was a little bit
disappointing that even it's
on this paper describe bacterial
species that were associated
with a good anti-PD-1 response.
The species they described
are shown here in red,
were nearly different
in each study.
There were almost
no communality,
no overlap between the bacteria
that were identified
before the study.
So that put the faith in a
little bit disarray for a couple
of years, but I think things
are really now start changing
and I think we can start seeing
some common result among the
different study,
and really start
to understand a bit
better how the bacteria
and which bacteria are regulate
the cancer immunotherapy.
I want to show you a series
of data has been published
by many different groups.
This is one example that
showed that if you're disrupt
in the patient the composition
of the gut microbiota
by using antibiotics,
you can see the patient
that use antibiotics
had much worse survival
than the patient did
not use antibiotics.
Antibiotic disrupt the
bacteria present in the gut
and make the patient less
responsive to therapy,
but also other pharmacologic
agent
that can change the competition
bacteria, for example,
the acid-reducing drugs,
the proton pump inhibitor,
you can see the patient
use proton pump inhibitors.
They respond less well,
and if they use antibiotics
and proton pump inhibitors,
they really respond very poorly
to the anti-PD-1 treatment.
Also, the different the
data in different study,
within different study, at
least, were quite strong
to show there are
certain bacteria.
This is our data in melanoma
patients in Pittsburgh.
We show on the top
three different bacteria
that were associated with a
good response to anti-PD-1,
and in red, you see the response
and survival of the patient
that have either of these
three bacteria, in blue,
the one with low levels, so
you can see here it is drastic
and significant different
response in the patient.
On the bottom are
three bacteria.
They are associated with
poor response to anti-PD-1.
You see [inaudible] the
patient that have high abundance
of these three bacteria
have a very poor response,
very poor survival after
anti-PD-1 treatment,
but if you put all
the result together,
these are five different
study in melanoma
and the patient here,
each one, the microbiota,
the bacteria present in the gut
of the patient is
shown by a red dot.
In blue, the one respond in
red, the one do not respond.
You can see that the patient
that responded different
from the patient do not
respond, and if you combine
in a meta-analysis
all this together,
even if its study really
describe somewhat different
bacterial species, you can see
that if you look this family
of lots of spirochete,
[inaudible], three family
of bacteria, most of the
bacteria that are associated
with a positive response
belong to these three families.
Wherever the bacteria they
belong to Bacteroidetes,
many of them shown
here by the --
shown to be associated
with a bad response,
so it did find some commonality
and probably some
share mechanism
in the result has been present
in the different cohort.
And more than that,
even if cohort,
like you show five
different cohort here
in five different
city, even if they --
each cohort was very different,
and the patient were very
different in the composition
of their microbiota, if
you get the information
of the composition microbiota
and a response to anti-PD-1,
derive from four of the cohort.
You can test this information
on the cohort that was not used
in this analysis, and you
can predict the response
to anti-PD-1.
That was done for all
five different cohort.
This is [inaudible].
This actually show that
in [inaudible] we can --
we have an accuracy about
80%, so it's not perfect,
but just by knowing the
composition microbiota
of the patient with
an 80% accuracy,
we can predict whether
they will respond
or will not respond
to anti-PD-1.
The other thing that
was discussed in detail
by that [inaudible] was that
when you get a good response
to anti-PD-1, often
it is associated
with immune related adverse
effect, and this slide
on the left, you know, just
showing the many different type
of adverse effect,
collateral effect that you get
with anti-PD-1 treatment, and
the study we did in Pittsburgh,
as many other study before
us, it showed that the patient
that have any type of immune
related adverse effect
[inaudible] had a better
survival of the patient
without immune related adverse
effects show here in blue.
And if we look the microbiota,
the bacteria they are in the gut
of the patient with or
without adverse effect,
we see that they are
different, in red,
the patient with adverse
effect, in green here,
the patient without
adverse effect.
There are bacteria significant
different in this two group,
but we'll also show that was
not unique type of bacteria.
There are different type of
bacteria doing different things
and using different
type of adverse effect,
and in particular, we found
that the Lachnospiraceae
family were associated
with various immune
related adverse effect,
and also like we show in
the totality of the patient,
were associated with
improved survival.
However, there was other
patient that had high number
of Streptococci in our gut,
and these patient also
had adverse effect.
They were slightly different the
one [inaudible] Lachnospiraceae,
particularly they have very
often after a [inaudible]
and arthritis, but they
had a much worse survival,
and these patients Streptococcus
species were actually most
of them were using a
proton pump inhibitor,
the acid-reduce drugs,
and that's because they use
the proton pump inhibitor
to actually increase
the abundance
of streptococcus species
in the gut to the patient,
and this is actually associated
with both side effect,
but in this case, to a worse
survival, worse response,
poor response to anti-PD-1.
The other thing that I mentioned
that if you have systemic
inflammation as show
by high neutrophils
in the blood,
particularly high
neutrophil PFS ratio.
This is associated with a poor
response to anti-PD-1 and again,
it's been shown by many
study, but what we found
that the neutrophil
to lymphocyte ratio also
distinguish two group
with a patient with a different
composition of the gut bacteria,
the fecal microbiome,
and when we look
which bacteria were associated
with this systemic inflammation
and show by a number of
neutrophils in the blood,
we found that the majority
of the bacteria they were using
these increased neutrophils
number on the blood,
where endotoxin produce
gram-negative bacteria,
and in a series of study
in human and the mouse
and in the fecal transplant
and other clinical study,
we could show that the
gram-negative bacteria
in the gut by producing the
toxic LPS, inducing inflammation
in the intestine with production
of inflammatory mediator,
but also attraction in the
guard of inflammatory cell
like neutrophils and macrophage.
These are also were
seen in the liver
where we have neutrophils
infiltration,
and that favor grow tumor
and metastasis in the liver,
at least in the mouse,
but in human we could show
that was [inaudible] in
the blood as I mentioned
to high neutrophil/lymphocyte
ratio and presence
of soluble factor like
the cytokine IL-8,
and this reflect a poor response
to immune-checkpoint blockers
at the tumor level
and also the presence
of this cytokine IL-8
we see in the blood
and then intestine also
being produced in the tumor,
tumor and patient I mentioned
that have a poor response
to immune-checkpoint blockers.
So why we see this
discrepancy different study?
Well, it's a study the gut
bacteria is very complicated
because the gut bacteria may
change with time and may change
with geography and so
on, and what we know is
that the composition of the
gut bacteria is really mostly
regulated, involved by
contact with the mother then
in the first few year
of age by interaction
with the environment, then
become relatively stable,
during adult life, but
can still be changed
by diet and lifestyle.
So what is really very
important is where you're born,
where you live, the geographical
organizational lifestyle,
diet and aging is
very important,
but also use a food
supplement like probiotics.
The use antibiotics infection
that can change the composition
of the gut microbiota.
So when you look at a different
study, you can immediately know
and I already mentioned
some of the city,
they really their
patient populations come
from different geographical
place,
and that's obviously associated
with different lifestyle,
and different type of food,
and these are all things
that can have an effect on the
type of bacteria that you have
in your gut, so we look
at that specifically.
We look in the United States.
We have the ability, because
of the American Gut Project has
analyzed more than 20,000
donor in the US to show
that the [inaudible]
U.S. is really clustered,
divide in different group
that have characteristic type
of bacteria in their gut, and if
you look this different classes,
different types of microbiota,
and you look different bugs,
different bacteria, you can see
that some bacteria present some
cluster in red, not in other
and for example, what surely on
top is bacteria, that are good
for anti-PD-1 response, the one
on top of the one they are bad,
so you can imagine that
this different type
of gut bacteria [inaudible] gut
bacteria may associate already
with good or bad response to
anti-PD-1, and what we will show
that if we get each one of this
type of cluster of composition
of gut bacteria, and we look
where they come United States,
you see that some are present
in different populated state,
but this one, for example, is
present only in the northeast,
this one only in
Southern California,
so they have different
geographical localization,
and not surprisingly, when we
look different melanoma patient
cohort, you can see
these are patient.
They're not only normal donor,
you can see they are different,
the different patient
study in different place,
they have different
composition microbiota,
and if you look their presence
of the microbiota type,
they are good or
bad for anti-PD-1,
they're really different
in its different cohort,
and that's probably one
of the reason explain
the different result,
the original has been described
by the different study.
So if the microbiome
is important,
the question always
immediately come,
can we target the microbiota?
Can we change the microbiota,
and we can do that in a way
to improve therapy response?
This was another slide
showing now at the beginning,
when we really had no
idea what was going on.
We knew that there
was this association.
We said the microbiota
with good response
or bad response to anti-PD-1.
We didn't know exactly
which bacteria were good,
and what the mechanism was.
We know a bit more
now but immediately,
everybody always was interested
we can change this balance,
this between different bacteria
and make the patient
better response to therapy.
Now what there are many
studies that are ongoing,
that they're trying to
use single bacteria,
or consortia bacteria probiotic,
and see whether we can change
the microbiota composition.
This is always difficult,
because as I mentioned,
we don't know exactly which
bacteria are important,
how they work, so we really have
no result even different study
are ongoing.
We have no result
from this study yet,
but where we have a result and
we have been directly involved
in the study is two
type approach
to change the microbiota.
One is a fecal microbiota
transplant from one patient
to another patient or change
or locally change in the diet
that the patient are intaking
during the before during the
therapy, so the fecal microbiota
transplant is based on the idea
that the patient did to
respond to anti-PD-1,
either they failed
completely respond to PD-1
and together we work out the
bar and since They're all
in Pittsburgh, we decide
based on their qualities
in this two group of patients,
the different microbiota,
the responders, a good one,
the non-responders the bad one,
see if we could transfer
the fecal microbiota
from the patient that
responded what's supposed
to be good microbiota implant in
the unresponsive patient and see
if we can change the response
to anti-PD-1 and indeed we --
it was a small trial
with the 15 patient.
Another group [inaudible] but
what we found that by doing
that we can transform
40% of patients
that were completely
unresponsive
to PD-1 before the fecal
transplant in response to PD-1
and the data showing here
the size of the tumor
in red are nine patient
that fail the even
after the fecal transplant,
but in [inaudible] the
six patients there respond
and they either have a
complete respond, part response
or stable disease
that let you say
that all the six patient now
are stable disease for more
than two years after
the fecal transplant
and the continuation
of the anti-PD-1.
The other data that
I mentioned is diet.
This is a study in collaboration
with the group Jennifer
[inaudible] Anderson,
and this is not an
intervention study,
but just to analyze
what the patient
that were treated melanoma
patient were treated anti-PD-1
how they responded to anti-PD-1
and look what they were eating,
and what it came up that if
the patient were eating more
than 20 grams per day of
fiber, so in high-fiber diet,
about two-third of the patient
[inaudible] of a patient
that respond to anti-PD-1,
but if the low fiber-diet,
only about 1/3 of them
respond to anti-PD-1,
and you can show the [inaudible]
America for survival here.
You can see the patient
with high fiber is a much
higher survivor than the patient
with low-fiber diet and the
study in human [inaudible] study
in the mouse were able to show
the high-fiber diet really
change the gut bacteria in a way
that the ratio between bacteria
that favorable to
anti-PD-1 response
to [inaudible] one is changed
by the high-fiber diet,
so what I've been
trying to tell you is
that our gut bacteria
really very much depend
on the way we interact
with the microenvironment.
Is very important where we
are born, where we live,
what we eat, what
is our lifestyle,
and all of these
affect the microbiome,
and based on this
emerging data show
that they may have
a major effect
in modulating the
response to cancer therapy
with different mechanisms
and some of the data
on fecal transplant
diet, and hopefully some
of the ongoing clinical
trial with single bacteria
or consortia bacteria are start
to suggesting the
microbiota could be targeted
through cancer immunotherapy
and this could be a future way
in a relatively non-invasive
way to change the ability
of the patient to
respond to therapy.
Just like briefly to
thank my laboratory group
for the data I presented,
the great collaboration
of the patient and the clinician
and the Pittsburgh Medical
School, particularly the group
at [inaudible] the group of
Jennifer [inaudible] Anderson
and obviously all the
great code that we have NCI
for doing this type of work.
Thank you very much.
>> Tomoko Y. Steen: Well, thank
you so much and, you know,
this has really proved that
the gut microbiome is really an
important part of
the immune system
and especially for
this treatment.
If you can put in the
questions, please put in Q&A
and it's the middle center part.
So next speaker is Dr. Sigal.
Actually, can you
put back to slide?
>> Ashley Cuffia: One minute.
>> Tomoko Y. Steen: Yup.
There some people putting
a question in the chat,
but please put in Q&A, and
if we can't answer on time,
we will answer to you or
send you the email answer
after the event.
So our last speaker is Dr.
Ellen Sigal, and she was speaker
in the 2016 Cancer
Moonshot panel.
It was in person,
and unfortunately,
this time we had to do webinar.
Hopefully we can do
in person next year.
So she's a patient advocate,
the founder and the chairperson
of Friends of Cancer Research.
And she has been working on this
reaching patients and clinicians
and scientists for
quite many years,
and she'll give background work,
and we will have
future of plans as well.
So floor is yours, Dr. Sigal.
Thank you for coming.
>> I believe you need to
start Dr. Sigal's video.
>> Tomoko Y. Steen: Yup.
>> Ellen Sigal: Good afternoon.
It's quite a pleasure to be
here, and I'm really overwhelmed
by the extraordinary
panel and the opportunity
to discuss cancer, and certainly
how it impacts the patient,
and thank you for being at
the Library Congress again.
Last time I was there in person,
and I'm hoping next time we can,
and I'm going to make
it a little shorter,
because I know there's
time for Q&A.
Friends of Cancer Research
is in existence now 25 years,
and it started as a result
of the 25th anniversary
of the National Cancer Act,
and now we're at 50 years,
so it's quite a lot
has been accomplished.
We've done a lot and we have
a lot of -- a lot more to do,
so I'm going to talk about some
of the major accomplishments
from the 21st Century Cures Act,
and the impact the
legislation passed
and many of you worked on it.
And Danielle Carnival,
you were extraordinary,
and what was extraordinary
about the moonshot is
that you actually listened to
the patient and the advocates
and what they thought
was really important,
and the fact has had
a profound difference.
The legislation has really
enhanced biomedical research
and development of safe
and effective new products.
One of the key provisions
is strengthening the FDA
and streamlining
clinical trials.
Clinical trials are the
backbone of science.
It's how we learn.
It's how we really get to
better treatments, but they have
to be accessible, and they
have to be meaningful,
and we have to get to the
patients where they live,
and we have to make sure
that underserved and patients
who normally do get treated in
a community get access to these
to these trials and
Cures went a long way
in streamlining these
clinical trials.
One of the other things it did
is modernize the regulatory
process, the OSE, the
cancer, the creation
of the Oncology Center
of Excellence
at the FDA's enhanced patient
centered regulatory decision
making through innovation
and collaboration.
It also organized all of
the different divisions,
so they all work together
which is really important.
It created a collaborative
scientific environment
in advance of the development of
regulation of oncology patients,
for patients, and
it also put patients
at the center of
drug development.
We are doing all of this for
science, but we are doing this
so we can benefit patients
and patients are really the
north star of what we're doing.
The provision created new steps
that operationalizing
corporations direct patient
feedback and assisted
advocacy organizations
and medical research
FDA for FDA and industry
to align drug development
programs
with the important information
provided by patients.
It also went into rare
diseases for limit --
where we have really
no treatments,
and now the FDA is empowered to
offer experimental drug approval
for narrow patient populations,
expanding options for patients
without established
alternatives.
That is incredibly important.
In some cases, we have
wonderful treatments.
In other areas, we really are --
really need to enhance rare
cancers and really deal
with these cancers where
we have no good answers.
One of the other things
that the moon shot did
in 21st Century Cures, it
advanced recruitment of best
and brightest at the FDA.
We have to attract the best
people and the brightest people
to come and do public service
both at the FDA, the NIH
and in government, and as
the responsibilities grew,
we were able to streamline
the process
and make career enhancement
more important for people
to join these really important
efforts, and the other thing is
that we built a framework
to better involve
and incorporate patients
in drug development.
You don't bring patients
in at the end,
you bring them in the beginning.
You try to find out trials
that are important to them.
Are they interested
in these trials.
Would they go on them?
And did they enhance
the knowledge?
And are they accessible
to these patients?
This is really incredibly
important.
Patients, it puts patients at
the center of drug development,
and patients first should
always be our mantra,
and I want to thank you and
look forward to our discussions.
>> Tomoko Y. Steen: Well,
thank you so much, Dr. Sigel.
Okay. We have a limited time
because of the beginning
of the technical
issue, but Ashley,
can you read some
of the questions?
>> Ashley Cuffia: Yes, we
do have some questions.
First, is there a way
to tell a cancer to grow
in reverse like an implosion?
>> Tomoko Y. Steen: That's
a interesting question.
Maybe Dr. Weiner can answer.
>> Louis Weiner: Okay, then.
So I think what you're talking
about here is not
necessarily immunotherapy,
but rather targeted therapy.
You'll recall my slide
I showed the smart bomb
that was the targeted therapy.
That's essentially what
you're trying to do there.
You're essentially
shutting down the systems
that the cancer cells need in
order to be able to survive,
and in doing so, those cancer
cells find no alternative,
but to go ahead and die, and so
they melt down, and that's one
of the mechanisms that an
implosion, as you suggest,
is a well-known biology
mechanism called apoptosis,
or programmed cell death, and
there's been an enormous amount
of work over the past quarter
century in developing therapies
that can cause targeted -- you
know, this kind of cell death,
and so while I'm not
sure it fits neatly
into the immunotherapy checkbox,
it certainly is another
approach that's generated a lot
of interest.
>> Tomoko Y. Steen:
Thank you, very much.
Ashley, next question,
>> Ashley Cuffia: What might be
the potential for this therapy
in treating sarcoidosis which is
difficult to diagnose and treat?
>> Tomoko Y. Steen:
Maybe Dr. Allison,
would you kindly answer
this, or Dr. Weiner.
>> James Allison: Weiner
would probably be a better one
to answer that one.
I don't know of any myself.
>> Louis Weiner: No.
I was hoping you're going
to take this one, Jim.
So you know, these are
different difficult challenges
because sarcoidosis isn't
necessarily associated
with mutations or altered
cell states of the type
that can be targeted by
the body's immune system.
So while I think it's
certainly possible
to manipulate the biology
that might lead to sarcoidosis
by going after some of the
underlying molecular mechanisms,
I don't know that the principles
of cancer immunotherapy
are going
to be highly relevant here.
Although some others on the
panel may have other thoughts.
>> Tomoko Y. Steen:
Yeah, that's great.
Next one, please.
>> Ashley Cuffia: Okay.
It seems that we are
finding cancers earlier.
Is this being taken into
account when people claim
that five-year survival
has increased?
>> Tomoko Y. Steen: This can
be again, Dr. Weiner or --
>> Louis Weiner: So there's
good news on all fronts in terms
of the improving survival
rates from cancer.
There's no question that earlier
detection and the development
of more effective early
therapies have combined
to put a dent in the
deaths caused by cancer,
but it's equally true
that improved therapies have
made an important contribution
as well, and from 1990, or there
abouts to the current time,
there's been a dramatic decrease
in the death rates from cancer.
I'll also point out that reduced
smoking has had a lot to do
with this as well,
because the burden
of lung cancer had been quite
enormous in our country.
And I'll also mention,
and this is really a shout
out to Dr. Allison
and colleagues,
the advent of these novel
immunotherapy strategies,
the checkpoint antibodies,
has not even yet begun
to show the impact that they're
going to have on death rates
from cancer, because certain
cancers like melanoma,
as he pointed out, that was
a disease when it spread,
there was maybe a seven month
average survival, and now more
than half the people are living
out their normal lifespans,
it seems or close to that.
And so there's going to be an
indelible impact on survival
as these treatments
for melanoma but also
for even more common diseases
like lung cancer become more
and more well integrated into
our therapeutic armamentarium,
so I think the outlook is
good for continued drops
in cancer mortality, assuming
we can get back ahead of cancer
with respect to getting
people to remember
to get their screening done,
as Dr. Carnival mentioned.
>> Tomoko Y. Steen: Yeah, yeah.
Great. Dr. Allision, would
you like to add something?
>> James Allison: Dr.
Weiner did an excellent job
of answering the question.
There was a study by the
American Cancer Society,
and I think they put
it out that melanoma,
the detection rate is actually
increasing while the death rate
is going down.
So it's just a matter
of numbers right now,
but it'll be a few years
before we see the full impact,
but that doesn't mean --
we still need to worry
a lot about prevention.
>> Tomoko Y. Steen: Yes, yes.
That's true, that's true.
>> James Allison:
[inaudible] been there too.
>> Tomoko Y. Steen: Yeah.
Dr. Trinchieri, maybe
diet issue as well,
so do you have something
you could add?
>> Giogio Trinchieri: Well, I
mean, diet is clearly important
for improving some
response, and diet is clear --
and diet and gene and many other
things, is clearly important
to change the immune system and
the interaction immune system
with cancer is not always good.
I mean, some cancer are
going up because we live
in different way, and we have
different lifestyle, and cancer,
and but I think once
we have cancer,
when we treat the
patient, possibly,
you know, change of life.
Another way is to I mean,
at the end of the day is
the body defending itself
against the cancer, the
immune checkpoint inhibitor
and approach of that is
helping the body to do that,
and it's possible that the
diet and the composition
of microbiota may also
help in this interaction.
>> Tomoko Y. Steen: Yeah.
Japanese has a traditional
[inaudible] diet for cancer, so.
Next question, one
more question.
>> Ashley Cuffia: Okay.
Ten years from now, what do you
think the headline regarding
cancer research will be?
>> Tomoko Y. Steen: That's
for everyone, please.
Maybe start with Dr. Carnival?
Is she out there?
>> Danielle Carnival: Yeah,
just coming back on video.
Yeah. I think for me,
I'll let the experts get
into the specifics of where they
think we will see advancements,
but I think it's not only
the kind of new treatments
and new understanding of cancer,
which I hope will be part
of that headline, but that
we've really reached everyone
in this country with
what we do now.
I think the disparities
around some of the prevention
and early detection and even
treatment access are some
of the biggest barriers we face
and 10 years from now hope,
even sooner than that, we've
made a lot of progress there.
>> Tomoko Y. Steen: Thank you.
Let's go with Dr. Allison.
Would you --
>> James Allison: I think
that what we're going
to see is a more integrated
approach to cancer therapy.
I think immunotherapy is
not going to be all of it.
It's going to be
part of it, I think.
We're going to have to learn how
to put multiple components
together.
Right now we're doing,
you know, doublets.
I think we're going to start
mixing three, four, you know,
different immunological
reagents, but also, as I said,
taking -- using radiation
and chemotherapy as vaccines,
basically, to start an immune
response and things like that.
I think it's going to be just
combinations and recommendations
for diet, and the
disparities to is a very,
really important issue
to getting [inaudible]
to everybody.
>> Tomoko Y. Steen: Wonderful.
Dr. Trinchieri, would you
like to add something?
>> Giogio Trinchieri: Yes.
I mean, if you look
back 10 years,
and we had tried 10 years ago
to predict what happening,
immunotherapy, we are never
being able to predict it.
What we could predict is that
by studying the immune response
in cancer, by studying basic
immunology, and that's applied
to all other areas of
science, metabolism, and so on,
you really end up to
identify a new way
that you couldn't predict
it, so one page is not
to disregard basic science
and where that's bring us,
but the other things that
what was just mentioned,
is that it's important
to cure cancer,
but it's even more
important to prevent cancer,
and even more important to
address all the disparity
that are in different
part of our population
in being affected by cancer.
We've been talking about cancer
prevention for a long time.
We are really not
doing very much yet,
so I hope that would we be
talk more in the next 10 years.
>> Tomoko Y. Steen: Yeah.
Very important.
Thank you.
Dr. Sigal, would you like to
add something from patient?
>> Ellen Sigal: Yes, I think
early detection is coming,
and that's going to
make a huge difference.
We now have multi-panel
cancer tests.
We can detect earlier.
We need to go still earlier,
and then we need to know how
to intervene, and we need
to get to all patients,
and we need to get
to underserved.
We have to get access,
and we have to get
better clinical trials.
We're doing much
better, but we still have
to make them accessible
and meaningful to patients,
so I'm very optimistic,
but we have to prevent,
and if we can't prevent,
we have to detect early.
>> Tomoko Y. Steen: So your
most important ambassador
to the patient in term these
wonderful research is going on,
so Dr. Weiner, would you like
to add a few words, or --
>> Louis Weiner:
Yeah, so I'm going
to just think about
the headline.
I think the headline is going
to be continued investment
in cancer research improves
cancer survival rates to 80% --
>> Tomoko Y. Steen:
Oh, wonderful.
>> Louis Weiner: -- and I
think that's achievable.
I really do.
And I think that that
is only going to happen
if all the things that my
co-panelists described actually
happens, you know?
We have to make scientific
advances.
We have to deal with the
science of disparities.
We have to deal with the
science of prevention
and early detection and improve
therapy, and it's only by,
you know, putting
all that together,
we're going to be successful,
but I think we can get --
we're at around 70% now.
I think we can get
80% [inaudible].
>> Tomoko Y. Steen:
That's wonderful.
On that note, next
slide, please.
Yeah, so I'm sorry, we
couldn't answer every questions,
but we will be happy to reach
out to all these speakers
and answer to your question, so
please send in your question.
Make sure to add
December 6th webinar
so we can prioritize
your question.
Next slide, please.
And this video is going to
be available on the webinar
under the Library of Congress in
few weeks, and I hope, you know,
you can use even classrooms
and spread the word.
It's important for everyone
to know about, you know,
how cancer research is going
on in the [inaudible]
for the patients.
So thank you so much
for all the speakers,
and this was a wonderful webinar
because of the wonderful
presentations
and hope we can do it again
next year, and even sooner,
so thank you so much for the
speakers and also audience.