- Good morning, and thank
you again for coming.
What I'm going to talk about
right now is a couple of topics.
First I'm going to introduce you
to my favorite cell in the world.
This is a CD8 T cell.
This is what my laboratory studies.
These are the cells that
are probably most important
actually, certainly most
important in cancer immunology.
I'm going to talk to you about some ways
to make these T cells
within tumors get activated
and I'm going to talk to you
about some more technologies
to activate these T cells outside
of the body and then put them back in
in order to kill tumor cells.
Finally, at the end I'll talk
about two very relevant and timely topics.
One is the idea of giving
two immunotherapies together.
We're fortunate to have Dr. Wolchok here.
He's a pioneer in this in melanoma
and we'll talk about how it works.
We'll talk a little bit
about the side effects, too
and then finally, I'll talk to you
about a topic called biomarkers
that is how can we
choose the right patients
for the right drugs, and then
also how can we make progress?
How can we go forward in this field
to design new and better therapies?
This beautiful orange cell
on your left is a T cell.
T cells circulate in your blood.
When they're activated, they
can go anywhere in your body.
They can go into the brain
they can actually go into the bone marrow.
What these T cells were designed
or evolved to do is to
kill infected cells.
They have multiple ways to do this.
A simple way is they
just poke holes in it
but a more interesting way is what they do
is they send signals to the target cell
to tell it to commit suicide.
They're the death whisperer.
Basically, those little blebs
those are called apoptotic blebs.
This T cell has told this tumor cell
to give it up, it's over, commit suicide.
It's interesting, T cells can kill cells
that chemotherapy cannot kill, actually.
There's really no cell that
seems to be totally resistant
to T cell killing, with
a few small exceptions.
These are cells, we love
these cells, and it turns out
if you look at tumors, lots of
tumors have T cells in them.
This is a clear cell kidney cancer.
You can tell because the
cancer cells are clear, right?
And these brown markings
are markings of T cells.
This is a tumor that's
filled with T cells
and the reason we have
this biopsy on this patient
is not because the tumor is shrinking
it's because it's growing.
This is a patient with kidney
cancer's original biopsy
and it's full with T cells, but
the T cells are not killing.
The major advances in the
field of immunotherapy
have come about from understanding
why they're not killing,
and this is kind of why.
We're going to take a
little time on this slide
walk you through it and show you it
a couple of different ways.
This is a CD8 T cell
that's come into the tumor.
T cells are so powerful, right?
I mean, they can kill anything
so your body designed
ways to turn them off.
One of the ways they turn off is
by building this molecule called PD-1
and whenever a T cell gets
into a tissue or into a tumor
it puts on PD-1 so that it
can be turned off, right?
Can be turned off.
Tumors have figured this out
and they learn to express the foot.
The foot that goes on the
brake, that's called PDL-1.
What happens is a T cell
comes into the tumor
the tumor feels like it's under attack
and it expresses PDL-1.
The T cell's in there,
it's trying to kill
but it can't cause there's PD-1
and that's a sort of a
quasi-stable interaction.
We call these T cells in tumors
that are not killing,
exhausted, so they're there.
What's interesting is they don't just die.
They kind of sit there
like I just showed you
in the last picture.
There's tumors that are full of T cells
T cells have PD-1, and
they're being turned off
so can you do anything about this?
The answer is yes, that's a
little bit why we're here.
It turns out that if you
block the interaction
between the brake and
the foot on the brake
between PD-1 and PDL-1 with drugs
usually they're called antibodies
then you can get the T cell
to restore its function.
It can come back to life, actually
and if you're lucky,
and in certain patients
these T cells can kill the tumor cells
leading to tumor shrinkage
and occasionally really nice responses.
Another way to think about
that is not so complicated.
In many tumors these exhausted cells
if you block that exhaustion
with PD-1 or PDL-1
their function is restored
and we know this happens, actually.
We have data in patients, real live data
showing that this happens,
and I'll show you some
of those data, not a
lot, just a little bit.
These are patients with kidney cancer
treated with anti-PD-1.
The way this graph works
is each line is a person.
These are real live people.
These are patients treated
on a clinical trial
the first clinical trials of anti-PD-1.
These are kidney cancer patients.
We start out with your
basis tumor as a zero.
That doesn't mean there's no tumor.
That means that's what it starts as, zero.
If it goes up, that means the tumor grows.
If your line goes down, that
means the tumor shrinks.
That's how these graphs are made.
These are individual
patients, tumors being treated
with immunotherapy in clinical trials.
You can see from this
image that not everybody
these drugs don't work for everybody.
I think it's important
for us to be realistic
and to understand the
challenges go forward.
In some patients, you
give them these drugs
you block the PD-1 or PDL-1
or the tumor just keeps growing.
That's unfortunate, but that's how
it doesn't work in everyone.
Some patients, though,
are reasonably fortunate
in that the T cells are poised to kill
and when you block PD-1 or PDL-1
those tumors shrink and
they shrink quick, actually
and that's what we want
to happen to everyone.
What's interesting. too, is many patients
have neither of those.
Many patients have their tumors go
into this long-term stable state.
And you might think like,
that's not a good thing
but you'd be wrong, actually.
Data show that patients who develop
long-term stable disease
do amazingly well.
They do almost as well as
if their tumor had shrunk.
Long-term stable disease,
at least in kidney
and bladder cancer, is a
very good thing, actually.
What's also amazing about this graph
and this is one of the things
that the field doesn't understand
is this was a trial
when we stopped treating
after about two years,
so these are patients
who stop getting immunotherapy
and their cancers didn't
grow any more, actually.
This is a property of the
immune system called memory
and you're probably familiar with this.
That's why you get a vaccine, right?
You get a vaccine to make immune memory
so that when you encounter that antigen
or that target again, your
immune system remembers it
and it fights it stronger
and better, actually.
We think that some of these patients
might have immunological memory.
That is, their tumor remembers
the immune system remembers the tumor.
Just to point out that this
is not just lines on a graph
these are real live patients,
this is a patient of mine.
This is a patient in 2002,
a very, very long time ago
had primary surgery to
take out a kidney tumor.
He only had cancer in his kidney
so the idea is if you do that
that can cure some of the patients.
Unfortunately for him, it
didn't cure his kidney cancer.
It came back about two years
later with multiple lesions
and he was treated on
several clinical trials.
When he saw me in 2007, early 2008
he had multiple metastatic lesions.
Easy to see on CT scan, not so great
for the patient in the
lungs, even in the bones
and also in the muscles in the back.
I'll show you a picture of that.
He, Brian will later on tell
you about clinical trials.
This patient enrolled in
the first clinical trial
of an anti-PD-1 immunotherapy
and he was actually the
first kidney cancer patient
ever treated with anti-PD-1 in this trial.
When he started treatment,
he had cancer every place
in the body, but this
is a beautiful lesion
not for him, but it's easy to measure
in the musculature of his back.
Two months after his original
treatment, that had shrunk.
We actually did a biopsy.
We couldn't find any tumor cells
and by July of that year
he had no viable tumor.
This was an early trial.
At this point we were very nervous
that immunotherapy would
cause adverse effects
autoimmunity, and so we stopped
stopped treating that, actually
and he went on to develop
a complete response.
He was last seen in early
this year, actually.
He's been off treatment now
and tumor-free for about nine years.
He didn't have a lot of adverse events
and they've all since resolved.
I need to emphasize very clearly
that this is not everyone, OK?
This is not everyone, this is
a small fraction of patients
but we do want it to be everyone
and that's the purpose
of a lot of the research
that you'll hear about later on, actually.
This is the patients who
develop immunologic memory.
Some of these patients
are still doing alive
and well off treatment many years later
so again the idea that the
immune system can remember.
Chemotherapy doesn't remember, OK
so chemotherapy doesn't
remember, so this is a difference
between immunotherapy and chemotherapy.
Are there any other ways besides
blocking those checkpoints
to help the immune system
recognize and kill cancer cells?
One way is if you look at this tumor
there are a lot of immune cells
but they're not working, right?
Maybe you could do something
to these immune cells
not in the body but maybe out of the body
to help them come back to life
and regain the ability
to kill tumor cells.
This is an approach called
adoptive T cell therapy.
This is used occasionally in melanoma
kidney cancer, other tumor types.
The idea is that you take
the tumor, you chop it up
frankly you chop it up, and
you isolate the immune cells
and then you grow them up over time
typically two to six weeks or so
until they're really activated,
really very functional
and then what you do is you
put them back into the patient.
This is done, again,
for melanoma at the NIH.
It's called adoptive T cell therapy.
It's really fairly nonspecific.
You just grow up many of the immune cells
and then put them back in.
There's a more advanced approach
probably you've heard of
it, we'll ask Dr. Diefenbach
to tell us a little bit about it later on
but it's called chimeric antigen receptor.
When you look at those
T cells in the tumor
some of them are specific for the tumor.
Some of them are not
specific for the tumor.
Some of them are really beautiful cells.
They're high affinity, ready to kill.
Eh, some of them are weak,
not so high affinity.
Can you take T cells and make them better?
Not just more of them,
but make them better.
The idea here is to reprogram that T cell
so that it can specifically recognize
a tumor target with high affinity.
This approach is called
chimeric antigen receptor.
You replace the T cell receptor
with this really simple
high affinity triggering molecule
so that these T cells can kill tumors.
This was recently approved
for some hematologics
malignancies, some blood cancers.
This is a patient in the
New York Times treated
with chimeric antigen T
cells who actually looks
like she's probably been
cured of her hematologic
or her blood cancer at this point.
Those are two ways to try to
make the T cells in the tumor
better, stronger, faster, by
taking them out of the body.
Some tumors, and I
specifically showed you this
some tumors are beautifully full
of immune cells, and
some are not, actually.
If there are not a lot of
immune cells in the tumor
we're in a little tiny
bit of trouble, right?
There's nothing for
PD-1 or PDL-1 to block.
We can't take these cells out
and make them better, stronger, faster
so there's other approaches to try
to bring immune cells into tumors.
One way that we sometimes talk about this
and you'll hear probably on the panel
is these are hot tumors, right?
They're full of immune cells,
and these are colder tumors.
Is there anything that we
can do to make a colder tumor
hotter so that the immune
system can have a better chance
of attacking or killing the tumor cells?
There is, actually, I just showed you
when I showed you the picture of the tumor
in the immune cells, I made
it kind of simple, right?
There's a tumor, there's immune cell.
It turns out that that tumor is full
of lots of different cells.
There's another kind of cell in there
that's a bad immune cell, it's
an evil regulatory T cell.
These cells turn off
our friendly CD8 cells.
These cells express on them
a molecule called CTLA-4
so what if you gave two kinds
of immunotherapy, right?
What if you gave anti-PD-1 or PDL-1
to get these CD8s
activated, to take your foot
off the brakes, and what
if you did something
about these evil regulatory
T cells with another drug?
There is, in fact, such a drug.
There's a drug that targets CTLA-4
and maybe eliminates
that regulatory function.
Dr. Wolchok is a pioneer in this field.
What I can tell you though, first of all
you can imagine if you do these two things
to activate the immune system
the immune system might get a
little bit more out of hand
might get a little bit more overactive
and you might see more
immune-related adverse events
and in fact that's what happens.
If you give these two immune drugs
you see more inflammation of the gut
we call that colitis, more rashes
more inflammation of the joints
all those things become reasonably common.
But on the plus side, what happens is most
of the patients have a response, actually.
This is a critical paper published
in The New England Journal of Medicine.
These are melanoma patients
treated with the combination
of anti-PD-1 or anti-CTLA-4,
combination immunotherapy
and you can see that
most of these patients
have their tumors shrink and shrink quick
so this is a good thing,
and this is now a standard
of care for melanoma and
for kidney cancer, as well.
That's a combination immunotherapy
and that's where the
field is going, actually
and that's a lot of the
research that Dr. Tormey
was talking about, actually
is what are the best
combination immunotherapies.
But what is the best
combination immunotherapy?
Probably not the same for everyone, right?
Different patients have
different things happening
in their tumors, and as I told you
maybe not everybody needs
combination immunotherapy.
There's a concept called a biomarker.
What a biomarker usually
means to us is we're trying
to take a look at the
tumor and try to predict
what kind of therapy that
patient might or might not need.
We, there's another word for
this is predictive biomarkers
and I'll show you a quick example of that.
Say we take a patient and
we biopsy their tumor
and it's full of T cells, and
it's full of PD-1 or PDL-1.
Then we can maybe just
give anti-PD-1 alone.
Maybe that's all that person needs.
We can spare 'em the side effects
of combination treatment,
maybe have a nice response.
Maybe we look in the tumor
and there's another molecule.
Maybe there's a molecule,
and I'll give you a name
LAG-3, so maybe those patients need
to have anti-PD-1 plus anti-LAG-3.
Maybe they need a combination
and maybe that's the
combination they need, right?
Some patients, maybe
they have cold tumors.
Maybe they need a vaccine
or they need a different
kind of combination.
That's the idea of predictive biomarkers
and this is a thing, OK?
For both bladder cancer
and for lung cancer
for first-line treatment, we
generally only give these drugs
to patients who look like
they're going to work it.
We look in the tumor and
we see if there's PDL-1
we see if there's T cells,
and if there's PD-1, PDL-1
and T cells, then those are the patients
that should probably get
first line immunotherapy
for kidney cancer, excuse me
for bladder cancer and for lung cancer.
PDL-1 expression, you might hear this
somebody with lung cancer
gets their tumor tested
it's PDL-1 positive, that's a good thing.
They go on an anti-PD-1 drug
then maybe the tumor shrinks, actually
so it's a pretty good biomarker.
But I told you before we
don't know all the biomarkers.
There's a lot of things
that we don't know
so how are we going to figure this out?
Brian will talk later
about clinical trials
but most of our clinical
trials now include the idea
that we got to get a biopsy of the tumor.
It's not just for fun, OK?
The biopsy of the tumor is so
that we can try to figure out
new biomarkers and try to
understand who responds
to the drug and who doesn't
respond to the drug.
I particularly pick lung cancer
because this is not just
for clinical trials.
This is for standard of care.
If your lung cancer
does not express PDL-1
you're not supposed to get treated
with these kinds of drugs, and
so that's why we do biopsies.
Where is the field going?
It's kind of complicated.
There are multiple
molecules on those T cells
that probably are turning them off.
Interestingly enough,
they also have gas pedals.
The T cells also have molecules
on them that you could push
to make the T cells go faster
to kill better, stronger
and that's these, some of
these molecules over here.
That microenvironment I talked about
and I made it even a little
bit more complicated
but basically we show that there's
in that microenvironment
there's lots of other things.
You don't have to memorize
these names or write them down
but there's a lot of
other things that turn
off the immune system
that are being tested
in the clinical trials that
Brian will talk about later.
But it's a promising time, as Joe said.
I mean, we have good responses
to either PD-1 based therapy
or combination therapy in many tumor types
and trying to move the field forward.
