[MUSIC PLAYING]
Today, I'm going to talk to you about a therapy that
has been developed entirely at this institution.
And the main researcher in this is
my mentor, Dr. Irving Weissman.
And this has been developed completely at this institution
from beginning to end.
So this is truly from the bench to the bedside.
And I happen to be in charge of the central nervous system
component of this effort.
So cancer, we tend to think of cancer as something old people
get.
But it's actually the leading cause of death
that's not due to accidents in children.
There's three main treatments for treatment
of cancer, surgery, chemotherapy, and radiation.
Unfortunately, these treatments have credible side effects,
which are both severe and permanent.
This includes permanent cognitive dysfunction,
permanent damage to the organs, permanent damage to the nerves,
a lifetime of disabilities.
And because they're so young, they
can even get secondary cancers later in life, just
from the treatment alone.
As a pediatric neurosurgeon, I'm particularly
interested in brain tumors.
Brain tumors are the number one solid tumor in children.
They are very difficult to treat because they
are often inoperable.
You can't remove a big tumor from the brain stem.
They tend to be resistant to all therapies.
No matter what you throw at them, they don't respond to.
And they occur in patients who are very,
very young and cannot tolerate the intensive irradiation
and chemotherapies that an adult would be able to tolerate.
And because we're focusing this treatment directly
on the central nervous system, these patients really
pay the price for the cure.
Now chemotherapies and radiation,
they're lifesaving drugs and they're lifesaving treatments.
But the mechanisms through which they work
are such that they're just a little bit more
poisonous to the cancer than they are to the normal cells.
That's why you see all the side effects.
Therefore, it is imperative for us
to develop new treatments that are
both more efficacious against a cancer,
as well as less toxic to the normal human body.
So one of the systems that we could potentially use
is the immune system.
And this makes a lot of sense.
The immune system actually can recognize self
and destroy non-self.
And the immune system actually possesses
the molecular machinery that can recognize a cancer
and attack it and destroy it, while completely
leaving your normal tissue alone.
And again, every cancer is caused by mutations.
So these mutations end up being antigens or non-self entities
that the immune system can react against.
And by some estimates, every single day
about one to seven cancer cells are destroyed
by your immune system.
Now for about four or five decades now,
research into immune therapies for cancers
has focused on two cell types of the immune system, the T-cell
and the B-cells.
Now, this makes sense because these are the actual cells that
possess the molecular machinery that
can actually attack a tumor.
The T-cells, they function in two ways.
One is, they're the generals of the immune system
or the conductors.
They say you go here, you go there.
And the other function they have is a CD8 killer function.
Basically they can touch a cell, recognize it as a cancer,
and boom, kill it.
It's just like the Vulcan death grip.
You're just going down.
The other one are B-cells.
Now, B-cells make little smart missiles.
And like the smart missile can say, oh,
that's the bad person that we're trying to rid of
or that's the building we're trying to destroy.
It can home in on that building specifically.
B-cells make these monoclonal antibodies that specifically
target the things that it recognizes
as non-self, including cancers, and it ends up destroying them.
So I'm going to talk to you about the macrophage.
Now for the most part, immunologically, macrophages
are kind of boring.
They're scavenger cells.
They eat up the old cells.
They eat up the extracellular matrix.
They basically mop up what the B-cells and T-cells destroyed.
They're like foot soldiers of the immune system.
And they actually lack any specific molecular machinery
that can attack a cancer specifically.
Therefore, very few therapies are directed towards them
in order to help them kill cancer cells.
But what I'm going to show you is that the macrophages
are, in fact, not so boring.
And by giving, we'll call it a medicine called anti-CD47,
we can stimulate the boring macrophage
to become a very exciting cell that can attack a cancer
and eat it up.
So what is CD47?
Well, it's a protein.
And it's expressed in a lot of cells.
In fact, most cells express it on the subsurface of its cells.
They are much more higher expressed
in cancer cells than non-cancer cells.
The original mechanisms through which
we have known CD47 works, the CD47
is expressed on red blood cells to protect them
from getting eaten by the macrophages.
And when the red blood cells age, the CD47 goes away.
And then the old red cells get eaten up by macrophages,
so the new red blood cells can replace it.
So mechanistically, CD47, the protein
that expressed on cancer, binds SIRP-alpha on a macrophage.
And this tells the macrophage don't eat me.
It tells the macrophage don't eat me.
And whatever we look at whatever tumor that we looked at,
it has a higher expression of CD47 than even normal cells.
And if we actually look at the tumor stem cells,
they had the highest expression of CD47 on their cell surface.
So how does this work?
So if you focus on the cancer cell, on a cancer cell
it expresses CD47, which tells the macrophages don't eat me.
Now, when we block the CD47 with our anti-CD47,
this disrupts the interaction between CD47 and SIRP-alpha.
The cancer gets eaten because the cancer also has an eat me
signal, that says eat me.
Now, all cancers express the eat me signal.
We haven't found a single cancer yet
that doesn't express the eat me signal.
They are physical properties of a stressed cell.
Every cancer cell is a stressed cell.
So in a normal situation, normal cells have CD47.
But they don't have the eat me signal.
So if you block them, if you block CD47 with the anti-CD47,
normal cells don't get eaten because they
don't have the eat me signal.
Now if they do have the eat me signal,
they need to get eaten anyway.
So that's why we expect the side effect profile to be very low.
Now if you don't remember any of that, just remember this.
If you played Pac-Man before, anti-CD47 is that power pill.
And it turns the cancers into the blue ghosts
so that you can eat them.
So we have actually develop a therapeutic humanized
monoclonal antibody that blocks the CD47, SIRP-alpha
interaction.
We call that the anti-CD47.
It stops the don't eat me signals, allowing macrophages
to eat all cells that express the eat me signals.
So I'm going to show you two types of experiments.
One is the in vitro macrophage eating assays.
We basically take macrophages from humans or mice.
And we take a tumor cell, that we get from a patient
actually, through their very generous donations to us.
And we make the tumor cell glow.
And then we take the tumor cells and expose them
to the macrophages, in the presence
or not in the presence of anti-CD47.
And we simply watch the macrophages eat them up.
These are different types of brain tumors.
And every single brain tumor we throw at it, more
gets eaten when anti-CD47 than not.
Here's a different experiment.
We actually can genetically engineer mice
to accept all human tissue.
So we take tumors and we inject them
into the mice that can receive human tissues.
And before we injected the tumors into the mice,
we genetically engineered the tumor cells to glow light.
So we could follow tumor growth by following
the light that gets emitted from their brains after they grow.
So after we confirmed that the tumor has
grown by looking at the light, we simply either
give them anti-CD47 or we give them no anti-CD47.
This is adult glioblastoma.
This is everything you think of when you
think of a deadly brain tumor.
It is absolutely uncurable.
We can take it all out and it will still get you.
But when you give anti-CD47, it completely
gets eradicated in the mice.
This is pediatric glioblastoma, the same thing.
You give anti-CD47, the tumor goes away.
This is c-myc amplified meduloblastoma, actually
one of the most deadly solid brain tumors in a child.
And it's one of the most common.
We give the mice the meduloblastoma from the patient
and it gets both the brain tumor and the spinal metastasis.
If you give anti-CD47, the brain tumors go away
and the spinal metastasis goes away.
And if you give anti-CD47, all the mice that get it live.
All the mice that don't get it succumb to the disease.
So here's a picture.
On the left is a tumor that did not receive anti-CD47.
As you can see, there's no macrophages inside of it.
But on the right, the brown staining of the macrophage,
this tumor had received anti-CD47.
We took it out of the mouse in the middle of treatment.
And you can see it is just infiltrated with macrophages
eating the tumors.
These are brains from mice.
At the top, if you look in the circles,
you can see that the back of the brain, where the tumor is,
is very swollen.
But in the mice that received anti-CD47,
the anatomy is perfect
So now, again, we want to treatment
that saves normal cells, but then hurts only the cancer
cells.
Correct?
So what we did is we actually exposed
normal human neural stem cells to the anti-CD47.
And you see the top graph.
We watched them proliferate over time.
No matter how much anti-CD47 we threw at them,
it didn't hurt them at all in the culture.
And we actually did macrophage assays
against normal cells, both differentiated neurons,
astrocytes, and oligodendrocytes,
mature cells of the brain system, as well the stem cells.
The addition of anti-CD47 did not
increase phagocytosis of these cells at all.
But here's what I think is a really good test.
What we did is we took normal neural stem cells
and we made them glow light.
Then we injected them into the pups of the mice that
can receive human tissue.
Then we waited for the normal neural stem
cells to grow into tissues.
More light, OK.
Once we established that there was plenty of light growth,
we then put a tumor on top of that.
And then we gave some anti-CD47 and some not.
Now if there was what we call a bystander effect, where,
in the presence of tumor killing we're killing off normal cells,
we would see the light go away.
But we do not.
The light does not go away from the normal neural stem cells
when we hit them with anti-CD47 in the presence of the tumor.
And, in fact, it continues to grow.
Now, which mice received anti-CD47?
Let's see if we can make this work.
You tell me.
Whoop.
Well, I guess it's not going to work.
That's OK.
Anyway, the mice that received anti-CD47, they're healthy.
They're playing.
They're doing their normal thing.
The mice that didn't receive anti-CD47,
they look fairly ill.
Now, it just doesn't work in brain tumors.
These are all the tumors we've tested.
And not a single one of them has been
resistant to this treatment.
And they were tested in the same vigorous way that I showed you.
The ones in the red are the pediatric brain tumors.
And the ones in the blue have been tested
in both pediatrics and adults.
Toxicity studies, these monkeys have the exact same CD47
sequence as humans.
They were given huge doses of CD47
and there was absolutely no dose-limiting toxicity.
The only thing we did see was a slight dip in the red blood
cell count because that's the normal biology of what
CD47 is used to clear them.
But what we learned is that if you
give a little dose of anti-CD47 first,
that the body will respond by kicking out
a whole bunch of new red blood cells.
And then we gave 30 times the amount of dose of anti-CD47
we would expect to be therapeutic.
So 30 times the therapeutic dose and absolutely no anemia.
So the only known side effect of anti-CD47, the treatment of it,
is just a little dose of anti-CD47 first.
So that's pretty cool.
So we are developing this antibody for clinical use.
In fact, 1,000 liters of it has been
made in a way that's suitable to be given to humans.
And so this is a 1,000 liter tank.
It's not really the tank that it's being made in.
This is the tank.
But I think this tank is funner.
So where are we at?
We are currently in adult phase I clinical trials,
where adults with any solid tumor
is eligible for the trial.
We're in the middle of the trial.
And we expect to start the pediatric brain tumor
trial in the first or second quarter of 2016.
So that's not that far away where
kids are going to start getting this treatment.
Again, this is just to review.
Phase I, is it toxic?
Phase II, does it work?
Phase III, does it work against the current treatment
in a formal clinical experiment?
So we're at the phase I stage.
But we're very hopeful that we can progress along to the phase
III as rapidly as possible.
So a therapy has been developed blocking CD47 on cancer cells,
causing them to be eaten by macrophages.
Normal tissues are completely spared.
It has potent activities against most cancer types,
including every malignant pediatric brain tumor
that we've tested to date.
There is no dose-limiting toxicity.
Clinical trials in patients are occurring.
And in the pediatric patients it will be in less than a year.
And actually we believe that this therapy
is going to make every other immune therapy against cancer
even more effective.
So currently in the lab we're combining immune therapies.
And we can already see that it works even better
with the other combinations.
So my dream is someday we won't have to do
radiation and chemotherapy.
We can just give anti-CD47 and some other immune therapy
and it'll take care of the cancer
without all the bad side effects.
Thank you.
[APPLAUSE]