What is immunotherapy? What immunotherapy options are currently available for acute myeloid leukemia?

What is immunotherapy?

So immunotherapy is obviously a very hot

topic for cancer in general,

and AML is no exception,
although I think AML is not as far along

with respect to successful immunotherapy
approaches as, say, other cancers,

perhaps such as melanoma or lung cancer,

but immunotherapy and AML,
I guess the gold standard

for immunotherapy would be bone
marrow transplant,

where a patient receives
a brand new population of bone

marrow stem cells from a healthy donor
and that stem cell population recreates

a brand new immune system
that is responsible for

fighting off and destroying any leftover
leukemia cells in the patient.

And that's felt to be related to

something called graft versus
leukemia effect, which is where the donor

immune system
basically recognizes the host cells,

the host's AML cells, as being foreign
and helps to eliminate them.

So that's

probably the the current definition

of the ultimate type of immunotherapy
is bone marrow transplant,

where you get an entirely new immune
system.

Other immunotherapy approaches
include things like monoclonal antibodies,

where you have an antibody
that is developed

and it targets
or it attacks a specific type of cell

that contains a protein
that the antibody recognizes.

So the main drug that we have approved for
AML is called gemtuzumab or Mylotarg,

and that is an antibody that recognizes
something called CD33,

which is seen on the surface
of the AML cells very often.

So the antibody basically recognizes a
CD33 latches onto it and then it delivers

what's considered a payload or a toxin

into the cell after it
attaches to the cell and kills the cell.

So that type of therapy has been

moderately successful in AML, most often

in combination with other drugs,
not necessarily by itself.

There are other antibody drug conjugates
that are being developed

that go after other targets,
such as CD 123.

So there are trials right now
that are looking at CD 123 antibody drug

conjugates either alone or in combination
with other types of chemotherapy

to help augment
the overall effect of chemotherapy.

By adding this antibody component,

we also have something called bispecific

antibodies, which are a little bit
of a different type of antibody

based therapy
in the case of bispecific antibodies,

you have an antibody that basically
recognizes two different things.

It recognizes
a target on the leukemia cell,

and it also recognizes a target on
the immune system cell such as a T cell.

And it brings those to the antibody
kind of links those cells

and kind of brings them into close
proximity wouldn't be achieved otherwise.

And by having this t cell close
by to the leukemia cell, it's felt

that that helps the t cell directly

induce leukemia cell death

through the release of various chemicals
and cytokines

that are based upon
the close proximity of those two cells.

There are other types of antibody

therapies being developed, that block
certain signals on the leukemia cells

that protect the leukemia cells
from the immune system.

So by blocking these,
these do not eat me signals, so to speak.

This antibody
can sort of turn on the immune system

in a way that now allows the immune system
to recognize the leukemia

cell and engulf and destroy it,
whereas otherwise it would be protected.

Are there any immunotherapies
currently available for AML?

I was blessed at Memorial
Sloan-Kettering Cancer Center

to be one of the first
to talk about immunotherapy

targeting, specifically

complications after allogeneic
stem cell transplantation,

a one of the disease that initially

that initially develops
after transplant is an EBV derived post

Transplantation
Proliferative disorder, or EBV-PTLD,

which has been very lethal
within a very short time period.

And we really had no drugs in the
early stage to treat this complication.

And then we found out
that the administration of donor

T cells or donor lymphocyte
infusions could control effectively

the disease, the EBV-PTLD,

the donor lymphocyte infusions
basically were

the birth of immunotherapies.

So now we know in more detail
than 20 years ago that specifically

that some of the T cells
can specifically recognize a tumor cell.

Nowadays
we can generate T cells in the laboratory

or modify T cells
to specifically genetically modified

T cells
to specifically recognize a tumor cell.

And the platform for
that is the car T cells.

Now we have a monoclonal antibody
genetically introduced into a T cell,

and with that the antibody can bind

to the tumor cell and bring the T cell
to the site of the tumor cell.

So that is the prime example
of of immunotherapies.

For acute myeloid leukemia,
we talked about this before a little bit.

It's complicated
because the the target of the car

T cells would be the CD33, for example.

That is also expressed
on the healthy hematopoietic stem cell.

Therefore,
we need to come up with novel approaches

to achieve a remission in patients

with AML by car T cells.

The way to do this is to downregulate

or silence the expression of CD33
on the normal hematopoietic stem cell.

Transplant the patient with CD33 negative
stem cell product Let them engraft.

Then we can treat patients
specifically targeting CD33

with donor derived CAR-T cells,

because the leukemia cells also
are the only ones that then express CD33.

First step we’ll collect
the stem cells from the donor.

We purify the stem cells,
which we do in the laboratory

by selecting all the,
the stem cells by CD34

selection, depleting
all the other cells that are left.

So you have a 99% pure population

of normal hematopoietic stem cells.

We'll send them to a different laboratory
to downregulate by CRISPR technology.

The CD33 expression, then you end up with
a CD33 negative stem cell

product
that gets infused into the patient.

They engraft the CD33 negative stem cells

have a normal immune reconstitution

and then you can come in
with specifically targeting

CD33 expressing cells

which are only the leukemia
cells left that have the CD33 molecule