There are a number of ways of harnessing the immune
system to attack tumors - non-specific immunotherapy,
the use of other types of monoclonal antibodies,
cell transfer, gene therapy and vaccines.
Looking at non-specific immunotherapy, there are a number of
agents that are very beneficial in the treatment of tumors.
Interferon-α is used in the treatment
of AIDS-related Kaposi sarcoma,
hairy cell leukemia, chronic myelogenous leukemia and melanoma.
Interleukin-2 has utility in the treatment
of renal cell carcinoma and melanomas.
And BCG can be used in the treatment of
melanoma, superficial bladder carcinoma,
acute myeloblastic leukemia, ovarian
carcinoma and Non-Hodgkin lymphoma.
Here are some examples of monoclonal
antibodies used for the treatment of cancer.
I’m not going to read
through this whole list.
You can see yourself that these
various monoclonal antibodies can
target molecules such as VEGF, RANKL,
GD2, CTLA-4, PD-1 and so forth.
We’ve already mentioned PD-1.
So as you can see, there are a variety of different monoclonal
antibodies that are available targeting
a number of different molecules.
And these have been approved by the FDA
for use in a variety of different tumors.
As well as using antibodies on their own to fight tumors,
for example by blocking the interaction between PD-1 and PD-L1.
One can use monoclonals to deliver
a toxic molecule to the tumor.
And we have three examples here.
Brentuximab vedotin is a monoclonal
antibody that is targeted to
CD30 which is present on the surface of a number of tumor cells.
And this antibody is conjugated to monomethyl
auristatin E, which is an antimitotic agent.
So the antibody delivers specifically to the tumor because
the tumor cell has this molecule CD30 on its cell surface.
The antibody acts to target the
antimitotic agent to the tumor cell.
This has been approved for use in Hodgkin
lymphoma and in anaplastic large cell lymphoma.
Ibritumomab tiuxetan targets CD20.
In this case the monoclonal antibody is
coupled with a radioactive isotope, yttrium90.
This is approved for use in
B-cell non-Hodgkin lymphoma.
Denileukin diftitox targets CD25.
CD25 is the α-chain of the
And this particular agent is a combination of interleukin-2
which will bind to its receptor CD25 with diphtheria toxin.
This is approved for use in
cutaneous T-cell lymphoma.
Normally the two antigen binding arms of an antibody
molecule are absolutely identical to each other.
They bind exactly the same antigen.
However in the laboratory, you can create
an artificial antibody where one arm has
specificity for one antigen and the other arm
has specificity for a different antigen.
And here we can see on normal
healthy cells, one cell type has one
particular antigen and another cell
type has a different type of antigen.
However on some tumor cells,
both antigens will be expressed.
And it’s only on the tumor cell that
both of these antigens are expressed.
On normal cells they’ll either have one antigen
or they’ll have the other but not both.
This characteristic of tumor cells can be capitalized upon
by using bispecific monoclonal antibodies that bind to
both of these molecules, and therefore will bind more
strongly to the tumor cells using this synergistic binding.
An alternative approach using
bispecific antibodies is to have one
arm of the antibody specific for a
tumor antigen, and the other arm
specific for something like CD8
that’s present on a cytotoxic T-cell,
enforcing an interaction between the
cytotoxic cell and the tumor cell.
Adoptive cell transfer is a term used for
the transfer of lymphocytes into a patient.
So here we have a tumor bearing patient,
and one can isolate lymphocytes from either
the blood of this patient or from the
lymphocytes that are infiltrating the tumor.
Having taken these tumor specific
lymphocytes out of the patient, one
can expand these in culture, using
cytokines such as interleukin-2.
So maybe the patient is making an immune
response to the tumor but it’s inadequate.
There simply aren’t enough anti-tumor cells
there to do the jobs that-- job that’s needed.
So take the cells out and grow them
up, so you have a much greater number.
You could also transfect these cells.
For example, with a CAR gene.
Now CAR stands for
chimeric antigen receptor.
And these chimeric antigen receptors can be
generated so that they will recognize tumor antigens.
For example, here we have a antibody
based chimeric antigen receptor with
the Variable region from the heavy chain
of an antibody, and the Variable
chain of-- the Variable region of the
light chain linked together into what
is called a single chain Fb, and
that is recognizing a tumor antigen.
This chimeric antigen receptor can
have ITAMs linked to it and other
desirable sequences linked to help
in causing death of the tumor cell.
So expanding up these tumor
infiltrating lymphocytes or lymphocytes
in the peripheral blood, perhaps transfecting them with a CAR.
And then transferring those cells back into the patient can
help the immune system, give it a helping hand if you like,
by expanding up the number of cells and modifying them in
various ways, can help these T-cells to cause tumor regression.