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Tumor-targeting
antibody treatment is an established treatment in cancer and is commonly used
in clinic. Antibodies (Ab) are proteins that bind to antigens and are produced
by immune cells called plasma cells. Antigens are proteins from either pathogens
or in this case tumor cells that are not regularly produced in the body, or in
some cases of tumor antigens, are normal proteins being produced in the wrong
place or at the wrong time in the body. Tumor-targeting antibody treatments
work by producing antibodies that specifically target tumor antigens so that
the Ab binds only to tumor cells to allow for localized treatment. This is
beneficial as treatments for tumor that are not localized can cause damage to
cells besides tumor cells which can cause health issues for the patient. The
current FDA approved tumor-targeting antibody treatments interfere with tumor
cell signaling1,2. This works by using antibodies that bind to
receptors on tumor cells that thus block cell signaling which then triggers the
cells to undergo apoptosis, programmed cell death. This paper focuses on
utilizing the other functions of antibodies to enhance tumor-targeting antibody
treatment. Antibodies can activate complement which is a bunch of proteins in
the blood that can result in priming pathogens among other things for
phagocytosis (engulfment) by certain immune cells. Complement activation by
antibodies can also result in complement dependent cell-cytotoxicity, which
results in lysis of the targeting cell, in this case the tumor cell3.
Antibodies can also activate natural killer cells (NK), macrophages, and
neutrophils by binding to Fc receptors (FcR) on the membranes of these cells4,5.
Antibodies are comprised of a region that binds to the antigen (variable
region) and a region that is constant among all antibodies that does not
participate in the binding of antigen (constant region). The FcR binds to the
constant region. The activation of these cells can lead to antibody-dependent
cell-cytotoxicity (ADCC), antibody-dependent cell phagocytosis (ADCP), and
production of cytokines and chemokines to alter the microenvironment of the
tumor6,7. ADCC is when the binding of antibodies to the FcR on these
cells ‘arms’ them to kill cells that have the antigen that the antibody binds to.
ADCP is when the antibody binding to the FcR on these cells primes them to
phagocytose the cells targeted by the antibody. The study focuses on these
functions of antibodies can be exploited to treat tumors rather than disrupting
cell signaling and how these treatments can be improved by the addition of
compounds that increase the adaptive and innate immune response.
(for a cool video explanation of antibodies by nature video go here:
(for a fun musical explanation of antibodies by some college students at Stanford go here:
TA99
is a mouse Ab that binds to Trp1 which is expressed on the surface of some
tumor cells and isn’t involved in cell signaling so TA99’s therapeutic effects
are not due to its direct disruption of cell signaling. Treatment with TA99
alone has been shown to be successful in preventing tumor growth when
administered to mice at the same time as tumor cells were introduced into the
mice8,9,10,11,12. However, it did not show significant therapeutic
effects when a solid tumor was already present13. Thus, the
researcher in this study set out to see if the addition of TLR agonists as well
as other immune system stimulating molecules would increase the therapeutic
effects of TA99 in the case of solid tumors. TLR agonists stimulate TLRs
(toll-like receptors) on immune cells which can stimulate them and activate
certain functions depending on the cell. TLR agonists have been shown to
stimulate both innate and adaptive immune responses and have been shown to
induce tumor clearance in some treatments14,15,16,17. The innate
immune system consists of cells that can bind to antigen and become activated
whereas the adaptive response consists of cells that require the antigen to be
processed and presented by other immune cells before activating. The
researchers treated mice that had an aggressive melanoma, meaning fast growing
and spreads rapidly, with TA99 and in some of the mice they applied a cream to
a shaven area of skin that contained imiquimod (a TLR agonist) and IL-2 (which
promotes the development of T-cells which are a part of the adaptive response).
The mice that received the cream had an increased rate of survival than mice
that received TA99 alone. They tried this same procedure but instead of using
imiquimod they used a different TLR agonist to see if different TLRs could
increase survival or if only imiquimod would work. They again saw increased
survival rate in mice that had received the cream compared to those that
didn’t. They also did a trial in which an agonistic CD40ab was in the cream,
CD40 is known to stimulate innate and adaptive immunity so an agonistic ab
would increase its function. This trial also showed increased survival rate in
mice that received the cream. These trials showed that the treatment of the
antibody TA99 has significantly higher therapeutic efficacy when administered
in conjunction with TLRs and compounds that promote innate and adaptive immune
activation like IL-2 and CD40ab. Therapeutic efficacy refers to the treatments
ability to produce and effect that in this case, prolongs the survival of the
mouse by reducing tumor size.
Once
they identified that increased adaptive function increased the therapeutic
efficacy of the treatment the researchers set out to determine if the increased
efficacy depends on CD8+ T-cells. CD8+ T-cells (cytotoxic T-cells) serve the
function of killing infected cells and tumor cells through multiple mechanisms.
To determine if these cells are important for therapeutic efficacy, they
treated mice with TA99 along with imiquimod and IL-2, the mice were either
normal mice, had no CD8+ T-cells, or no CD4+ T-cells (another branch of the
adaptive response). The therapeutic efficacy of the treatment only decreased in
mice that had no CD8+ T-cells so this showed that the treatment depended on the
function of these cells.
The
researchers also tested to see if the innate immune response was important in
the therapeutic efficacy. They did this by blocking the FcR receptors on innate
immune cells (macrophages, NK, neutrophils) so that these cells could not be
activated by the TA99 treatment. Blocking of the FcR receptors resulted in
decreased therapeutic efficacy thus showing that the therapeutic efficacy of the
treatment is also dependent on the innate response as well as the adaptive.
Although imiquimod is known to increase levels of NK cells around the tumor,
when the researchers tested the treatment on mice that had no NK cells the
therapeutic efficacy of the treatment decreased but was not fully gone. When
the researchers depleted macrophages in some of the mice, these mice showed
decreased survival than normal mice when both received the treatment with TA99,
imiquimod, and IL-2. This shows that macrophages are important for the
therapeutic efficacy of the treatment.
The
research in this paper showed that tumor-targeting antibody treatments, that
are not focused on disrupting cell signaling, can be improved by cotreatment
with TLR agonists and other molecules that stimulate the adaptive and innate
immune response. They showed that both adaptive cells (CD8+ T-cells) and innate
cells (NK cells and macrophages) are important to the therapeutic efficacy of
the treatment. This allows us to understand the mechanisms by which that the
treatment works. The fact that these cells are the underlying mechanisms behind
why the treatment works show that the functions of antibodies discussed at the
beginning of the post are being utilized. The importance of this paper is that
through combining tumor-targeting antibodies with molecules like imiquimod and
IL-2 we can significantly increase the effectiveness of the antibody treatment
even against aggressive cancers like the melanoma used. This information could
be used to produce new tumor-targeting antibody treatments that can effectively
treat solid tumors to increase the repertoire of physicians beyond the current
FDA approved treatments.
References
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