new type of therapy has emerged during the past ten years: the immune
checkpoint therapies. The efficacy of such treatments has been proven in several
cancers. An immune checkpoint is a security check for an immune cell. It is a
switch that will turn the cell on or off. These
therapies would not have been possible without the development, during the last
twenty years, of monoclonal antibodies. Those antibodies look like the usual one
produced naturally by our body, but they are designed to aim a specific target
on the cell membrane. These particular antibodies play the role of an adhesive
tape that you would put on the switch in order to keep it on a “on” or “off”
position. Nowadays, those molecules are on trial tests for use in other
Ying and yang
There are several types of cancer which
can be classified in two categories, solid or liquid cancers. Plenty
of research works have shown a particular immunological environment in solid
cancer. Immune cells exist within tumors, but the latter is not eliminated. In
other words, the enemies are here but soldiers are not fighting. Healthy cells
become tumoral and first they are eliminated since they express danger signals
and show new antigens. To visualize this, take a crowd of people with some
renegades wearing pink hats (cancer cells). Our soldier (immune cells) will
easily detect and arrest them (see article “Immune system ‘s G.I. in action”). However,
selection pressure will be exerted on tumoral cells and they will mutate and
become immune-resistant. Within the crowd, renegades are forced to change their
rallying sign in order to avoid being targeted. They will swap their pink hat
and wear a black wristband instead, more difficult to detect. The equilibrium
is maintained for a while since tumoral cells trigger an immune response. As
long as there is a visual on pink hats renegades, soldiers are attacking. But
when only immune resistant tumoral cells remain, cancer progression is
inescapable. Moreover, cancer cells show an environment globally immunosuppressive.
Renegades are less visible, proliferate and avoid soldiers.
1 : Balance between equilibrium and immune escape
(Source: Immune Suppression and Tumor Growth, Cancer Immunotherapy, 2013)
checkpoint antibodies research development has been led at the same time as
oncological research. Immune regulation depends on cell membrane receptors. Immune
cells activation or inhibition (switch) is related to several signals
associated with the presence of those receptors (electrical cables). A functional
switch is linked to a reliable electrical circuit with good electrical wiring. These
receptors are what define the immune checkpoints.
→ One of the first receptor to be discovered is
CTLA-4.Scientists found out that this protein has a role in the
down-regulation of lymphocytes, which consists of turning off the cells. CTLA-4
(inhibition=switch off) and CD28 (activation=switch on) have both the same
partner CD86. You must picture an electrical series circuit with one cable way
that would turn the cell off (CTLA4/CD86) with a stronger
intensity that over pass the way turning the cell on (CD28/CD86).
→Another star inhibitor receptor, PD-1, has been quite the talk for
the past ten years. PD-1 is located on lymphocyte membrane and interact with
PD-L1 on APC or cancerous cells membrane.
2018, scientists James Allison and Tasuku Honjo have won the Nobel prize in
Physiology and Medicine for their discoveries and research work on CTLA-4 and PD-1.
Afterwards, a great amount of research projects has been initiated in order to
comprehend and find more about other proteins linked to the immune regulation. Immune
checkpoint therapies are basically targeting a blockade within a receptor and
its ligand (lock and key). For that purpose, many monoclonal antibodies engineered
to aim those checkpoint proteins, just like an adhesive tape that would
maintain the switch in the wanted position. Discoveries of Professor Allison
and Honjo have resulted in two anti-cancer treatments ipilumab and nivolumab which
have been approved by the FDA for skin cancer.
2 : Schematic representation of ipilumab and nivolumab operating mode.
immune checkpoint therapies have a great efficacy and many research projects
have been started for other diseases such as auto-immune diseases or
neurodegenerative disorders. For the average Joe, immune cells are educated to
disregard our own antigen in order to not react against us. However, for some
people the immune system has not been well trained and autoimmune diseases will
occur. In other words, immune cells will backfire on us. For example, in
diabetes, immune cells detect pancreatic cells as dangerous for our own good.
The infantry (innate immunity) is recruited and release messengers who will
also enroll the cavalry (adaptive immunity). In another example, Alzheimer’s
disease is a neurodegenerative disorder caused by β-amyloid aggregation. A
layer of it will cover the neuron surface and information exchanges will be
altered because of neuron disruption and inflammatory cells in the brain. For
those diseases, immune checkpoint therapy will aim to decrease the amount of
activated immune cells. The activating receptors will be blocked so that immune
cells are turn off and that we avoid a chronical inflammation.
Figure 3: Activating and inhibitory
receptors of T cells and their corresponding ligands.
(Source: The immunological synapse as a pharmacological target, Pharmacological Research, 2018)
checkpoint therapies have become a major focus in treatments for the future but
can also be associated with serious side effects. As a matter of fact, disinhibiting
immune cells can lead to autoimmunity, which mainly results in intestinal
inflammation, hepatitis and hormonal diseases. At the same time, immune cells
blockade could induce immune suppression and a decrease in immune defense may promote
a dangerous tumoral cell spreading. Nevertheless, these treatments are a
revolution and the preferred treatment in anticancer therapy for the years to
come. Pairing an immune checkpoint therapy with the pre-existing treatments
would enhance the efficacy of anticancer medications which were previously of
little value. That is why, there is a need to fight those adverse effects. For
this purpose, many studies to identify markers have been started in order to
detect and take care of these side effects.
by Anne Clerico
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