In the field of cancer research, Cancer Immunotherapy, Immuno-Oncology
or I-O have been buzzwords for quite a few years now. For those who are not
life science professionals but actively follow the developments in the field, these
may be some popular terms come across on TV, newspapers or magazines. Yet for
many, including some scientists not very familiar with immunology, the
understanding of how immunotherapy could treat cancer remains either elusive or
a mystery. In this blog, I will try to simplify some key principles of
Immuno-Oncology for anyone who has always wanted to learn more about this
revolutionary field.
Our body is nature’s highly sophisticated creation equipped
with a very efficient defense called the immune system. This immune system is
made up of different kinds of cells, each specialized in carrying out certain
tasks. One of the cell types, known as killer T cells, can identify the foreign
cells/invaders in the body and kill them (yes, literally). You could think of
them as the ‘soldiers’ of your body who know how to find intruders and
neutralize them. In Immuno-Oncology, scientists use these T cells to recognize
and kill cancer cells. But wait…cancer cells are your own cells, not foreigners,
right? Why would T cells kill your own cells?! The answer to this lies in the fundamentals
of how the T cells identify their targets.
Every healthy cell in our body needs to present a normal pattern
of immunological signals, called ‘antigens’, to be accepted as ‘self’ or
‘body’s own’ by the immune system. However, when a cell incurs numerous genetic
mutations and/or the biological processes within it go haywire, this pattern of
antigen presentation is changed enough to label the cell as ‘foreign’ in the
eyes of the immune system. This is often the case for cancer cells. T cells
would then identify the abnormal antigens on cancer cells using their receptor-
called T cell receptor - and get rid of these cells. But if it was this simple,
then no one would ever get cancer as the T cells would keep killing the cancer
cells as and when they arise. Hence, there is something that’s certainly not very
efficient about this process. While we don’t completely understand the underlying
reasons yet, the scientists have been able to turn the tables on cancer by
strengthening the T cells’ anti-tumor activity in two major ways in the clinic so
far.
The first one is chimeric antigen receptor (CAR) T cell
therapy which enables T cells to recognize the cancer cells that are otherwise
undetectable. As we talked about antigen presentation in previous paragraph, it
is worth knowing that many cancer antigens exist in forms that are not recognizable
by the T cell receptors. Consequently, these antigens always go undetected by
the T cells. CAR was designed to overcome this limitation. It combines a part
of the natural T cell receptor with a part of an antibody that can recognize a
desired antigen (the one that’s unrecognizable by T cell receptor). Just like
giving a new tool to a solider to spot a hidden enemy! With this technology,
scientists can identify new cancer antigens invisible to the immune system, design
CARs against them, and put them into our T cells to empower them to accurately kill
those cancer cells.
The second approach, called the ‘check-point’ blockade, basically
stops the T cells from being stopped by cancer cells. In general, T cells in
our body are always on the call of duty, looking out for threats and dealing
with them. In this scenario, our body has natural mechanisms in place to
control the T cells from over-reacting and potentially hurting the healthy
cells. One such mechanism is ‘check-point’ signaling, wherein the T cells that
are over-worked show significant presence of check-point receptors like PD-1
and CTLA-4 which serve as ‘brakes’ on them. It’s when these receptors (brakes)
are ‘engaged’ by the molecules called check-point ligands, the T cells
slow-down their function or stop completely. This very mechanism is exploited
by cancer cells to escape the immune system. They increase the engagement of
the brakes (PD1, CTLA-4) on T cells by simply increasing the amounts of
check-point ligands- resulting in attenuation of T cell function. To tackle this
problem, researchers developed antibodies which block the interaction between
check-point receptors and their ligands. This allows the T cells to continue
killing cancer cells without stopping! So far, the check-point blockades of PD-1
and CTLA-4 signaling have shown resounding success in treating many cancers in
the clinic.
So, do we finally have the magic bullet against cancer? Not quite
yet. The clinical success of immunotherapy has been exciting; however, studies
show that most patients do not respond to it if they have more aggressive,
solid tumors. However, the good news is that years of research work has revealed
to us biological reasons (e.g. various ways the cancer fights back against
immune system) behind failure of immunotherapies in such cases. As the new
treatments developed based on this knowledge make their way into the clinical
trials, exciting times are waiting ahead for cancer immunotherapy!
[Disclosure: This blog is intended to educate general public
and non-experts about the basic concepts of cancer immunology and clinically
available immunotherapies. The author does not intend to undermine the efforts
behind other cancer immunotherapy approaches that are currently under clinical
investigation]
