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Immunotherapy promises next leap forward in cancer treatment
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**We have explored who is getting cancer, and of what, and we've
learned about the mechanisms of the disease and how we can use that
understanding to develop better ways to screen and pick up cancer
early. We can also use that knowledge to optimally treat the disease.
Generally, this begins with surgery to remove the primary tumour where
the cancer originated. We may then use radiation to kill off cancerous
cells that might multiply very quickly, and chemotherapy - toxic drugs
- to target malignant cells that may have escaped.**
**But some of these treatments can come with very severe side
effects. By their nature, cancer cells are relatively similar to
healthy cells, so drugs designed to take them out often cause
collateral damage. So scientists are trying to work around this
problem.**
**John Maher is a consultant immunologist at King's College, London.
He is also the chief scientific officer at Leucid Bio, a biotech
company that develops next-generation cell therapies for hard-to-treat
cancers…**
John - We target general properties of cancer cells, such as the fact
that they tend to grow fast. But the problem with that traditional
approach is that other cells in our body also have a tendency to grow
fast, such as blood cells, for example, and cells in the intestine.
These more traditional, blunderbuss type approaches tend to have a lot
of side effects. The way we're beginning to look is to achieve more
targeted drug therapies, which hit molecules that are different in
cancer cells compared to healthy cells.
Chris - Is that because the cancer cells are effectively afflicted by
a genetic disease: cancer is caused by changes to DNA and that makes
the cells look different so there are therefore things we can pick on.
We can identify those things and go after them because they single out
the cancer as different from the rest of the body.
John - Yes, that's exactly right. Cancer cells have been described as
being like mutation factories where, as the disease progresses, you
acquire more and more of these mutations and it's a bit like a Charles
Darwin type process where you get the selection of the fittest cancer
cells tending to grow out. But that, in a certain sense, is an
achilles heel of cancer as a disease because the more it mutates, the
more it makes itself different from a normal cell and the more
opportunities that gives you from a treatment perspective to design
drugs which can tell the difference between what is normal and what is
malignant.
Chris - So how are cancer doctors and scientists trying to exploit
those differences? How are you pursuing this?
John - Certain genetic abnormalities that are common in cancer can be
targeted using drugs which specifically hit that property of the
cancer cell. These are so-called targeted therapies. There are pills
which can block those abnormal proteins and slow the cancer down.
That's one type of approach which people are developing. But the area
which I think has really exploded onto the map in this century has
been immunotherapy. What that means is actually harnessing the
patient's immune system so that it can attack the cancer.
Immunotherapy as an approach is as old as the hills. It's been over a
hundred years in development and, until about 20 odd years ago, it was
considered to be an absolute disaster zone in terms of being
completely ineffective. But that mindset has changed radically.
Chris - How do they actually work?
John - So I think we're all familiar with the idea of an antibody as
being a protein which can bind onto something. Traditionally what
people have done is made antibodies, as a drug, which can bind onto
cancer cells and that makes a lot of sense and it can be effective in
some cases. But more recently what people have done is to make
antibodies which don't actually directly attack the cancer, but
instead take the brakes off immune cells. So your immune system is
constantly sniffing around the body, looking for things that look a
little bit abnormal. But there are a lot of checks and balances
involved in how the immune system is controlled. If you can, as it
were, disable the brakes of the immune system, you can enable immune
white blood cells to see cancer cells more effectively. This kind of
approach can be very effective in certain cancer types, particularly a
skin cancer called melanoma, for example.
Chris - Does that also have the advantage that, because cancer is
growing so fast, there's a chance that it will become resistant to
drugs just by bypassing whatever blockade we put in its way by
evolving round the problem. If on the other hand you are just
unleashing the immune system, it's much harder for the cancer to
evolve around that?
John - Yes, that's exactly right. These targeted drugs that I referred
to a few moments ago, they will typically go after a single abnormal
target in the cancer. Because cancers are mutation factories, what
they simply need to do to fly under the radar of that treatment
approach is to make another mutation which removes the target of the
drug. But when you develop an immune therapy approach such as an
antibody that takes the brakes off the immune system, you may have
many different immune white blood cells seeing different abnormalities
in the cancer. These abnormalities, to use a jargon phrase, we call
them antigens, these are essentially things which look different in a
cancer cell compared to a normal cell. If you can envisage that you
have an army of white blood cells which can each individually see a
variety of differences in the cancer cell, it makes it much harder for
the cancer cell to mutate its way such that it can avoid this entire
army of the immune system.
Chris - I thought, though, that one of the aspects that makes cancer
such a malignant disease is that it manipulates our immune system and
it even does so through manipulating healthy cells to turn off the
immune system or, as you said, fly under the radar. So will this still
work if you've got cancer cells effectively hiding from your immune
system? Won't they just become better at doing that?
John - That's absolutely right. That goes back to the point that I
made about the fact that there are many checks and balances in terms
of how the immune system actually works: a very complicated series of
molecules, proteins, some of which are designed to turn on the immune
system and some of which are designed to turn it off. It's that
balance that is critical. You're right in saying that cancer tends to
exploit that to increase the negative signals that tend to make the
immune system quiet as it were, but these treatments are about
disabling brakes on the immune system which will render these immune
cells more twitchy, as it were, more likely to attack the tumour.
There's a bit of a price that you can pay for that sometimes. That
price is that this twitchy immune system can also cause diseases known
as autoimmune diseases where the immune system actually attacks your
own body. Colitis, for example, where the bowel becomes inflamed, or
diabetes where cells in the pancreas that produce insulin are attacked
and no longer function.
Chris - Could we go a step further, though, and probe the cancer and
say, there are certain molecules that this makes that make it look a
bit different and so I'm going to engineer an immune response. So
rather than rely on just the twitch of the immune system, actually
probe the immune system: this is the target I want you to go after.
John - Yeah, absolutely. So there are two approaches that I'd like to
comment on briefly in response to that point. Actually, the first of
these is again a very old approach: the development of cancer
vaccines. What people are doing nowadays, for example, is you can
precisely map out the molecules that are abnormal in the cancer cell
compared to the healthy cells. These abnormalities can be used to
develop personalised vaccines whereby you inject the patient with
something which stimulates immune cells that can naturally see those
abnormalities. This is an approach which is beginning to achieve
impact in patients at the moment. The second approach that I would
comment on, and this is something that I spend my time engaged in
quite a lot, involves actually engineering white blood cells of the
immune system so that they can detect abnormalities on the surface of
cancer cells. Immune white blood cells normally see these
abnormalities, these antigens as I referred to them earlier, using a
protein which is called a receptor. But what you can do in the lab is
design your own receptor, which can enable a very large number of
immune cells to recognise a particular abnormality on a cancer cell.
This is an approach which is referred to in jargon terms as CAR T-cell
immunotherapy. This approach has been dramatically effective in the
treatment of patients with selected blood cancers: leukemias, for
example. These are patients who have otherwise untreatable disease
who, when they are treated with their own genetically modified CAR
T-cells, up to 90% of these patients can achieve a complete remission
of their disease. These are just two examples of how we are using a
variety of engineering strategies to reprogramme the immune system
against cancer.
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