Immunotherapy: The next step in fighting cancer

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.