Alan Worsley - Targeting cancer

Kat - It's time to take a closer look at one of the biggest cancer stories to come out in the past month, grabbing headlines such as "A cancer cure in just one jab?", "Scientists find cancer's Achilles' heel", and "Scientists claim cure for cancer is closer". So is it? And what's the science behind the headlines? I spoke to Alan Worsley, senior science information officer at Cancer Research UK - who funded the work - to get the background to the story, and what it all means.

Alan - One of the researchers, Professor Charlie Swanton who works now at the Francis Crick Institute, for the last few years, he's been really trying to look at how the genetic landscape of a tumour is shaped. So what this means and he's particularly been interested in how there are differences in mutations across the tumour. How does a tumour begins, starts off? And how certain mutations has got it to that point, has got the cells growing more quickly? But as the tumour grows, different sections will take on their own mutations, particularly if the cancer has developed in such a way to make more and more of these mutations happen. This is what they call "tumour heterogeneity" which is a really fancy way for just saying that the tumour looks very different depending on what part of the tumour you look at.

Kat - I like the idea that it's a bit like a patchwork blanket - that it's made up of all these different bits that are related but kind of look different.

Alan - Exactly. The reason he's been looking here, he's long been researching in the cancer such as lung cancer, kidney cancer where they tend to have a lot of these mutations. The tumours do look much more like a quilt, patchwork blanket than other cancers which usually are - there's kind of one or two main mutations driving that growth. The problem is, this patchwork makes it really difficult to use standard chemotherapy and radiotherapy - drugs that do their best to wipe out fast growing cells. Because there's so many mutations, it seems to be easier for these cancers to evolve a way around it, to evolve resistance.

Kat - I guess there's a chance that even if a small pocket of cells is resistant to that treatment then they're just going to carry on growing it and start again.

Alan - Exactly. So that's what we tend to see, that a treatment might seem to work but then the patient relapse and then that pocket of cells has by chance happened to have a mutation that makes them resistant to that particular treatment, they then grow back. So this is what has made these types of cancers so difficult to treat for so long. It's really been kind of one of his goals to try and find a way around this. How do we get past this? So initially, his thoughts were, if we can find treatments that effect what he calls "the trunk". These are the mutations that are right at the beginning that should be present in most of the cancer cells. If we can hit that with drugs and find out which drugs would be best for which patients, we might have a better chance.

Kat - These are these kind of molecularly targeted drugs that we've heard about lately?

Alan - Exactly. So, this is for the past 10 years, where 10 years ago, this was seen as the future of cancer research - targeted therapies, going after precisely the molecular problems that are associated with your individual tumour. Now, the problem is that for every single one of those mutations, you need a different drug. For every single one, you need to find a targeted therapy that suits that patient and they're difficult to make. They're difficult to find the chemicals that will accomplish this.

Kat - And incredibly expensive.

Alan - Exactly. So, it's going to take a lot of work to come up the suite or arsenal of target therapies you would need to hit every tumour.

Kat - And of course, when you start adding drugs together, you've got more side effects, the chance of more toxicity. I've heard people say, "Well, if we could have the right combination, there's no guarantee that it wouldn't harm the patient before it's actually treating their cancer."

Alan - Precisely and that's really been the biggest challenge facing that.

Kat - So, with this new study, what's the twist on it here because that seems almost like an insoluble problem and I've sat through conferences where people go, "I don't know how we're going to make this work." What's this new study all about that actually gives us hope that there could be a way through this problem?

Alan - So, the big difference within the last five years has come the rise of immunotherapy, using the immune system to fight cancer for us. So rather than banging our heads against the wall, trying to find what small chemicals can stop these mutations, the difference is that every one of those mutations and there are hundreds, hundreds of these in every cancer gives a chance for the immune system to recognise that something is wrong. And that was the big revelation.

Kat - Why doesn't the immune system normally just mop up cancer cells because these are kind of rogue cells, they're not right? What goes on that the immune system doesn't go, "Stop! Let's get rid of you. You look dodgy"?

Alan - Well, this is the exact paradigm that's so fundamentally changed in recent years. We used to think, it must be just rubbish at curing cancer. If we had an immune system that could take this out, why are we even getting them? The answer is actually, it's probably wiping out cancer in you all the time. It's actually exceedingly good. In fact, it's the other way around. For any cancer to develop, it has to have found a way to escape the immune system. And that's been the real change that people have realised, if you just find out how to get the immune system to target cancer, you can have really stunning results.

And that's been shown in new drugs that have come in the last few years. These are drugs specifically that take the brakes off the immune system for any established tumour, especially the very tumours that Professor Swanton has been looking at, these highly mutated ones are precisely the ones that actually would be most recognised by the immune system. And for them to exist, they have to have one of a handful of tricks to get past the immune system. And one of the things they found in this research is that precisely, the most mutated tumours are the ones that are most likely to have to have very specific immune evading mechanisms.

Kat - What are the sort of topline experiments that they've done and the key findings that have come out of this?

Alan - So, the main thing they did was that after years and years of trying to track down how mutations are different across cancers, these are specific DNA faults, they said, "Well, what does this mean for the immune system? What is it that the immune system could be recognising that maybe our drugs can't be hitting?" So, they applied the same computational power to look at what's known as antigens. An antigen is any protein that through a DNA fault, looks a bit different than it normally should. Now, every cell on the body, does what's called as antigen presentation. They take a sampling of the stuff they're making inside a cell and hold it out for inspection. It's like factory managers coming in, taking a small sample saying, "Yeah, this looks right. This lot is good to go. This looks funny. No, no, no. Stop the whole line. Something is wrong here." This is known as immune surveillance. They're surveying all these cells to make sure they're doing what they should be doing. So what they found is they used computational power to predict what sort of antigens might be there. Their theory was based on the same thing they're doing with mutational stuff is that, can we find antigens that are present across the entire cancer? Can we find ones that, if the immune system had to recognise something, we want it to be one of this lot.

Kat - And that should be present on every single cancer cell.

Alan - Exactly. This is a whole problem, it's that for some treatments, this is getting back to the whole relapse. If you've got a drug that only targets a portion of the tumour, all you're going to do is leave behind resistant ones that are going to grow back and now, you've got a cancer that's resistant to the treatment you had. So, if we're going to aim this at something, aim it at something that's across the entire tumour. So that's what they did. We didn't know if these things actually existed. We just didn't know until this paper had come out.

What they did is they went into samples they had already analysed, a prior study, and said, "Right. Can we find out whether or not the immune system can find these antigens?" So what they did, ran their analysis, they predicted hundreds of possible antigens and then they essentially fished out, to see if they can find any immune cells that recognise them. And they got three hits in two different patients - 1in one, 2 in the other, and each hit was exactly one of these, what they called a "trunkal antigen", an antigen present across the tumour. So proof of principle, these things are there. If we can find them, then we can either take them out, multiply them in a lab and stick them back in, or use the drugs that release the brakes and help those cells get to where they need to and hopefully, kill the entire tumour.

Kat - This at the moment is research that's been done on samples from a handful of patients. People have got very excited about this, the idea that maybe you could have a personalised immunotherapy - you could take samples from a patient and say, "Okay, this is the kind of things that we need to be targeting." Realistically, how close is this to being a treatment and what are the steps that need to be taken to turn this into a viable treatment?

Alan - So, I think the main thing about this research is that this isn't a new treatment per se. this is a guidance system for treatments that we've already been trying. So even in the news recently, we've heard about scientists taking immune cells out of the body and re-engineering them so that they could target cancer and then putting them back in or just simply taking immune cells that we think recognise a right thing and growing them up in the lab and putting them back in. Or these checkpoint blockers - these are drugs that take the brakes off the immune system. This gives us the guidance that we've been lacking.

At the moment, we've been sort of flying blind. We've been trying these treatments and in a portion of patients, they looked really, really well. But the vast majority don't seem to respond. So this guidance could say, "Right. For these patients where we could see they've already got immune cells that are targeting the best possible target, we didn't need to cut the brakes. The immune system is already locked on. It's just being held back. Those patients, they just need those drugs. For other ones, maybe we could say, "Right. These patients, they've got a lot of possible antigens. There's a lot of distractions for the immune system here, but we know they've got cells that lock into the right target. Maybe those guys need a bit of help and it can help guide what we should be doing."

Kat - That was Alan Worsley from Cancer Research UK, and that research was published in the journal Science.