Lynch syndrome vaccine: Cancer treatment of the future?

We’re going to conclude today’s programme by examining the next generation of cancer vaccines. Scientists at the University of Oxford are hoping to develop a vaccine for people with a genetic disease called Lynch syndrome; affected patients have an increased risk of developing cancer in a number of different organs. The project is called Lynchvax, and it’s been funded by Cancer Research UK. Here’s David Church, an oncologist at the University of Oxford who leads the project…

David - Lynch syndrome is a genetic condition, and it's the commonest cause of genetic cancer, hereditary cancer, that's cancer that runs in families, in the UK and globally. It's caused by a faulty copy of a gene. These are a combination of genes that are responsible for ensuring that when our DNA is copied, before our cells divide, that copying is accurate. What happens is that we're born with two copies of each of these genes and people with Lynch syndrome are born with one faulty copy of those genes. That means that, during their lives, if they have a defect in the backup copy, their cells lose the ability to copy their DNA accurately. As a consequence of that, there are errors, and we call them mutations, and then collectively, cumulatively, over multiple cell divisions, those errors can affect genes which are critical for growth of cells or death of cells and that can cause cancer.

Chris - Does it affect any tissue in the body, then? If it's affecting all your cells, does that mean that everywhere could develop a cancer or are there hotspots in the body?

David - The latter. It is interesting that, even though this is a universal process, the tissues, the organs of the body that are affected, are particular ones. The biggest risk for cancer is the bowel. For women, cancers of the womb, and also other cancer types like the stomach, the piping that connects the kidneys to the bladder, and elsewhere.

Chris - Who gets this - age wise - and how would they know?

David - The increased cancer risk is from a young age. Young people with bowel cancer, we find they have Lynch syndrome. The critical thing with Lynch syndrome is that we only know about a small fraction of people that actually have the condition, so there's a large initiative to correct that.

Chris - You are trying to treat it in an innovative way. Can you just compare what we used to do for it with what you are doing now?

David - At the moment, people with Lynch syndrome are diagnosed typically because when we diagnose someone with a cancer we do some testing to see if there's the signature alteration that Lynch syndrome causes in the tumour, and then follow on testing to test the DNA that they were born with. That can tell us whether the person has Lynch syndrome or not. But of course that means that they've already been diagnosed with the cancer so they have all the standard cancer treatment: surgery to remove the cancer, possibly chemotherapy afterwards. In a proportion of cases that's all too high, by the time the cancer is diagnosed, it's already spread. What we need to do is to think about novel strategies to diagnose these people earlier, and also of course to prevent cancer in people with Lynch syndrome. But we are exploring an alternative approach, which is a vaccination.

Chris - I suppose the complexity here is, unlike someone who doesn't have Lynch syndrome and they do get a cancer (you treat that cancer, they can then regard themselves as in remission, let's say) if someone has Lynch syndrome, the same mechanism that caused them to have the cancer in one part of their body or one part of their bowel, it could put all of their bowel at risk so they're continually at risk. So having a way to keep the immune system on high alert has got to be the way forward?

David - Absolutely. What we're working towards is targeting the power of the immune system to recognise and, we hope in time, prevent cancer in people with Lynch syndrome. In so doing, our hope is that that would work in all the tissues of the body, not just the bowel, but also in the womb in women who have Lynch syndrome, and elsewhere.

Chris - Talk us through it then. How will this work? What do you actually do if you pick somebody up who's got it and you want to do this for them? What's involved?

David - We're analysing cancers and precancers in people with Lynch syndrome. Precancers are lumps, tumours, but they haven't actually had the alterations which mean that they're able to spread elsewhere in the body. There's a period before a precancer becomes an actual cancer and has the risk of spreading and all the consequences that entails, of course. Now, I've already mentioned that people with Lynch syndrome have an error in copying their DNA which means that the cells with this error accumulate errors or mutations. What this means is that those errors can cause abnormal proteins to be produced by the cells that carry this defect. Those abnormal proteins, we've known for some time, can be recognised by the immune system. It's similar to if we get an infection, the body recognises that the infection isn't part of our normal body and the immune system can target the abnormal proteins, the proteins that the infection causes. It's the same with cancer, and the abnormal proteins that cancer mates can be recognised by the immune system. We've known for some time because cancers in people with Lynch syndrome have a large number of DNA errors or mutations that can be recognised by the immune system, but the immune response is ineffective. It is unable to control the cancer in these people. What we are hoping to do is, by identifying these alterations in DNA and consequently in proteins, we can actually anticipate the development of cancer and, by vaccinating against them, turbocharge or prepare the immune system to recognise these abnormal proteins so they can intercept the precancer before it becomes a cancer. That's the ambition that we have.

Chris - Would it be different proteins or different constellations of proteins in each individual? In other words, this is almost personalised medicine in the respect that you go in and you've got to look and see which abnormal proteins this person's pre-cancer might be making and that's what you then turn into your vaccine. Or have you got a one size fits all strategy?

David - The latter. There is a lot of interest in personalised vaccines and there's a big initiative in the UK NHS to deliver personalised vaccines including for bowel cancer. However, what we are talking about and thinking about here is an off the shelf approach. What we know from the analysis that we and others have done is that cancers in Lynch syndrome have predictable alterations in their DNA and that really raises the possibility that we could develop a one size fits all vaccine.

Chris - Are you not worried, though, that in the same way that flu virologists know that when we vaccinate people around the world against flu, we basically force the flu virus to evolve in a different direction? It's a bit like herding sheep. If you start vaccinating people against particular predictable tumour types, is there not a danger that their disease might mutate to circumvent your vaccine and then you'll start to get new kinds of cancer that we miss with our vaccine initially?

David - It's a great question. We know that, in advanced cancer, that's the majority of cancers that we diagnose and treat, the cancers are able to do that. Like a virus, it adapts and is able to become resistant to that therapy. However, what we're hoping to do by going after multiple targets early in the disease process, before the cancer has had a chance to get that variability and that ability to evolve to become resistant, that we can intercept that and prevent that.