Press Pack Interview with Professor Sarah Blagden for Episode 1

What first inspired your interest in oncology and cancer prevention?

When I first qualified as a doctor in the mid ‘90s the cancer wards were full of people recovering from chemotherapy. Treatment was so harsh in those days and medicines like the potent anti-sickness drugs we use today hadn’t been invented. I felt frustrated that we couldn’t do more for our patients and this compelled me to become an oncologist. Later in my career, I started my own research lab and ran clinical trials where I tested new treatments in people with advanced cancers. We had many successes but also a heart-breaking number of failures and I increasingly felt we were testing these treatments too late. I started to think more seriously about ways to prevent cancer and how we could redesign clinical trials so we could prevent cancers in high-risk populations.

You’ve called this a “once-in-a-generation opportunity.” What’s changed now that makes a prevention vaccine for lung cancer genuinely possible?

Right now, there seems to be the perfect alchemy of new discoveries revealing how cancers actually develop, advances in AI, an appreciation (post COVID-19 and the HPV vaccine) of how vaccines can work, and there is interest and support from funders like Cancer Research UK and the government. Archbishop Desmond Tutu once said "There comes a point where we need to stop just pulling people out of the river. We need to go upstream and find out why they're falling in." That time to stop them falling in is now!

In the film, you say “research is where hope starts.” Where did the idea for a pre-emptive strike on cancer begin for you?

It actually started about eight years ago when I met families affected by Li Fraumeni Syndrome (LFS), a rare heritable condition where people are born with a specific genetic mutation that gives them an almost 100% risk of getting cancer in their lifetimes. Scientists in the USA had shown that the anti-diabetic drug metformin delayed cancers from starting in mice with LFS. I was invited to an LFS meeting in London to discuss this and heard from parents about how their children dealt with – but eventually died from - the condition. I came out of that meeting feeling terribly upset and vowed to try and do something to help. We are now running a cancer prevention study using metformin (Ellie is featured in the Channel 4 show) and it has led me into more cancer prevention research. We are lucky to have support from many families affected by cancer and they regularly remind us that “research is where hope starts”. 

LungVax is described as the world’s first lung-cancer prevention vaccine. What makes it a world-first and what makes this moment in cancer research so pivotal?

There are studies of vaccines that treat lung cancer (once it has developed) but not of vaccines that prevent lung cancer starting in the first place. Our idea for the LungVax vaccine came from conversations with the TRACERx team at the Francis Crick Institute/UCL. TRACERx was the first study of its time to track people with lung cancer over time and gave a detailed record of how the cancer cells changed. This helped identify which changes happened first so that we could make the very first inroads into design a vaccine to stop those early changes from occurring. 

Your episode explains that cells can spend a decade in a precancer ‘cocoon’. What sets those cocoons apart from other cells, and what needs to happen for them to become moths?

When someone has just been diagnosed with cancer, they tend to think it has taken a year or two to develop in their bodies but we now realise it can take much longer than that, even decades in some cases. It actually starts as a precancer, a very small cluster of abnormal cells that look cancerous but don’t have all of the features of a cancer. An example is a bowel polyp. We know that some but not all polyps eventually turn into colorectal cancer but, biologically-speaking, polyps are quite different from a tumour. It is wrong to imagine that they are miniature versions of colorectal cancer. That’s why I liken precancers to a cocoon that is very different from the fully grown moth. This helps explain why many cancer blood tests (like the colorectal cancer CEA test or the prostate cancer PSA test for example) - that reliably detect advanced cancers – aren’t so good at detecting them at the early, cocoon stage. When we are thinking of prevention vaccines, we need to design them to teach the immune system to recognise the earliest changes in precancers (the cocoon stage) so we can really nip cancer in the bud. 

How does the vaccine teach the immune system to spot those early changes before cancer starts?

Our immune system is probably already defeating precancers on a daily basis. They recognise if one is starting in our body and send in immune cells to stop it. Our body’s inbuilt defence mechanism is great but imperfect so some precancers escape detection and grow. The purpose of our vaccine is to give the immune cells a refresher, a reminder, of what a precancer looks like so it is better at recognising and destroying these abnormal cells as they develop.           

You liken tumour cells to using a “cloak of invisibility.” In simple terms, how does the vaccine strip away that cloak?

Once cancer has developed in our bodies it manages to hide from immune cells. We call this immune evasion. This “cloak of invisibility” enables the tumour to grow because the immune system cannot see it. Immunotherapy works by removing the cloak to help the immune system recognise the cancer, but it doesn’t work for everyone. Vaccines designed to treat established cancers often cannot work on their own for this reason. However, we think that precancers may have not yet learned immune evasion and a vaccine may be much more effective, even on its own, at stimulating an immune reaction against this early stage of precancer. 

Prevention trials are tough because you’re “waiting for a lack of cancer.” How will you measure success in the early trials?

This is a challenge because precancers are often too small to be measurable on a scan (like a CT or an Xray) and if you can’t see them with the naked eye (like a polyp for example), we don’t currently have a clinically approved blood test that reliably detects precancers either (I’m working on one but that’s another story!). Therefore, you cannot tell if the vaccine is hitting its target and the precancer is disappearing. This is very different to studies done in cancer patients where you can measure their tumour size and show if it shrinks over time. Instead, we compare the number of people who develop cancer over a set period of time after being vaccinated and compare this to the unvaccinated group. If our preventative treatments work, we will see fewer cancers in the vaccinated group. That’s what I mean when I say we are “waiting for a lack of cancer”. 

Who will be able to get the prevention vaccine when trials open?

The first recipients will be people at high risk of lung cancer. These will be people who have recently had an operation to remove an early-stage lung cancer but are at risk of new cancers in their lungs or elsewhere in their bodies or of developing a recurrent lung cancer. We are also testing the vaccine in a small number of people who are participating in the NHS’ Lung Cancer Screening Programme. At the beginning, we mainly need to check the vaccine is safe and decide how many boosters people should get. 

If the early trials are successful, who do you think should get the vaccine and why?

It depends a bit on the outcome of our studies but I would like to give the vaccine to people who are at risk of lung cancer but have not yet had it. Lung cancer is a really horrible cancer to have and is currently diagnosed in around 50,000 people every year in UK. 

How vital is the backing of Cancer Research UK and other funders – and what does that support deliver for your research?

The backing of charities and other funders like CRIS Cancer Foundation and Rosetrees Foundation is absolutely essential for our work. Cancer Research UK invested significantly in TRACERx over 10 years ago and in the follow-on TRACERx EVO study. These studies were run by our collaborators at UCL and the Francis Crick Institute and laid the foundation for the LungVax project. Cancer Research UK also supports the Oxford’s Oncology Clinical Trials Office (OCTO) which runs LungVax, MILI and other prevention trials. We designed and manufactured the vaccine with funding from Cancer Research UK, CRIS Cancer Foundation and Rosetrees Foundation. Cancer Research UK is also funding the clinical trial with the support of CRIS Cancer Foundation and commercial partners. 

You also study Li-Fraumeni syndrome in the MILI trial to understand the very earliest steps of cancer. What have you found out about the relationship between p53 and mitochondria and how you can use different drugs to lower people’s cancer risk? 

The MILI study looks at whether metformin helps delay or prevent cancers in people with LFS. Metformin is taken by around 120 million around the world to control type 2 diabetes. It is derived from French lilac and works in lots of different ways in our bodies including in turning down mitochondria (which are like mini boilers) in our cells. There is evidence that people with LFS (who carry mutations to the gene for p53) have altered cell metabolism because their mitochondria are turned up too high. This is normally held in check by a protein called p53 but - without it - the mitochondria spill damaging molecules into the cell which might explain their higher cancer risk. 

How could insights from MILI feed into future prevention vaccines for everyone?

While people with LFS are born with mutations in the gene for p53, around 50% people with any kind of cancer acquire defects in the same gene within their tumours. For some cancers, like ovarian cancer, a mutation to the p53 gene is a very early event in the development of their cancer. Participants in the MILI study donate blood samples once a year which are analysed to help us understand how p53 contributes to starting cancer and this will guide the way we design treatments and vaccines in the future against cancer in general. 

The ultimate vision is a single pooled vaccine protecting against multiple cancers. What’s the roadmap from a lung cancer vaccine to that universal prevention concept?

LungVax has opened the door to us thinking more generally about preventing cancer with vaccines. We have other studies starting in Oxford, for example with a vaccine to prevent cancers in people with Lynch syndrome and we are designing vaccines to prevent other cancers. If we can show these are effective, we hope we could eventually pool them all into a single prevention vaccine to protect the population from cancer. This seemed like a crazy concept only a year ago!

What keeps you motivated through the inevitable setbacks that come with scientific work?

I’m lucky that my family is very supportive, particularly my husband Steve. When I arrive     home (completely exhausted) he runs me a hot bath! I am really motivated by the people I’ve met in my career and I passionately believe cancer could become a predictable and preventable disease. This is what gets me out of bed in the morning. 

Viewers will see your personal side – supporting your mum during breast cancer treatment, and your father’s influence as a problem-solver. How do those experiences shape your approach to your research?

My father was a military man who was legendary in his determination to overcome obstacles. His nickname was “Brigadier Bludgeon”! One of his proudest achievements was swiftly repairing the Port Stanley airfield in the Falkland Islands after it was bombed in 1982. He never sugar-coated his advice which was always to keep turning up, keep working and keep delivering. I think of him often, particularly when I hit an obstacle. He would just say: “F**k the f****rs” and plough on regardless!

Your work requires extraordinary focus and perseverance. What helps you switch off or keep perspective when you finally step away from the lab?

My two children are now teenagers so there is always a distracting drama to help me switch off: one has lost their football boots, another has an exam coming up, has let the bath overflow, wants help with homework. It’s never ending. One day I’ll have hobbies but, right now, I haven’t got time.

What impact do you hope your work will have in ten years’ time, and how does it feel to know that your work might one day benefit so many people?

I would love to help break the stranglehold that cancer has on our society by demonstrating that it can be prevented. This is a massive team project! I feel we revere cancer too much – we call it the “big C” and put it on a pedestal and that, I think, is why there is so little prevention research – because it’s viewed as a futile mission. Little breakthroughs with prevention vaccines will go a long way to changing that perception. Blood tests that actually tell us when we’re first starting to develop a cancer will also be transformative.