Lung cancer: looking at the latest developments

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0:35Hello, welcome to the Naked Scientist podcast, the programme that brings you the biggest breakthroughs and talks to the major movers and shakers in the worlds of science, technology and medicine. I'm Chris Smith, and this week we're finding out how science is taking the fight to lung cancer.

1:00Lung cancer is one of the world's biggest killers, claiming more lives every year than breast, prostate and colon cancer combined. Often linked to smoking, although not exclusively, lung cancer can remain undetected until it's very advanced, which is why survival rates tend to be so low. But we'll be hearing how science is trying to change that picture, from early detection to new treatments and even a vaccine designed to stop the disease. But first, behind the statistics are lives that it cuts short, including here at The Naked Scientist. Listeners will fondly remember our regular contributor on all things tech, Peter Cowley.

1:39He was a good friend and a long-term supporter of what we do but he lost his life to the disease last year just a couple of years after discovering he had it we got together not long before his death last year to talk about his life legacy and his diagnosis what i've actually got is a primary lung cancer a non-small cell lung cancer and i've never smoked and about one in five of all lung cancer sufferers have never smoked and because the never smokers don't cough up anything we're detected very late so most of us have got this will already already metastasized in my case it was in the brain it was in the liver it was in the spine it was in the hip it was in the bones it's in the limb system so this was really late had about 14 tumors luckily i mean it's very unlucky to get that and lung cancer is still the biggest killer of cancer even though it's the most not the most common i was very lucky that some years ago, one of the big pharmaceutical companies had decided there's a big enough cohort of potential patients.

2:42They'd invest some money into designing something. And I never heard of targeted therapy before, but I have now. You've heard of chemotherapy and radiotherapy, et cetera. Targeted therapy is very specific and has very few side effects. And in my case, it's a tablet I take every day and four out of five people it works for. And in my case, again, my side effects, I've been incredibly lucky with the lack of side effects because there are a few side effects, even though it's very targeted. So I've led a remarkably normal life. For instance, I slept in Antarctica earlier on this year. I've been to all seven continents in a year.

3:17I've got time and I've got some money. So I've just got out there and traveled. But on top of that, of course, I've done other things like still be on investment boards and written the book. So I've really, I've been unusually busy in hopefully an inspirational way. I hope people look at me and think, yeah, just get on with life in these circumstances. Peter Cowley, entrepreneur and our tech correspondent who died from lung cancer late last year at the age of 70. Peter's diagnosis was just one small part of his incredible life and one that was lived very much to the fullest. he devoted some of the time he had left to writing an incredible book that charted the ups and downs of his life it's called public success private grief and the recording you just heard came from a long conversation that we had not long before peter passed away when we read together pieces from the book and discussed them we've actually released that whole conversation as a special podcast which you can hear at nakedscientist.com forward slash specials.

4:22It is incredibly moving and highly recommended. Peter's story is a moving reminder of the toll that lung cancer can take on people and their families but what exactly is the disease? Who's at risk and how does it develop in the first place? Our next guest has devoted his career to answering these questions. He's called Charlie Swanton and he's a leading oncologist at the Francis Crick Institute and Cancer Research UK. Lung cancer is a disease, broadly speaking, of roughly three different types. Firstly we have non-small cell lung cancer which is the commonest type, responsible for over three courses of diagnoses.

4:59And then you have the rarer subtypes such as small cell lung cancer which you'll hear from Caroline on later and mesothelioma are the three commonest types. Predominantly I deal with non-small cell lung cancer for the most part. This is a disease that's almost overwhelmingly caused by smoking. At least in my experience, over 90 % of cases have a smoking or ever-smoking history associated with them. There are other risk factors too. Air pollution is one that we're studying as a risk factor for never-smoking lung cancer, as well as germline genetics, that is family history risk as well. So those are the sort of three major risk factors for this disease.

5:37How does it tend to present? Because obviously a person doesn't say, oh I've now got lung cancer, they'll obviously notice some symptoms. What sorts of things do people tend to notice that tend to then take them off to the doctor? I guess the commonest presentation is with cough, prolonged cough, possibly associated with blood in the sputum, breathlessness potentially, weight loss and then potentially symptoms of metastatic disease, that is the disease that is spread from the primary site to distant sites and that might include the bone for example or liver adrenal or even central nervous system metastasis and those can present in different ways according to the anatomical site of the spread from the primary site of the tumor.

6:20But by the time cancer has started to spread that usually means the disease has become quite advanced so why is lung cancer presenting so late like that? So this is the major challenge and I guess equally one of the most exciting breakthroughs in the last, I'd say, decade or so has been the introduction of low-dose CT screening for people at high risk of the disease, that is people who are over the age of 55 and have had a smoking history associated with their lives. And we know these individuals are at higher risk of lung cancer. And as a result, they are eligible for low-dose CT screening. We've witnessed a massive stage shift from stage four disease, that is advanced disease, which is for the most part incurable.

6:59It's a much earlier stage disease, stage one or two disease, where surgeons, oncologists have a much higher chance of achieving cure for the patient. And when you say words like cure, how have we traditionally tried to cure people? What sorts of things have been in our armoury? So for early stage disease, that is disease which is confined to the chest, small volume tumours in one lobe of the lung, for example. The mainstay of treatment to date has been surgery, surgical resection of the lung lobe that harbors the tumour. Now over the last five or six years we've witnessed an improvement in the way in which care is delivered where we're seeing the introduction of what we call neoadjuvant chemotherapy, now that is chemotherapy and immunotherapy given before surgery and the immunotherapy works by boosting the body's immune system against the emerging tumour and this has been associated with much improved outcomes and better survival times.

7:57If the tumour presents late, that is the tumour has spread beyond the chest, then for the most part treatment is now aimed at palliation rather than cure. And here we would integrate multiple disciplines of medicine which may include radiotherapy, chemotherapy and immunotherapy and occasionally surgery if the disease is confined to a for instance a single site of disease what we call oligometastatic disease that is spread that only involves a few sites and there we're increasingly managing these cases much more aggressively with surgery as well as all the other modalities of treatment i just mentioned peter had osimertinib what's that how does that work and where did it come from?

8:41I liken it to a traffic light on the cancer cell that's permanently on green signaling the cancer cell to divide and osimertinib is a small molecule that switches the traffic light to red and stops the cancer cell from dividing and osimertinib is sort of the latest development in that evolution of drugs and it's a remarkably effective world tolerated drug that leads to very significant improvements in both progression and overall survival. Unfortunately it worked for a while in Peter's case but then stopped working. Why would that happen and how? You can imagine that a patient who presents with disease that spread beyond the chest has hundreds of millions of tumour cells in their body if not billions and each tumour cell is subtly different from the one next to it due to a process called genome instability and this creates diversity across the tumour mass which essentially means a little bit like microbial resistance to antibiotics, if you give a drug over time, resistance develops because one or more cells will harbour a mutational event, a chromosomal event in the genome that will permit that cell to become resistant to the drug in question.

9:46And that's broadly speaking how resistance emerges due to a few cells in the tumour mass that maybe have a resistance event even when you start the treatment or acquire resistance events over time. Where do you think the big therapeutic opportunities therefore lie in the future and what sort of shape do they look like? I think there's sort of two areas that I'm very excited and I continue to be very excited about leveraging the body's own immune system to fight the cancer but that's not always going to be possible and the other area I'm particularly interested in is this new area over the last sort of five or six years of a drug approach called antibody drug conjugate so this is where you use an antibody to target the cancer cells specifically and you arm that antibody with a cytotoxic or a targeted therapy, a chemotherapy or a targeted therapy.

10:33So you bring the drug very close to the tumour cell and that overcomes to some extent this problem that I was mentioning earlier of this therapeutic window. This allows us to target cancer cells much more specifically, thereby limiting side effects to normal tissue. Now, what other areas am I interested in? I'm particularly interested in early detection, early diagnosis for the reasons I mentioned earlier. The earlier we detect a tumour, the higher the chance of cure. And then an area that we're studying in the lab that I'm very excited about is preventing cancers from emerging in the first place.

11:08So prevention is better than cure. And we're trying to understand that first initial step in tumour initiation and we're trying to block it. And that's what we're going to be studying for the next five or six years, we hope. And we wish Charlie Swanton at the Francis Crick Institute and Cancer Research UK the very best of luck with those endeavours. We'll also be hearing about the work that's being done on a cancer vaccine a bit later on. But first, we're going to explore a type of lung cancer that is particularly pernicious. Charlie mentioned it at the start of his explainer, and it's called small cell lung cancer.

11:42Caroline Dive studies it at the CIUK Lung Cancer Centre of Excellence, which she co-directs. This is the most aggressive of the lung cancers. I call it the Ferrari of lung cancer because it develops so quickly. And one of the reasons it's so challenging, I think, is that when patients come to clinic with a diagnosis of small cell lung cancer, most of them have already got secondary tumors around the body. So it's already spread. So we don't yet have any good way to detect small cell lung cancer early, whereas screening is really beginning to pick up the very earliest stages of non-small cell lung cancer.

12:21That's one of the main differences. If it's different from the vast majority of the rest of lung cancers, what's the origin of this one? So there's two hypotheses. One is it's a basal cell and one that it's a pulmonary neuroendocrine cell. These tumours have a reputation for secreting things into the bloodstream that can mimic the body's own hormones Therefore they have effects beyond just the physical presence of cancers, don't they? They do, and one of the things about small cell lung cancer is I often refer to it as a sort of a shape-shifter of a tumour Because it has a high degree of what I call tumour plasticity So one minute the tumour cell is behaving in a certain way, it then can change the way it looks and behaves and become a different type of cell with a different behavior.

13:10So it's a sort of a moving target in many respects, which again confounds good effective ways to treat it. So these neuroendocrine cells, they can behave like what we call epithelial cells. They can secrete hormones because they're neuroendocrine and they can mimic neurons. One of the cardinal features is the rate of cell division is really high, Perhaps more than 80 % of the cells are actively dividing at any time of analysis. So it really is the Ferrari, but it's the Ferrari that can take different guises and have different behaviours. Do any of those disadvantages nevertheless give you an opportunity in terms of treatment?

13:53Is that exploitable in terms of how you're trying to tackle it? Just to take a step back, it's 15 % of all lung cancer cases worldwide and has a really bad prognosis. So only on average, 7 % of cases of small cell lung cancer will the patient still be alive five years after diagnosis. So super aggressive. Up until quite recently, and certainly recently in the UK, the patients were treated with chemotherapy. So drugs that bind to DNA and act on rapidly proliferating cells. And of course, they come with toxicities because they also are toxic to normal rapidly proliferating cells. And then recently, immunotherapy has been introduced for patients with small cell lung cancer.

14:36And this is interesting because 15 % of patients have a response. So that gives them an additional length of life. But we don't know who to treat. We don't know which 15%. So there's a lot of work globally now, to get back to your question, of really studying the biology with new models. Some of them are models made from the circulating tumour cells from patients with small cell lung cancer that give us an insight into the biology of the tumour as it grows and as it spreads. Because most tumours for small cell lung cancer, the immune cells don't get in. So the tumour cells are finding ways to keep them out.

15:14And that's something that we're studying. It's only one of several problems, but it's certainly a very interesting one. So we are trying to understand the biology of the neuroendocrine cells. We're trying to understand how they transit to these non-neuroendocrine cells. These tumour cells have the ability to mimic different types of cell and to their own advantage to grow and spread. And I think it's just worth pointing out that of all the human cancers, we think that small cell lung cancer has the most circulating tumour cells in the bloodstream. So that's work we've been doing for many years.

15:49and we're getting to the point actually with new technologies where we can look at the behavior of a single cell so we can isolate the circulating tumor cells from a patient's blood sample and we can see how different one is from another we can find them in the blood so that's like a needle in the haystack experiment finding these circulating tumor cells and then we can ask questions are they the same are they different are the differences in the ones that go up to the brain versus the ones that prefer to grow in the liver. So there's all sorts of new technologies that are allowing us to explore the biology of this very aggressive and very capable tumour type.

16:28I see why you call it the Ferrari and the shapeshifter. I don't think I've ever talked to anyone who's been able to set out a cancer which has so many horrible facets to it. Yes, that's our challenge. Only by understanding the biology in great detail, which is why we need to do the research, can we really come up with sensible strategies to treat patients better so that they live longer with good quality of life? I think we are making progress. Actually, one of the things I'm super excited about is there is a new type of immunotherapy called T-cell engagers. So these are therapies that bring the immune cells and the tumour cells together so that the T-cells see the tumour and can attack it.

17:10And that's a really impressive therapy that is actually being trialled in small cell lung cancer. And it looks like we're getting better responses in these early clinical trials. So it's still early days, but it's actually, I think, of all of the different developments therapeutically for small cell lung cancer, this looks the most exciting at the moment. So some grounds for optimism in the treatment of small cell lung cancer there from Caroline Dive at the CRUK Lung Cancer Centre of Excellence. This Monday.com ad was created by a team of people and AI agents. The agents wrote the copy and managed the timelines, while our human creative director made sure it all made sense.

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18:06businesses. Find out how Spitfire can empower your company at spitfire.co.uk. Music in the programme is sponsored by Epidemic Sound, perfect music for audio and video productions. This is the Naked Scientist podcast with me, Chris Smith, and today we're putting lung cancer under the microscope. As we heard earlier, one of the challenges with lung cancer is that it's often diagnosed at a very late stage when treatment options are much more limited. But there is promising work underway to change that. That involves scanning people who are at high risk, something Charlie Swanton mentioned earlier in the programme.

18:46But the problem with that is if we do see something on a scan, without a sample of it to examine more closely, we can still miss the diagnosis. But many potential early tumours are tiny and they're hard to biopsy, frustrating the process. But scientists in Bath and Edinburgh are about to embark on a trial of a new technology that might change all that. It's a system that can get far into the lungs, well beyond the reach of existing endoscopes. Here's Jim Stone, who's a physicist at the University of Bath and Chief Technology Officer at Prothia Technologies. Typically, a patient would present with a quite developed cancer, so they would have developed symptoms such as coughing up blood and that's when they would present in a hospital and this is obviously quite a developed disease by this point and is largely untreatable.

19:37So what many countries across the world have done and are doing is introducing screening programs so what they're trying to do is catch early cancers while they're still treatable. A target patient population will come in and they'll have a CT scan of their lungs and small what we call nodules will be looked for. Now in a lot of cases these nodules won't be cancer so what's important to do at this point is a bronchoscopy so to go inside the patient's lungs with a small camera and take a biopsy so that it can be sure that the nodule that is going to be treated is either cancer or not cancer. Now the bronchoscope can only go in so far through the airways with its camera so the biopsy tool passes out through that bronchoscope and if the nodule is in the extremities of the lung the camera on the bronchoscope can't see it at that point so the tool is passing out blind and so this is the real problem for us is if the biopsy comes back negative the clinician isn't sure whether the sample is not cancer or whether they simply missed so this is the target yeah so So what's your proposed solution then, especially for those tumours which are right at the peripheries of the lung, where the airways getting to them are so tiny that it is a physical impossibility to thread an instrument down there?

20:59So what we've developed is a very small endoscope, which actually passes down the conventional bronchoscope and a complementary imaging system for this endoscope. Our endoscope is small enough that it can get into the periphery of the lung. it images whatever it's pressed up against. So if the endoscope is pressed up against the abnormal tissue our imaging system is able to see this and our endoscope remains in place whilst the biopsy tool is passed through that. So it is clear that the target tissue has been found but also it's clear that at the point of biopsy you're still looking at the target tissue and so this really should enable us to get high quality biopsies with confidence.

21:43How have you solved the problem that traditional endoscopes struggled with then which was the size problem? How are you shrinking it down small enough to get down those very tiny, I mean we're talking sub-millimeter down right at the end of those airways? How we've done this is with fiber optics. So the bronchoscopes which are used are small cameras, we're all kind of used to those with large what we would call working channels, which are basically holes which go through them. The smallest hole in those conventional bronchoscopes is about two millimetres. Sub two millimetres will get you to the peripheral lung.

22:16So what we've had to do is develop an endoscope, which is sub two millimetres, but still has its own working channel large enough to take a biopsy tool. And what we didn't want is separate illumination and detection. Our optical fibre provides the illumination detection all in one element and so our optical fiber is about 300 microns in diameter so it's really by using fiber optics that we've been able to do this effectively then you've got a straw with a straw going down it and a straw going down the straw you're sort of three things nestled one inside the other you're able to see using the fiber optic that's illuminating the tissue and then you're threading a device right down the middle of all of that which you can then stick into the tissue that you think looks suspicious.

23:03Yeah so if you imagine it the fibre optic is embedded in the wall of the straw. It's very good I mean does it work the way you want it to though are you finding you can reach the parts that other endoscopes can't reach and therefore get these diagnoses and get them more reliably. So the trial is just starting that is what we are obviously hoping to see the testing that we've done out external to humans it looks good. And what would be the approach then that when a person has a sinister looking lesion they'll have traditional sampling first and then they'll get your technique if they don't think they've got a satisfactory collection or will you default straight to your approach are you hoping your instrument becomes the gold standard for sampling lung tissue for anything peripheral where you can't see with the mother bronchoscope so to speak we would hope ours became the gold standard because if you can't see the target.

23:57Taking the biopsy is always going to be blind. This gives you eyes on the biopsy. So we want this to become the gold standard for peripheral lung sampling. One of the other things that you can do with imaging is to tell a lot about tissue just from the light that comes back without even having to take bits of it. Are you doing that too? By shining light on tissue, can you interrogate that signal and say, well, the light is telling us, although it might not look iffy, this also looks dodgy and we'll take a piece while we're here. We have got quite a sophisticated imaging technique which comes through our optical fibre.

24:33We've developed a system which uses fluorescence lifetime imaging. Now what that really is, is we're shining light down through our optical fibre and we're essentially measuring the amount of time the photons of light interact with the tissue and then come back up the optical fibre. So that's what the lifetime part really is. And when you move from normal to abnormal tissue, we've seen that you get a shift in this lifetime and in this duration of interaction. So this is how we're really telling that we're in the abnormal part. So there is this lifetime shift. It could be that as we do more and more patients and this technology comes out, we get more and more confidence in saying what the specific target is, rather than it is just you are in the abnormal region.

25:21How impressive is that? Jim Stone at the University of Bath and Prathia Technologies. Finally today we're going to ask if it might be possible to prevent lung cancer altogether. Prevention is after all always better than cure and one of the most promising approaches for doing that is a vaccine designed to train the immune system to recognise the earlier signs of cancerous change. Mariam Jamal Hanjani at the UCL Cancer Institute and and the Francis Crick Institute is leading a clinical trial known as LungVax, which is the first of its kind in the UK. Traditionally, vaccines are used to train our body's immune system to fight infection.

26:02For example, vaccines used in the COVID-19 pandemic. But cancer vaccines specifically are helping the immune system fight cancer cells that already exist or are beginning to emerge. and the aim is to destroy these cancer cells and prevent their return. One of the big problems with cancer though is because it is our own tissue, the immune system is really strongly deterred from attacking our own tissue because obviously the consequences would be really bad news for healthy tissue. You've got to surmount that then and get the immune system to tell the difference between a cancer human cell and a healthy human cell.

26:42How? Yes, that's absolutely right. So the idea behind a cancer vaccine, in particular this one in the LungVax study, is that we specifically have designed a vaccine that will target abnormal cells that have what we call proteins on the surface of the cell. let's call them red flags. And these red flags are only present on cancer cells. So the vaccine would recognise them as foreign and would target and attack them so that they're specifically killing cancer cells and not normal healthy cells. Does the cancer make those because it's a cancer? In other words, because cancer is a genetic disease and because cancer cells have messed up genetic material, is that where these red flags come from?

27:27Yes, that's absolutely right. We know that a healthy cell can become abnormal and turn into a cancer cell typically because of an abnormal change in the DNA of that cell, what we call a mutation. And that mutation equates to these abnormal proteins on the surface of the cells that are foreign to the immune system. And are they repeatable enough across cancers? Because if they're not, it will make it very, very difficult to have anything other than having to make a new vaccine for every patient. This is a great question. And there are approaches for vaccines that are designed specifically customised, if you like, or bespoke to each individual.

28:08And then there are vaccines that we'd like to be able to offer all individuals or patients that specifically look for, as you say, repeatable or what we call recurrent red flags or abnormal proteins. And that's the idea behind lung vacs. We're specifically targeting these red flags that we know are very common and come up over and over again in lung cancer. How do you though overcome that natural suppression of the immune system that happens around human tissue? Because one of the problems that people often say with cancer is, well, the immune system would normally get rid of these cells, but they've evolved some kind of mechanism to stop it doing that.