Cancer vaccines, tumour-killing cells and does fasting work as a treatment?
Professor Brian Cox takes a deeper dive into the science of cancer, with a panel of returning experts answering more of your questions.
Do tumours communicate with the brain, is glucose carcinogenic and could our immune system’s natural killer cells be used to combat cancer?
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Panellists
More Questions of Science gives you extra episodes that continue the conversations started in A Question of Science.
From his home studio, Professor Brian Cox catches up with expert panellists from earlier in the series. Together, they tackle your follow-up questions, explore new angles and go deeper into the topics that sparked your curiosity.
Producer: Before we begin, a warning that this bonus episode starts with content that some listeners may find upsetting, including specific descriptions of how cancer causes death in some patients. To avoid hearing this discussion, skip to four minutes and 19 seconds in.
Brian: Hello, and welcome to this bonus episode of A Question of Science, the show where we tackle your questions on everything from Artificial Intelligence to the future of fertility with the help of a panel of experts. The original debates were recorded in front of an audience at the Francis Crick Institute in London, and this show is a follow up, or a companion really, where we'll tackle more of your questions. In today's bonus episode, we're going to delve even further into the science of cancer and the research that's developing to help us cure it. I'm joined by Professor Charlie Swanton and Professor Gerard Evan, both from the Francis Crick Institute and working on different aspects of cancer and how to treat it.
Now, as we discussed last time, one in two of us will develop a cancer in our lifetimes. Worldwide, ten million people die of it each year, and so I wanted to start with a very important question from Karen Smith who asked: What part of untreatable cancer actually kills you? Gerard?
Gerard: This is a very interesting question. Different cancers kill in different ways and it's very difficult to define sometimes what it is that's deadly. I mean, cancers muck up a lot of processes within the body of the patient. They grow into various organs and metastasize around, and that degrades the performance of the organs and the tissues.
But they also have systemic metabolic effects, which are often seen in terminal cancer patients. And then cancers of specific types like an insulinoma for example, that's made from the cells that regulate your blood sugar, that can cause you to go into a diabetic coma by virtue of what happens when you get too many of these cells in your body.
So it's difficult to know exactly what kills a patient who has cancer, but it can be lots of different things at the same time.
Charlie: Yeah, there's a wide range of sequelae we call them, in relation to metastatic disease. That's disease that's spread beyond the primary site. The systemic effects that Gerard mentioned are very well recorded in the literature. It's, for example, liver metastases, which upset and disrupt liver function. Protein synthesis affects clotting, for example your ability to clot. And one of the, you know, major impacts of cancer on the blood system is this problem we call thrombophilia, which is a tendency to hyper coagulate, basically the tendency to clot more, and that causes deep venous thrombosis, clots in the leg, they can spread to the lung.
And cause what's called pulmonary emboli, which can cause patients to become critically unwell and sometimes die. Then there are the mass effects of the tumour, for example. But then, Gerard sort of alluded to this briefly. We do see some patients who have very little disease at all, and indeed we have an autopsy programme at University College London funded by Cancer Research UK called PEACE.
And the aim of this study is to answer exactly your question, Brian, how do patients die of cancer? It's actually not as straightforward as perhaps we once thought. And what is clear from these studies is the total burden of disease doesn't always correlate with longevity. And there are some patients who die from their disease with very little disease burden at all, pointing to this sort of systemic effect that Gerard was talking about. And one of the thoughts we've had is it disrupts the ability of the immune system to recognize infection, for example, because the immune system's too busy tackling the cancer. So there's a lot we don't know. There's a lot we do know, but this is still an unexplored area actually.
Gerard: It's like a modern version of the knee bone's connected to the thigh bone. Everything's connected to everything else in the human body and it's an integrated package. And, once something goes wrong, it can spread and distort the functions of other organs. And we need to understand what that's all about, because that's often, part of the morbidity of the disease.
Brian: Well, Charlie, actually, you mentioned lung cancer and since we recorded the debate, you've been part of a project to develop a vaccine to prevent lung cancer.
Charlie: Thanks, Brian. My colleagues at University College London, led by Mariam Jamal Hanjani, have led this initiative in the Cancer Research UK Lung Cancer Centre of Excellence. And the idea is we know a lot of the initiating mutations in patients who've had a heavy smoking history, and we've mapped all of the common early initiating mutations that contribute to lung cancer growth in smokers. And what we aim to do is create a vaccine against those common mutations that are found in many patients, actually.
And we are about to initiate a phase one trial of a vaccine in high risk smokers who haven't got lung cancer that we've identified through the lung cancer screening program. And indeed patients who have had cancer but have, that have had the cancers resected who we know are already at high risk of getting a second cancer.
And the aim is to, first of all, test the safety of such a vaccine and then in due course roll it out to we hope, phase two and phase three studies to actually prevent lung cancer from initiating by boosting the immune systems effect against those early mutations so we can eradicate and extinguish those early clones before they become evidence on a chest X-Ray or or CT scan.
Brian: It's really interesting that you say that 'cause I remember some debates we had, at the Royal Society actually online during the COVID pandemic and one of the things that was said there was this vaccine development technology may lead to, well, vaccines for cancer. And so it's very interesting to hear that about, what is it, four, four or five years on that that's progressing.
Charlie: Well, yeah, it's a good point, Brian. Actually, historically, the mRNA vaccines started off in life in the cancer domain before COVID started. COVID gave them an additional boost, obviously, but, there's been a lot of interest in mRNA vaccines for some time, and I'm glad to say they're beginning to deliver.
In melanoma, for example, there's already evidence, some early evidence in pancreas cancer that after resection a mRNA vaccine against common mutations can reduce the risk of relapse. So there is emerging evidence that they're effective. The key thing is to boost the body's immune system. I liken the body's immune system to a pharma company, if you like, within every patient, the patient has the answers to their cancer. It's a question of just giving it a boost, potentially.
Brian: You mentioned there that at the moment it would be for high risk patients, so you identify who's at risk and you vaccinate them. Can you see a time in the not too distant future where there are routine vaccinations for particularly common cancer?
Charlie: That's a good question. Look, first of all, this study 'LungVax' has got to be successful and other studies like it. So we need the evidence, assuming we have that evidence, the question is, could we roll it out across all cancers? I think the answer to that question is, it's gonna be a little bit tricky because for many cancers there aren't these recurrent mutations that are common in multiple individuals.
There are for some, I mean, for example, pancreas cancer, very commonly has mutations in KRas. So, that would be something we consider. There's a disease called Lynch Syndrome, which relates to mismatch repair deficiency in colon cancer, and there recurrent mutations there that could be targeted. But for other cancers, for instance, that involve loss of what we call tumour suppressor genes that can affect any part of the protein, it's gonna be harder to develop a cancer. It's easier when you've got a, what's called an oncogene, where you have we call a driver event that occurs in the same hotspot of the protein every time that we can boost an immune response against.
Brian: Thank you. turning to cure now, rather than, prevention. A few people wrote in with questions about particular types of treatment. And Cara Arrowsmith asked about stem cell treatment. Her question was: Do you think that stimulating the bone marrow to produce more natural killer cells would help to combat cancers?
Or do you think that the stimulation drugs could give rise to more cancers in the bone marrow? So maybe we could start, Gerard, by explaining what these natural killer cells are.
Gerard: We've got two general sets of, immune defense against pathogens and various, infectious entities. One is called the adaptive immune system and the other is called the innate immune system.
The innate immune system is far more, far more ancient, goes back about 400 million years, and we know that because squids and octopuses have much the same innate immune systems as as we do. Whereas the adaptive immune system starts with a vengeance on in fish and everything after fish. So what we're trying to do here is to understand how the adaptive immune system works against cancer because it's all very well to say we make antibodies against foreign things, but as Charlie says, not many cancers have the same representative things going wrong with them, such that we can make an immune response against it. But the innate immune responses, contain some cells called natural killer cells. And natural killer cells are far more cunning in a way, they sense things that have gone wrong with tissue structure.
They sense things that have gone wrong with cells that are stressed or damaged. The NK cells recognize foreign cells. They recognize also cells that are engaged in suppressing immune responses against them, so the tumour cells can suppress immunity, by blocking a protein on their surfaces that presents foreign molecules to the immune system.
But we have a sensor which senses when those molecules that are presenting themselves as foreign actually shut down their presentation program. And these NK cells can sense when something is evading the immune system and they attack the attackers.
Charlie: Yeah, it's, it's amazing biology. Gerard's hit the nail on the head. One of the ways in which lung cancers, for example, escape the immune system, and stop the predatory immune system from eating it, so to speak, or killing it, is to downregulate these major histocompatibility complex molecules that Gerard just mentioned. We call them MHC, and these NK cells monitor that and they monitor tissues that have lost MHC. Now, unfortunately, cancer evolution is an extraordinary process and you end up getting selection for tumour cells that haven't lost all copies of the MHC. So they may have lost five out of six copies or four out of six, but we never see a cancer that's lost all six copies. Which is very interesting, and it tells you that there is a huge selective pressure to retain one or more copies because of those cells, the NK cells that Gerard mentioned that are so good at recognizing tissues that are trying to hide from the immune system.
When I gave a talk at a school in front of sort of 13 to 15 year olds, a 13-year-old student picked up on this and said: Well, why don't we create therapies that can specifically recognize the loss of these major histocompatibility complexes and cells that have lost them and specifically target those cells? And it's something we're thinking about, but it's not trivial.
Gerard: We're in an arms race. Yeah. We bear that in mind, right? Yeah, against bacteria. We're in an arms race and against tumour cells. We're in an arms race as well, and we just gotta keep our defenses up.
Brian: And the question was about this particular treatment, the stimulation drugs, and I suppose it's a wider question about how we manage risk in clinical trials and how we discover whether these drugs have, I suppose we're talking about side effects essentially there.
Charlie: So just to go back to the original question, stem cell transplants are used in liquid tumours, hematological tumours very effectively. Obviously, they come with major risks 'cause you have to suppress the blood system to enable individuals to take up the stem cell autograph or allograft, but they've been tried in solid tumours with much controversy actually in the early days. I mean, there was a period where patients with breast cancer, were undergoing stem cell transplantation till it was found out that actually it didn't work after all.
So, so for solid tumours, for the most part, we don't think about stem cell transplantation. And there is some sort of early preclinical evidence actually that some of the growth factors that stimulate the myeloid cells, the sort of blood cells can also somehow perturb tumour growth and in some circumstances potentially enhance it, at least in preclinical model systems.
So there's some theoretical reasons why potentially boosting the myeloid compartment might actually not be a good thing for tumour control. It might actually do the opposite and promote tumour growth and tumour spread.
Brian: I'd like now to turn to the importance of the patient's attitude when it comes to cancer treatment. So Tristan Sidhu asked: Do you think psychological factors play a significant role in cancer trajectory and recovery? If so, are people looking at mental health as part of cancer research?
Charlie: Maybe I could start on this, Gerard, if you don't mind, because this is an area that I'm pretty passionate about, having sort of experienced this firsthand with a member of my family who suffered from mesothelioma.
And this is a cancer that involves the lining of the lung. It was my grandfather and I watched him waste away. And this is a chap who was 85. He used to garden every day. He was very, very active. He still worked, but he gradually lost his sort of joie de vivre, he lost his appetite. He became depressed, he lost his sort of will to live almost.
And I watched this happen in front of me and it was, it was ghastly for the family because, you know, his wife, my grandmother was constantly urging him to pull himself together and get out in the garden and go back to work and do all the things he used to do. But the fact is he couldn't, and this is a chap who'd never been depressed in his whole life, had always, you know, he fought in the war.
And he was extremely active. Never sat down for a minute. And it was quite unlike him to behave like this. And, you know, I was sort of a, a oncology trainee at the time and you know, we, I've become aware of this phenomena called cancer cachexia and depression associated with cancer. But I'd never sort of witnessed it in a family member.
But seeing this made me realize really for the first time that that cancer has this, we talked about systemic impact, tremendous systemic impact on the body. And actually it's well described that cancer itself can cause depression. Cancer itself can cause body wasting, cachexia and loss of appetite and nausea that puts one off one's food and makes one depressed.
And there's a whole new field developing in oncology now of neuronal-cancer interactions where actually the central nervous system and peripheral nervous system interfere and actually communicate with the cancer. And it's perfectly plausible in fact, the cancer communicates with the central nervous system, and in fact, may render the patient depressed.
So this idea that one has to look after one's mental health when one is suffering from cancer, of course that's true, but what I think one has to be very careful of is assuming that boosting the mental health of the patient will necessarily improve one's chances of survival. Because, quite frankly, there are systems at work in a patient that we don't understand at all where the cancer's actually actively communicating with the brain and making the patient depressed or putting the patient off the patient's food, stopping the patient wanting to get up and exercise or garden in the case of my grandfather, that that's not the patient's fault at all. And so this idea that a patient can pull themselves together and boost their mental wellbeing actually may not be true.
It may be very hard unless we can actually control the underlying cancer. And I think that's important because patients often get very concerned that they can't get on top of their depression or their nausea or their cachexia, and it's not their fault at all. It's simply the tumour communicating adversely with the host.
Gerard: If I can say the other problem is that the language that we use about cancer, that it gives the impression that it's an evil entity that's plotting to kill us. It's constantly looking for better ways to become more horrible and everything else. And we anthropomorphize that. Cancer has got a plan and it's an evil plan.
This is just not true. This is just a disease. It's part of a, part of the software of our cells and our organs and our bodies, and they glitch occasionally and we've gotta fix the glitches and stop blaming the patient or allowing the patient to blame herself or himself.
Charlie: Yeah, that's a very important point Gerard makes. And Gerard, I've sort of learned from him over the years that there is a tendency when describing cancer and the way in which it evolves to anthropomorphize it and sort of model it based on what a human would do. And that there, there is sort of method in its madness, but there isn't, it's all natural selection, ongoing selection over time of the most aggressive clones that survive and the weakest and the less fit being eradicated.
Brian: Thank you. we have a question now from Rebecca Gerling who wants to know how differently should we be investigating childhood cancer, given that it's less influenced by environmental factors or the environment than adult cancers?
Gerard: Essentially, we have to understand that pediatric tumours are more like developmental abnormalities where you get, clones arising due to a combination of missteps, sometimes not even mutations, but very often mutations, chromosomes breaking and realigning with other bits of other chromosomes and turning genes on inappropriately and at the wrong time and or failing to switch them off at the right time. And they're very different.
And then there are these cancers, of course, of people who are young but not pediatric patients in their twenties and thirties. And again, they appear to be very different in guise to the cancers that older people get. But what is happening is that there's an increase in younger people between 20 and 50 in getting these cancers that are normally associated with, much older patients. And we don't know why that is rising as a disease state.
Charlie: Yeah, that's exactly right. It's an interesting point the person who asked a question made. I don't think it's entirely true actually, that pediatric cancers, at least in a minority, aren't forming in response to environmental triggers. Actually, there is some evidence in childhood leukemias that early onset infections might actually be protective of leukemia and little children who are, are not sent to nursery school versus those that are sent to nursery school are at a differential risk of acute leukemia.
So now we don't know why that is. We don't know whether the immune system needs to be trained somehow early on in life. But I think there's still a lot we don't know about the triggers of pediatric childhood cancers, as Gerard says, they are quite distinct from adult cancers in that they have very low numbers of mutations that are often driven by these, what we call complex chromosomal rearrangements, where the structure of a chromosome or several chromosomes, are altered and fused together to create sorts of new fusion genes, as it were, but there's more to it than that, actually. I think there's more to it than simply the fusion gene being derived and there may well be environmental inflammatory triggers as well that combine with those fusion genes to stimulate the first initiating cell. So there may be more similarities between a pediatric and an adult cancer than perhaps we've appreciated. And this is an area of really active research.
Brian: It strikes me as you talk that it goes back, Gerard, to something you said earlier about these being a, you, you could consider it software, software problem in the, in the body. I think when we had the, studio discussion, the initial programme, the idea that cancer is a thing.
And so you say we will find a cure for cancer. It seems to me as you're talking, it's a catch all term for a very large number of problems and that are just not related in some sense.
Gerard: Yes. Well, this is why, I think cancer is such an important area of research because it's sub-science of processes that go wrong.
Often, they're normal processes, but the timing's slipped, the cells can no longer turn the processes off. So, there's a huge similarity between injury and repair. After you injure a tissue and it repairs, it rebuilds itself and everything else. And while it's rebuilding itself, it looks very much like a cancer.
The difference is that it stops and we don't know how it stops or why it stops. If we did, then we'd probably have different therapies or better therapies against cancer or certainly more different kinds of therapy against cancer.
Charlie: We should pause for a minute and just think what Gerard just said. Gerard has been sort of the pioneer of this of understanding a field that has so far evaded our ability to comprehend it. And this is sort of going back to sort of 19th century pathologists who first coined this idea that, that cancers are wounds that don't heal. And Gerard has shown very nicely how cancers don't invent new ways to proliferate and evade the immune system and spread, they hack into developmental or wound healing processes that have been activated but can't be switched off.
And Gerard has spent his entire career he's very modest, so I have to talk him up, working on this particular molecule called MYC, M-Y-C, that drives a wound healing response. So if you were to cut your wrist or your hand or whatever, MYC would be activated and it would set up a sort of wound healing program.
And once the wound begins to heal, MYC is switched off and the skin realigns and all is well. Now I'm simplifying it grossly, but the problem with cancers are that oncogenes cancer-causing genes like MYC can't be switched off. So we need to find ways of, of, of blocking MYC and other genes like it to allow that wound to heal again. And Gerard's very elegant, preclinical work has shown beautifully how that can happen. You switch MYC off and the cancer disappears.
Gerard: Thanks, Charlie. The cheque is in the post.
Brian: There's actually a question from Michael Woodruff, which is related. The question is: Can our immune system attack and destroy a developing cancer in some instances without medical intervention?
So I suppose it, because I know that you said too in our initial discussion that, of course our immune system is always preventing cancer all the time. That's one of the things that it does. But is there a point where you can begin to develop and get past a certain point and then it can deal with it?
Charlie: That, that's a very good question. I mean, there are some tumours like renal cancer for example, where there are spontaneous regressions and they are observed and well reported in a minority of patients. And we know renal cancer is one of the actually earliest tumours to be studied in the context of immunotherapy.
A mentor of mine, Martin Gore, and others pioneered Interferon Interleukin-2 in, in the treatment of this disease to boost the immune system to recognize it and tackle the tumour. So there are spontaneous remissions in patients with established disease. In the context of lung cancer I can only say that there is a very clear historical record in the majority of tumours we look at that show that the immune system has had a role in leading to the evolution of the tumour that we can see in the patient.
What does that mean exactly? Well, it's purifying selection. The clones, we can't see leave a footprint in the genome. And that sort of fossil record, if you like, is a reflection of prior immune activity, eradicating clones that should be there, but aren't there, so to speak.
Gerard: But spontaneous remission is actually very important in some pediatric cancers.
Cancers like, uh, neuroblastoma, which can be very, very, aggressive. There are four grades and fourth grade is, is terrible. You know, the, it affects kids and they're very, very sick. And then there's a variant called 4-S, which spontaneously undergoes remission relatively frequently. I mean, I don't know too much about the, the medical side of things, but it's driven by MYC, which we've talked about just now.
And, for some obscure reason, it fills the patient up with bad cells and then they all go away.
Brian: Finally, we've had quite a few comments and questions from listeners who wanted to know about the importance of glucose when it comes to developing and treating cancer. Oge Zogie-Odigie wondered: Is the theory of fasting to kill cancer cells reliable?
And if so, why is not more done to promote fasting? So do we really need to eat three meals a day and should sugar be labeled a carcinogenic food?
Charlie: Okay, so, this is a very good question. Actually it's a question I often get asked. Fundamentally, the body needs glucose. The brain is very dependent on glucose, and so this idea that glucose is a carcinogen we need to put to bed straight away: it's not. Glucose is a fundamental molecule of life that keeps our cells alive.
The reason for the question is actually well-founded, and that's because of something called the Warburg effect, where as tumours evolve, they become more dependent on glucose. They upregulate glucose transporters. They become dependent on a particular pathway, a metabolic pathway called glycolysis, which actually is a relatively inefficient way of generating energy.
But it's the cancer cells become very good at it and it forms the basis of cancer imaging, the PET scan where you give labeled glucose, and that is taken up by the cell and we can image it and see where the cancer cells are in the body, and they generally take up glucose much more than surrounding tissue, with some exceptions, the heart and the brain being two of them. And obviously the heart is very dependent on glucose, as is the brain. And depriving of patients of glucose is a very bad idea. We alluded to insulinomas earlier. Depriving of patients of glucose is very like having a very bad insulinoma. You end up in a coma very quickly because your blood glucose plummets.
So unfortunately, normal cells depend upon the same metabolites and the same molecules that survive as cancer cells. It's just cancer cells are more greedy. And so this sort of forms the basis, if you like of modern cancer therapies. We're constantly trying to work out what cancer cells need more than normal cells and to target those dependencies. And unfortunately, so far, targeting glucose dependencies has not proven very fruitful.
Gerard: And there's a subtlety here because not only do heart and and brain require a lot of glucose all the time. But normal cells, when they divide and replicate and regenerate tissues after injury again, are reliant on glucose as well.
The difference is subtle, but the difference is this, which is if you deprive normal cells of glucose, they shut down until glucose comes back into the system you have. But when you turn off glucose or supply of glucose to tumour cells, they can't control it and they can't deal with it. They can't adapt to it. So these are the sort of weaknesses and susceptibilities that we're trying to capture in our therapies. What it is that tumour cells can't bear, but normal tissues can.
Brian: Would you say that you shouldn't really try to invent your own treatments based on things that you've heard? Is this an, would this be an example of that, where you hear there's some glucose has got some role to play, therefore I should not eat glucose or cut down on it?
Gerard: Yeah. It's like oxygen. That's bad for you as well. Obviously it's not, you need oxygen to survive, but if you, starve a human being of oxygen who's got cancer and the human being's got, patient's got cancer, it'll kill the cancer. But unfortunately, it'll do bad things to the patient as well. Killing cancer cells is not difficult. You can just pour sulfuric acid on them in a, in a plate. They're not indestructible. You can't do that inside a patient.
Charlie: You know that, that's a crucial point. The take home message here. Patients and actually scientists often think, you know, curing cancer. Why is it so difficult?
It should be straightforward based on, for example, lessons from microbial bacterial, infections where we treat patients with TB with three different antibiotics or treating viral infections like HIV with multiple chemotherapy drugs that can inhibit viral replication, etc. and so people say, well, if you can prevent HIV and attenuate TB, why can't we do the same for cancers?
And the answer to that question is exactly to Gerard's point that microbes and viruses on the tree of life are very distant from us. And so we can target a viral or microbial genome very easily with drugs that don't affect the human genome at all. Well, the problem with cancer is that they've only diverged from us on the tree of life, you know, a year or a few years ago. And so they're very, very similar to us in almost all ways. And so targeting them specifically is very difficult because they share our same genomes, essentially.
Brian: Thank you both. We've run out time, unfortunately, but, do come back next week to hear another pair of experts. So Professor Charlie Swanton and Professor Gerard Evan, you are described as a pair of experts. Goodbye.
Charlie: As my dad would say, an expert is, is somebody who comes from at least a hundred miles away.
Brian: Yeah.
