Buddhini: Hi everyone, thank you for joining our first Cancer Research UK Hangout On Air. We’re doing this as a partnership between Cancer Research UK and Science on Google+. Joining me is my co-host Kat Arney, and also our two guests Fran Balkwill and Ben Willcox. Please could you introduce yourselves?
Fran: I’m Fran Balkwill and I work at Barts Cancer Institute. I work on cancer inflammation and immunity.
Ben: My name is Ben Willcox, I’m professor of molecular immunology at the University of Birmingham, I work on a certain type of immune cell and how it can recognise and destroy abnormal cells such as cancer cells.
Buddhini: You two are the perfect guests for this hangout because you have the molecular experience and also the clinical side of things as well. So let’s jump right in and ask what does the immune system have to do with cancer?
Ben: I think the bottom line is that it has a lot to do with cancer, and actually a lot more than we have thought. So we know that for people that have compromised immune systems, we know that they are more likely to develop cancer – for example organ transplant patients that have to have immunosuppressive drugs so their immune systems don’t attack the new organ. We know that they are more likely to develop certain types of cancer. But we also know that patients that develop cancer do much better clinically, they survive for longer, if they have higher numbers of immune cells in their cancer. And the third point is that certain treatments we’ve known for quite a long time, such as bone marrow transplantation, when they cure patients they depend on the immune cells in the graft attacking the tumour in the patient’s body – that’s a treatment that is used for various types of blood cell cancer.
I think on top of all that there is a whole host of experiments for many years in many different laboratories around the world that have shown that, given the right circumstances, a whole range of different immune cells are capable of recognising and destroying cancer cells. But I think aside from all of those points is the really striking amazing success of some of these new immunotherapies that have just come along in the past three years. And they are showing that a particular patients, sizeable patient subgroups, we see long-lasting responses against their tumours – even when these are late-stage patients when cancer has already spread, and even when those patients have failed other therapies such as chemotherapy. So I think that tells us something extremely exciting, and that’s that we’ve grossly underestimated the extent to which cancers can actually induce an immune response but also the extent to which that can be harnessed therapeutically, and that’s a really positive point going forwards.
Kat: I wanted to ask Fran, one of the important things in the immune system is not just the immune cells, but also inflammation, which is really your area. What we know about inflammation? Tell us a bit about what we know about that in cancer.
Fran: Inflammation is very good thing if you’re fit and young. In fact we probably wouldn’t get past our first birthday if we didn’t have the whole inflammation system because that’s the body’s first response to any noxious stimulus – anything that threatens us – the immune system fights it first with inflammation. So inflammation is generally very good. But inflammation can also be bad and that’s when it becomes chronic, not when it’s acute. When it becomes chronic and sustained, it’s that chronic, sustained inflammation that seems to promote cancer. So all the cells that we associate with acute inflammation and getting better, we find that they linger in cancer and there’s lots of evidence from experiments in animals and studies in human patients that the cells and the chemicals that prime inflammation are very prominent in cancer. And although, as Ben said, there are some very exciting treatments that showing that if you can wake the immune system up then you see responses in some cancers in some patients, but there are also a lot of earlier-stage trials going on that haven’t yet come to fruition that are targeting that inflammatory response as well. So inflammation is good when it’s acute, but when it’s chronic and sustained it can actually promote cancer. And another idea that is very interesting is how cancer is like a wound that does not heal. And you see many of the cells that are involved in healing wounds, like when you cut yourself, they never managed to resolve that wound – fibroblast cells, for instance, that normally close a wound, they’re there in cancers but they help them grow and spread.
Kat: I wanted to bring Ben in here – we’ve heard from Fran about cancer and the wound that does not heal, but what we know about the cells of the immune system? Why don’t they seem to recognise and get rid of cancer cells?
Ben: That’s a really fascinating question and I think the first point to make on that is that the immune system is phenomenally good at recognising and eliminating foreign invaders – I’m talking about things like viruses and bacteria. But problem number one with cancer is that it doesn’t derive from foreign invaders, it derives from our own cells going rogue and growing out of control. And actually our immune system has evolved rather sophisticated mechanisms to precisely avoid attacking its own tissue, and most of the time those systems work very well. But as a byproduct of them, a key point is here that because cancer derives from our own cells it’s much more inherently unlikely to be recognised by the immune system.
On top of that – we’ll maybe get onto this point in a minute – cancers are actually very clever at finding ways to deliberately dampen down the immune response. A second point here is that having said all that there is evidence, particularly from model systems, that our immune systems can do a job in eliminating cancers at the very early stages. We call this immuno-surveillance. So what we say when people develop cancer is the failure of those mechanisms, but actually when people get to a ripe old age and live to 80 or 90, a significant reason for that may be that their immune systems have been eliminating cancers at an early stage.
And a final point that is relevant here is to think about this from the evolutionary perspective. Of course cancer is primarily a disease of old age – it can strike when we are young, but it’s predominantly a disease of old age. It strikes when we’re past the age when we have kids and past the age when we’ve had time to bring kids up. And so to a certain extent if our immune systems have got us through that whole lifespan in the face of a barrage of foreign invaders and infections, actually our immune systems – evolutionarily speaking – have probably done their primary job. So judging the immune system on whether it eliminates cancer in our 80s is unfair because it hasn’t primarily evolved to do that. So a follow-on final point from that is that if our immune system is to beat cancer then it needs a bit of help, and that’s where the scientists and clinicians come in.
Buddhini: You mention how cancer is quite clever and disables the immune system. Can you tell us a bit more about that?
Ben: I’ve heard it said that the stupidest cancer is cleverer than the cleverest cancer immunologist, but maybe that’s changing! One key point is that cancers are continually dividing, the cells are dividing and making new cells, and those cells may look slightly different and actually behave slightly differently to the parental cells. And certainly evidence from model systems suggests that in the face of a strong immune response, the cancer cells that tend to survive out of that are the ones that have avoided the immune response – again, that’s this question of immune evasion, but you can also call it survival of the sneakiest in a way. You could think of it as a Darwinian process of selection. That evasion can take many forms. In its simplest form it could be one particular cell that has got rid of a particular target protein that immune cells were previously recognising and using as an initiation point to destroy those cells. If that target isn’t there the recognition doesn’t occur and the cancer cell escapes and divides, and comes to dominate the population.
I think a second point would be the idea of emergency off switches. Immune cells need to be controlled, and actually we depend on control of our immune system the whole time. So we have evolved emergency off switches on our immune cells, and cancers are very clever at pushing those buttons. Some of the new immunotherapies deliberately interfere with that process which is essentially for the cancer means they’re able to turn the immune cells off, turn them into a standby mode. And the last point is that maybe some tumours are very good at recruiting special regulatory cells, whose specific job is to calm things down – almost like getting health and safety involved – but at a time when if you want to eliminate the cancer you’re better off not having so much regulation there. So we are continually finding out new ways in which cancer eliminates and suppresses the immune system, but each of those mechanisms becomes a potential avenue through which to therapeutically exploit these mechanisms.
Buddhini: This leads me to the next question to Fran. So we talk about how chemotherapy can have a disabling immune effect on the immune system, how does that pair with how the immune system can protect against cancer? It sounds like a dual way for the immune system to work.
Fran: Let’s go back and think about what cancer is. Cancer is not just a ball of malignant cells that spread around the body and make more – that’s only half the story. What we’ve been talking about today is that the other half of any cancer is what we call the tumour microenvironment. That’s all the cells of the immune system, the ones that are suppressed, the ones that are capable of killing the cancer that have been disabled – we also say some of them are exhausted, they just can’t do any more. So at least 50 per cent of any tumour that you look at is not malignant cells at all, but it’s all these other cells that are recruited by the tumour, and often corrupted from what they should be doing to help that tumour grow and spread.
So when you treat the cancer with chemotherapy or radiotherapy, which are very common cancer treatments as everyone knows, actually you’re not just attacking malignant cells, you’re attacking all the other cells that form part of that tumour mass. And often in many cases they respond to the treatment as well as the malignant cells. The understanding about what that does – if you have very heavy chemotherapy people become very immunosuppressed and they become very susceptible to infection, but on the other side there is also evidence that some forms of chemotherapy, certainly there’s been a lot of data from mouse models of cancer to show that chemotherapy can stimulate an immune response in a tumour. So why would it do that? Is because the cancer cells are dying, and they are slightly different, and they have lots of different things inside them and they get released as they die, and that really wakes up the immune system. So it’s a bit of the yin-yang. And that’s also true of radiotherapy. And just today my lab is submitting a paper studying how short courses of chemotherapy in some of the cancer patients we work with, what it does to the tumours – we’ve been able to take samples pre-and post chemotherapy and it shows there’s some very interesting changes in the immune system. Nobody’s been able to look at this before. But this is tempered by the fact that cancers make more of those blocking molecules and try to exhaust the immune cells even more. So there’s this continual battle I think, and we must remember that lots of the treatments that we don’t necessarily think of as immunotherapies can actually affect the immune system, and our understanding of that is really at quite an early stage.
Kat: This would be a good point to bring in these new immunotherapies. They seem to have been all the rage for the past year, year-and-a-half – big stories coming out about immunotherapy being the cure for cancer. Fran please can you explain how these work? They’re called checkpoint blockers – we hear words like PD-1, PD-L1. What are these drugs, how do they work and are they as good as they sound?
Fran: They are antibodies, so we’re using a weapon that the immune system uses anyway and making them in the laboratory. What they do is that they target some of these immune checkpoints, very much as Ben explained. The immune system has to have brakes on it to stop it over reacting, but cancers have corrupted and harnessed this system and so they prevent the immune cells from recognising the cancer. So within a cancer you will have many immune cells called T lymphocytes, for instance, that are really capable of recognising and destroying the cancer cells but they are exhausted – they are inhibited. And what these antibodies do, they get into the tumour and they stop that way the tumour is suppressing the lymphocytes, they wake the lymphocytes up, if you like – they wake up and smell the coffee! – and they’re able to reject the cancer.
I think the important thing to remember though is that this approach does not work in all patients, it doesn’t work in all cancers, but to me what this is, is a really exciting light at the end of the tunnel. Some people say it’s the beginning of the end, if you like, of finding cures for cancer. Now that may be a bit of exaggeration, but it does work in some cancers in some patients. And particularly as the immune system has more than one brake, more than one way of tempering the immune responses, if you combine maybe two of these approaches, then you’re beginning to see even better responses.
A final point is that it’s also becoming clear, although is controversial, that the more mutated, the more altered, the more variable the changes in a particular type of cancer, the more chance there is that there will be an opportunity for the immune system to fight it. Because the other thing is that the immune system so enormously powerful, we always recover from colds and flu and everything else, because it attacks on so many different levels. It’s very sophisticated. And if you can just wake it up then it seems to be able, really for the first time we’re seeing that it can fight cancer.
Buddhini: I love what you said about immunotherapy making the immune system waking up and smelling the coffee. Ben, do you have anything to add? What new treatments are you excited about the most?
Ben: We’ve mentioned checkpoint blockade and that’s hugely exciting. The obvious other one is the idea of engineering immune cells to target cancer. So this idea of making designer receptors that you can transfer into a patient’s immune cells, then put them back into the patient as a kind of self replicating drug, because these immune cells can divide and expand and make a bigger immune response against the cancer. I think that’s hugely exciting and work particularly in the US has shown that that can be a really powerful way of attacking certain types of blood cell cancers. And I guess that’s really shown that it’s a very powerful platform, but one of the questions is how far can we take these therapies? Fran mentioned the idea of combination therapies. I think that’s a really exciting development because ultimately they will have limitations, and we’ll have to think about combining them to get the maximum benefit from them. But yes definitely the CARs [engineered receptors], and I could go on, but vaccination you could add to the list. Perhaps vaccination is one where perhaps there have been the absolute breakthrough results from these two other areas, but it’s certainly one to watch. There are plenty of exciting developments at the moment.
Kat: Ben, one of the things I wanted to ask you – we read a lot in the media, lots on the Internet about how to boost the immune system. There’s this idea that if you eat certain foods, or do certain activities you will boost your immune system to cure cancer. Is there any truth in this, is there mileage? It’s something that seems very prevalent in the public idea.
Ben: I’m pretty sceptical of this idea. So let me preface my answer by saying there is very good evidence that if we are going to minimise our risk of getting cancer to have a healthy lifestyle, not overeat, take some exercise, not smoke. There’s very good evidence for all of that. But beyond that, generally I’d say that our immune systems are pretty resilient, and actually something really quite extreme needs to happen for us to get massively immuno-compromised. So this idea that you can substantially boost your immune system with a natural product like yoghurt I think is probably wrong. Now I like yoghurt as much as the next person, but I just think there is no strong evidence that it’s going to be transformative. So I would urge caution – I would caution people against believing those kinds of promises. My advice would be if you have some money and you want to boost the immune system to fight cancer, you’re better off supporting a cancer immunologist than buying yoghurt. Buy the yoghurt if you like yoghurt, but don’t buy it because it’s going to transform your immune system, because it’s not.
Kat: Fran, have you anything to add on that one?
Fran: I completely agree – healthy diet, exercise. But a lot of whether you’re going to get cancer or not is in your genes – in a very subtle way, in a multigenic kind of way, and also ageing. And there is no strong scientific evidence apart from a healthy diet. The major thing to avoid getting cancer before your time is not to smoke.
Buddhini: One important thing to bring up is that a boost to the immune system isn’t always a good thing, because that’s what auto-immune disease is! Allergies and so on, that’s what a boosted immune system looks like.
Ben: It’s about how you boost the immune system.
Buddhini: I love what you said that the best way to support the immune system is to fund researchers working in it, not juicing or yoghurt. So what’s next in the pipeline, what should we be looking forward to in the future?
Ben: Watch checkpoint blockade, that’s going to be transformative. There are a lot of challenges in this area – some of these therapies are up £100,000 per patient per year so how do you apply that without breaking your entire healthcare system? The idea of engineering we’ve spoken about – expanding that. I think that combination therapies are one of the things we need to look for. What is the basis of combining two therapies over to other therapies? We can’t test them all, so that’s a real challenge but I think opens up some major opportunities. And I think another point is that coming back to the patients themselves: having the therapy is one thing, but how do we best apply it to the right patient group? We know the patients don’t respond uniformly to these therapies, so finding the right treatment for the right patient – the idea of personalising or at least stratifying the patients into different subgroups, means effectively trying to find groups that are going to respond, so you reduce unwanted side effects and increase the chances of therapeutic effects having an impact on the patient. And I think that’s one to watch – how we most effectively do that.
Kat: Fran, have you got a little crystal ball gazing for us?
Fran: I think we need to understand more about why they work so spectacularly in some patients, I think we don’t fully understand that. I agree about combinations. I think it’s going to be very interesting to look at some of these therapies that target the inflammation rather than the cytotoxic T cells, because I think that they could help the other cells. And also understanding why some cancers, sites of cancer, respond better than others. I think it’s an exciting time. There’s an awful lot to do, but I just think that to me this is the biggest progress in cancer treatments since chemotherapy.
Kat: Thank you very much. That is all the time we’ve got. I’d like to say thank you to our wonderful guests – they’ve been fantastic. That’s Fran Balkwill from the Barts Cancer Institute, Ben Willcox from Birmingham University, I’m Kat Arney and my colleague Buddhini from Cancer Research UK. This has been our first big scientific hangout so we’d like to know if you’ve got any questions you can leave them on the Google Event page, also if you’ve got any feedback for us, because we’d like to do these again. Thank you for taking part and for watching at home.
Buddhini: Thank you very much for joining, and feedback would be appreciated because we hope this will be the first of many to come. If you couldn’t watch this live we’ll be sharing the video on YouTube afterwards. Thanks for joining, bye!