Immunotherapy: Cure for Metastatic Cancers? - James Larkin

Immunotherapy cure for metastatic cancers. I'm gonna be thinking, um, a little bit about that, about what we've seen, particularly in the last 10 or 15 years with immunotherapy to treat cancer, some of the challenges, uh, and also what we might, um, expect to see, uh, over the next five or 10 years. The Gresham College lecture that you're listening to right now is giving you knowledge and insight from one of the world's leading academic experts, making it takes a lot of time, but because we want to encourage a love of learning, we think it's well worth it. We never make you pay for lectures, although donations are needed. All we ask in return is this, send a link to this lecture to someone you think would benefit. And if you haven't already, click the follow or subscribe button from wherever you are listening right now. Now, let's get back to the lecture. So, um, when I was at medical school, um, and to some extent when I was training in oncology, I think many people thought that cancers that had spread metastatic cancers were intrinsically incurable, uh, contrast, uh, with leukemia lymphoma. So-called hematological cancers, which we've known for decades, actually really since the 1950s, are potentially curable often with traditional, so-called cytotoxic chemotherapy, even though the cancers have spread. But solid tumors really a different story altogether with one or two exceptions. So, for example, germ cell tumors, it's a rare type of cancer, are, uh, potentially curable. Um, but most solid tumors were regarded historically as incurable. Uh, and I think that's one of the reasons perhaps, um, that oncology may not have been considered necessarily an attractive career for, uh, doctors in training to go into, which I think historically really was the case. Um, and an example of this would be melanoma, which is the type of skin cancer that I treat. Metastatic means spread around the body. So melanoma spread around the body historically. Um, and these are some curves. I'll explain a a bit about that in a minute, um, from a paper about 10 or 15 years ago now. So these, uh, are called survival curves, and if you start at the top left hand corner, um, that means that everybody's still alive. And then with the passage of time moving from left to right, and if you look at the bottom, and you can see that's measured in years here, as people die, um, from the disease, then the curve goes down. So if you, and I dunno how well this projects, but if you look at, say, the five or the 10 year mark for people with metastatic melanoma, historically you could see, uh, that only five or 10% of people were still alive reflecting, if you like, the aggressiveness of this disease once it had spread. And also the fact that actually we didn't really historically have any effective treatment at all for this disease once it had spread. And in fact, when I started as a consultant about 15 years ago, the same drug was being used to treat melanoma that had spread, uh, as was first used in the 1970s. So really in this disease, at least decades, uh, without seeing much progress, you may be able to see there, um, that the different colored lines, uh, represent the fact that according to which part of the body the cancer had spread to, and, uh, a blood test, LDH lactate dehydrogenase, there'd be a little bit of variation in survival. But the general picture here is that unfortunately, most people with this disease, um, did not survive long in the average, which it says in the title of the slide, the average survival for this disease was six to nine months. Although you will see, uh, and I've said this already, that actually for reasons that I'm still not sure we really understand that there is a group of people who, despite the fact that cancer had spread, um, they survived in the long term. So what about cancer immunotherapy? Uh, the first point I think I'd like to make is that this is not a new idea. Um, I could have picked lots of examples historically, um, but I mention here William Coley, who was a US surgeon, um, and actually he treated, uh, cancer patients with bacteria, which is, uh, now known to be a streptococcus. And notice that in doing that and in a sense, um, uh, causing infections in the patients, sometimes that was linked, uh, with cancers, uh, regressing. So that was well over a hundred years ago. And there are other examples on the right. Um, and this is out of date. Um, it's really a graph that's showing the interest in cancer immunotherapy over the last 10 or 15 years really has grown. So a couple of points to make there. One is that there's actually lots of different types of immunotherapy that have been looked at in clinical trials over the last 10 or 15 years. And I would also make the point that prior to that, although there was interest in cancer immunotherapy, uh, it really wasn't a major enterprise. And, um, I could probably use as an example of that sort of 20 years ago, if you went to a, a big, uh, international cancer meeting and you went to one of the immunotherapy sessions, that'd hardly be anyone in, in the room at all. Uh, whereas now if you were to do that, it would be one of the, the most popular sessions at the meeting, sort of standing room only. So it really has changed a lot in my working lifetime so far. So if you've got a good immunotherapy for cancer, what would it look like very broadly? Well, you would want long-term benefit. In other words, you'd want the treatment if you delivered it to have, um, durable impact on the cancer, meaning over years, it's a treatment that you'd want to work for years. I think that almost goes without saying. The driver for that, I think is the second point I make there duration of response, meaning that if you give a treatment, you want it to work for a long period of time, if the disease is gonna be well controlled From the patient perspective, it would be good if you didn't need to give treatment for a long time. In other words, if you could give treatment for a period of time, however long that is, maybe weeks, months, something like that, stop the treatment, but then you would want the cancer to still be controlled after the treatment has finished. So that's quite an important idea. And I would potentially contrast there some of the other treatments that we give for cancer, some of the other drug treatments. So targeted therapy, for example, I'm not really gonna talk about that much, but typically if we're giving targeted therapy for cancers that have spread, we will give it for very long periods of time, sometimes even, sometimes even indefinitely, meaning as long as it was working. So there's no real idea there actually with targeted treatment of the idea of stopping the treatment and the benefit being maintained, generally speaking, safety of the treatment is obviously important. This needs to be a treatment that you can deliver to patients and, um, ideally not have too many serious side effects. And I think to some extent, all of those will go together, um, to generate the maximum possible quality of life for patients, which is the final point there. So what does cancer immunotherapy mean? Um, I would make the point that often, particularly in the last 10 or 15 years, uh, people will interchangeably use the term cancer immunotherapy with immune checkpoint inhibitors. And I'll say a bit more about that in a minute. Um, immune checkpoint inhibitors, uh, are listed at the bottom of this, um, slide. Sometimes the term immuno-oncology is also used, and you'll hear that being bandied about a little bit. I'm not particularly fond of that if I'm honest, but I'm just making the point with this non, uh, exclusive diagram, if you like, that there are lots of different possible types of immunotherapy for cancer. It isn't just checkpoint inhibitors. So I've listed cytokines, uh, t-cell therapies, vaccines, dendritic cell therapies, and oncolytic viral therapies. As other examples, and I apologize to anyone who's listening, uh, if I haven't included something, um, which is their particular interest, but it's a broad term and immunotherapy is a broad term as well to treat human diseases. So I think that's, uh, worth bearing in mind. But I am going to spend at least, uh, the bulk of this talk thinking about immune checkpoint inhibitors because, uh, I think that's what re really has brought immunotherapy for cancer center stage, um, in the last 10 or 15 years. And we've seen real impact in clinic, uh, with immune checkpoint inhibitors. So what does this mean? Well, this is a cartoon and that blue blob in the middle is a T-cell, an immune cell, and at the top, uh, where it says interferon and interleukin two. So those are cytokines. They're actually substances, which our bodies are producing the whole time as part, if you like, of normal life and normal physiology. And the idea with cytokines is that they give, if you like, a, what you might call a non-specific stimulation to the immune system. And in fact, cytokines have been used therapeutically to treat cancer for a long time now, really decades. And sometimes cytokines can work, uh, to treat cancer, although often the doses at which they're given means that there are quite a lot of side effects. And interleukin two is a good example of that. The doses that are used to treat cancer are orders of magnitude greater than the normal cellular doses at the bottom. Uh, I've shown immune checkpoint inhibitors. So rather than stimulating, uh, at the top, we're talking about removing a break from the immune system at the bottom. And maybe that's the sort of critical concept to bear in mind here. And I've listed CTLA four and, uh, PD L one, which are probably at the moment the best known immune checkpoint inhibitors and certainly the immune checkpoints, uh, that have been targeted most with drugs over the last 10 or 15 years. But actually, and again, this is a T-cell in the middle, there's lots of possible, uh, immune checkpoints which can be targeted with drugs on the right. And again, this is a non-exhaustive list. Um, there are inhibitory receptors and I would pick out CTLA four, uh, at the top, and then PD one just underneath and perhaps lag three at the bottom. All of those targets have drugs, uh, which have got regulatory approval to treat cancer globally. But if you look on the left and you look at some of the other, um, targets that I've listed there, there's actually been intense activity over the last 10 years or so to develop drugs that target these molecules. But at least so far, I'm not really aware that any of those efforts have actually resulted, uh, in drugs which have been approved to treat cancer. So this isn't a, uh, a straightforward, um, problem. Uh, and the immune system is par excellence, a complicated system. Just to take, uh, one final step back if you like, um, before I start showing you some data and talking about the benefits of these treatments, I think it's really important, uh, to note that the work, the scientific work that led to the development of these drugs was recognized over five years ago now with the Nobel Prize in physiology or medicine, uh, to Jim Allison and Suko Honjo who are shown there. And, uh, I'm not expecting anyone to read the small print at the bottom, but perhaps you can read the headline, uh, discovery of Cancer Therapy by any emission of negative immune regulation. So it was really their work and others around the world to scan. This has been a global effort that provided the basis for the development of these drugs. So, uh, what are the benefits of immune checkpoint inhibitors? Well, remember the curve that I showed you earlier on, which you could think about as, uh, what metastatic melanoma looks like in terms of survival before we had any potentially effective therapies. What I'm showing now is something similar, but this is a group of people who've been with metastatic melanoma treated with a drug called ipilimumab, which is an anti CTLA four drug. If you think to what I just showed you about immune checkpoint inhibitors. And this is the chances of surviving after treatment with ipilimumab. Now this is a drug, uh, that's given four times every three weeks as an outpatient. So it's only three months of treatment. And we can see here, and this is, uh, a pooled analysis of just under 2000 patients that actually, if you look at the passage of time there, it looks like there's about 20% of people who are long-term survivors after treatment with this drug. That is more than what I showed you before. In other words, the five or 10% of people who might be long-term survivors because of the natural history of the disease. And also the other point I would make here is if you look at the shape of that curve, let's, if we pick out 36 months, the curve's really quite flat after that. So meaning that if you have this treatment and you're still alive after three years, there's a good chance that you'll be alive at five years and there's also a good chance that you will be alive at 10 years. And that's certainly something over the years that I've discussed with my patients in the clinic, uh, when they're having this treatment. So for me, this was the first, um, clinical, uh, evidence if you like, that this might be, uh, a treatment with potentially long-term benefit. So then if we come up to date or more up to date, at least, this is another clinical trial, and again, I'm showing survival curves. And that black line at the bottom is the people who were treated with ipilimumab. But this trial actually looked at two other things. So ipilimumab was, if you like, the control arm at the time the trial was done, and it started about 10 years ago. The green line in the middle is nivolumab, uh, so-called anti PD one drug. And the sort of orangey line at the top, um, is the combination of nivolumab and ipilimumab together. So again, we've got over five years of follow up here. Again, you can see that the curves are flattening, as I showed you before. And for me, the real take home message here is that with treatment with nivolumab or the combination of nivolumab and ipilimumab, around about 50% of people were alive at five years and beyond. And, uh, for the record, I'm gonna say that pembrolizumab, uh, a very similar drug to nivolumab actually shows very similar results. But I'm not gonna show you the data for that. So that was survival. In other words, the chances of, um, being alive. Um, but do we know what the chances are of actually, uh, surviving the melanoma? In other words, if people are starting to die at these later time points, is it because they've died of the cancer or they're beginning to die of other things? It's a really important question to ask. And so from this trial, we actually analyzed melanoma specific survival. And actually you can see if you look at this, that the melanoma specific survival is even better suggesting at least that once you control the melanoma in the very long term, then it might be that people start dying of other causes. If We move to kidney cancer, which is the other disease that I treat, and I don't necessarily, uh, want you to focus too much on the specific shape of these curves, but this is a kind of a similar trial to what I've just showed you in kidney cancer of nivolumab and ipilimumab together. And actually these data were presented very recently in the last few weeks at a meeting in San Francisco in the us again, with over five years of follow up. The shape of the curves is actually a little bit different. If you look at the left hand curve, there isn't that flattening at the early time point. And you can see even at 5, 6, 7 years, the curve is still, if you like, going downwards, meaning that people are still dying. The question though, for me, and I dunno, the answer to this question, is what is the disease specific survival here? Are these people at these late time points who are dying of kidney cancer? Or is the kidney cancer still under control and are they dying of other causes? So I don't know the answer to this in kidney cancer, but for me it's a really important question for these new treatments, what's really happening in the long term? Which brings me to the question of how you define cure. I don't really have an answer to this, but one way to define it might be to say, to return to normal life expectancy for your age and level of health. Um, and so from a formal perspective, it's difficult to say that these drugs are curative because we haven't really been using them for long enough, because we'd need decades of follow up really to be able to say that with formal confidence, if you like. But nevertheless, from what I've shown you and certainly from my experience in clinic, having been using these drugs for 10 or 15 years, it does seem that people are potentially cured with these drugs. And I've shown you the example of melanoma. I've shown you some data from kidney cancer. Obviously there's lots of other different types of cancer and certainly in lung cancer, uh, for example, we can see what looks like to me at least, the possibility of cure of people with lung cancer with these drugs, albeit a, a lower proportion. So the next, uh, point I want to make is that it's not just about immune checkpoint inhibitors. And I've said a little bit about this already, but I think it's an important point to make. And I'm just gonna show, uh, a couple of slides, um, for a drug called tivas. Now, uveal melanoma, meaning melanomas that start in the eye, they're rare, but they behave very differently from melanomas that start in the skin cutaneous melanomas. And they've been even more difficult to treat than skin melanomas in the past. And the drugs that I've just shown, immune checkpoints, inhibitors, nivolumab, ipilimumab, pembrolizumab really don't work very well in uveal melanomas in many ways. Actually. Uveal melanoma biologically is a different disease from cutaneous melanoma. So, um, these data, uh, that I'm showing here, and this was presented at an oncology meeting in Madrid, uh, within the last, uh, six months or so, uh, for something called tifa. And that that diagram on the left may not, um, project particularly well. But the idea is that this is basically, uh, something t-cell receptor bispecific is the technical term for it, but you can see at the top is the melanoma cell at the bottom, uh, is a t-cell and immune cell. And what this is doing, this drug is to connect the two together connecting the immune cell to the cancer cell. And the reason really to show this is actually it's working in a really different way from the immune checkpoint inhibitors I've just shown you. This is a class of drugs. This is just one of a class of drugs that's being developed. And in uveal melanoma, this is another, um, survival curve. And this is with three years of follow up for the trial of tus and uveal melanoma. This is actually the first ever treatment in this disease which has been shown to prolong survival. So that's an important landmark. If you look at those two curves, the people with the tuss, but the top and those who were in the control arm of the study, um, below you might say, well, there isn't really that much difference and the curves are, are still dropping off after three years. But prior to this trial, there had been dozens, hundreds of trials in this disease, nothing had previously shown any impacts. So for me, that's the main important point that I want to make in showing this, and I'm sure we'll see more of this in the future. So what about adjuvant treatment? What does adjuvant treatment mean? Um, I always forget <laugh>, I say this in clinical lot to patients as well, whether it's in the Latin or Greek, I'm sure most people in the room will know. But the idea of adjuvant treatment is it helps the definitive treatment. So the definitive treatment usually being surgery or radiotherapy, sometimes the point being that someone might have a cancer removed and then they may have an adjuvant treatment afterwards to reduce the chance of the cancer coming back. So this idea of adjuvant treatment, um, is very commonplace in oncology, in breast cancer and bowel cancer. People have been using adjuvant treatment for decades. It might be hormonal treatment, it might be chemotherapy, but the idea that you have your surgery, then you might have drug treatment afterwards for a period of time, often a year to reduce the chance of the cancer coming back in the future. So what does immunotherapy look like? What do checkpoint inhibitors look like? Um, in the adjuvant setting, the reason this is important is obviously if you can prevent cancer spreading in the first place with adjuvant treatment, then it's a better place to be in from the patient perspective and actually from the oncologist perspective than having to treat cancers that have spread. So it's, it, it's an important concept, and again, this might not, uh, project particularly well, but in melanoma until about five years ago, we had no evidence for the benefit of using immunotherapy earlier in the disease stage three disease, which means involving lymph nodes. And this is now around about five years of follow up from an immunotherapy trial, um, in stage three melanoma showing very clearly that if you have a year of immunotherapy after you've had surgery for stage three melanoma, there's a significant reduction in the chance of the cancer coming back. And this is now a treatment that's been widely adopted, uh, from a regulatory perspective and a reimbursement perspective around the world. So the point I'm making is that generally the way that anti-cancer drugs are developed as they're initially treated in stage four or metastatic cancer, but the nature of it, the nature of of this is that then we try and test them in earlier stages of the disease to see if we can reduce the chance of the cancer coming back. I show melanoma as an example here because I think we've got the most, uh, mature follow up for melanoma at the moment. But actually this is a very widespread approach in lots of different types of cancer. So, uh, a couple of words about, so-called neoadjuvant, um, treatment. So, uh, I may have labored, uh, adjuvant treatment, uh, a little bit, but the idea of neoadjuvant treatment is simply starting the adjuvant treatment before you actually do the surgery. So the conventional approach would be do the surgery, then give the adjuvant treatment. And the idea of neoadjuvant treatment is really simple, is that you give that, you start the adjuvant treatment and then you do the surgery after a period of time. So shown here in this, um, cartoon, um, is along the top, um, the conventional approach to this that you remove the tumor, uh, and then you give the immunotherapy afterwards. And then along the bottom you can see the idea, well, if you give the immunotherapy first, perhaps you can stimulate any immune cells that are in the tumor, particularly in lymph nodes. And maybe as a consequence of doing that, your immune system is activated better and then it results in less chance of the cancer coming back in the future. Very, very, very simple idea. How does that translate into clinical practice? Well, um, in the world of oncology, and I think probably in most branches of medicine, our kind of gold standard, if you like for evidence for benefit, is doing a randomized trial. This is a randomized trial. It is a US academic study, SWOG 1801 is the name of it. And again, it's this really, really simple idea shown here, uh, that you have the standard approach, which is along the top. Um, and so the, the, the people in the trial had surgery for stage three melanoma, and then they had a year of treatment with pembrolizumab, an anti PD one immunotherapy drug. So that was the standard approach up until that point. And then at the bottom you have the neoadjuvant arm of the study. And the only difference here is that the treatment was started around about nine weeks before surgery. Then the people went on to have their surgery and then they finished off their treatment afterwards. So very, very, uh, simple and I would say powerful clinical trial design. And the, the headline here, and this is from a, a paper published in the New England Journal of Medicine around about this time last year, is just from this one very simple manipulation, the chances of the people being, uh, event free, which means that basically the melanoma hadn't come back after two years of follow up was a difference of over 20%. And again, you may or may not be impressed by that, but that's the kind of level of benefit that we actually pretty rarely see. And so in melanoma, uh, there's various, uh, regulatory issues associated with this. But in melanoma, those of us in the community think that this is ideally a treatment that we would want to use based on the results of this trial. So I really want to make the general point that actually it's not just about having immunotherapy or checkpoint inhibitors. There's a lot about how you use them best to get the best outcomes for patients. So moving on to challenges, I've talked about benefits, um, well this is probably the subject of a talk in its own right. I've put a list here. Um, it's not an exhaustive list. Again, uh, I think first and foremost the challenge to is to increase the cure rate from what we're doing. Um, and I wouldn't just apply that to melanoma, I apply that across the board. Do we really understand why the drugs work and why they don't work? Well, I'm not really sure we do at the moment, although there's plenty of work on that. If we did, could we develop useful biomarkers, in other words, markers of biology, that it would allow us to select a particular treatment for a particular patient in a particular situation? I think that's still in its infancy, honestly. Um, can we combine these drugs to get more out of them? Are we giving the treatments for too long? I said at the beginning that one of the things about immunotherapy if it was successful is that ideally you wouldn't give treatment for a long period of time. Perhaps you could give it a short period of time. Again, most of the clinical trials have used quite long periods of treatment a year or two years or something like that. Is that too much? Well, I suspect it is in certain situations, but we don't really have the tools at the moment in clinic to work that out. I haven't really, uh, said much about, um, side effects, but I'll say a bit about that later on. But again, the management, the dealing with side effects in my view for these drugs is still, uh, relatively in its infancy in terms of trying to manage them as best we can. Um, we tend to give people high doses of steroids to manage side effects, which are powerful immunosuppressive drugs. Is that the best way to do that? Is there a one size fits all? We dunno the answer to that. And there's a quite a big question as well about understanding long-term side effects. So with checkpoints inhibitors, this is a new class of drugs that's only been used in the last 10 years or so. What are the long-term consequences of these drugs? We simply do not know at the moment. So that's a really important area of study. If we're saying that we're gonna be curing a group of people and returning them to normal lives, are there any unexpected long-term side effects? So just to pick up, um, a couple, uh, of those points for the purposes of illustration. Uh, might there be new targets for checkpoint inhibition or, I've said a little bit about this already and I've shown the cartoon again, but a massive amount of effort has gone into this, um, certainly in industry and in academia over the last 10 or 15 years, and I'm not sure about that, whether we're gonna see more from other immune checkpoint inhibitors in the next five or 10 years. Um, this point about biomarkers, I'm making it on this slide as well, if we could rationally select who to treat with a particular drug, it might be different. But again, we haven't really got that, at least not in any detail at the moment. Um, can we get more from the targets that we have at the moment? So CTLA four and PD one, PD L one? Well, that's a very interesting question actually. There's quite a lot of, uh, so-called second generation anti CTLA four drugs. Umab is, uh, an example of one of those. And so this is kind of a question of trying to re-engineer the drugs. So you're still hitting the target and potentially minimizing the side effects associated with that, which is a problem for anti CTLA fours. Uh, and this again, may not project, but actually from some very preliminary data from a couple of years ago, you can see activity for this drug really in, uh, types of, uh, cancer that we haven't really seen much benefit from immunotherapy. So sarcoma, uh, and ovarian cancer, and also some colorectal cancer. So that, I would say watch this space in terms of second generation CTLA fours. So what about side effects? Well, I'm talking about immune checkpoint inhibitors and, uh, par excellence, and I say this to patients, almost any part of the body can be affected by side effects from immune checkpoint inhibitors. And that's a really important point. This is a list of, its for want of a better word, meaning inflammation of different parts of the body that the drugs can cause, uh, colitis, inflammation of the colon causing diarrhea, pneumonitis, lungs, and so on and so forth. So the point is that some of these are more common than others, uh, on the left of the vertical line, uh, but some of them are more serious than others on the right of the line. So for example, uh, myocarditis inflammation of the heart is a particularly dangerous side effect. Um, and I would really make the point here that some of these side effects can be permanent. And again, if we're thinking about curative treatment and people trying to return to a normal life, that's obviously extremely important. We don't really have anywhere near the quality of evidence for managing side effects as some of the evidence I've just shown you for benefit of the drugs. And again, if people are interested, we can talk about why that is, uh, in questions afterwards. Um, and I've said this already, but a lot of the time we're using very high doses of steroids like Prednisolone, uh, to manage these side effects, and certainly some that's something that worries me, um, for various different reasons, not least the side effects of steroids. So the final, um, segment, I would like to think a little bit about, um, new Frontiers for cancer immunotherapy. Uh, back to my, uh, cartoon diagram about different types of cancer immunotherapy. And I'm just gonna pick out a a couple of things. One of them, um, is, uh, vaccine therapy. And this is one example in melanoma. And so, uh, basically this is a small randomized trial, uh, looking at, uh, a, so-called individualized neoantigen therapy, INT at the top in combination with pembrolizumab, an anti PD one drug, uh, in melanoma in the adjuvant setting. And I've explained what that means, um, already. So just to focus on how this works, and again, I apologize, this is a little bit involved. I think the important point here is that this is individualized, and the reason for that is that how this works is the tumor is sequenced and as a consequence of sequencing the tumor, uh, proteins are defined and they are used to make a vaccine, and then the vaccine is different for every patient. And so that's the sort of left hand side of this, and some of the workings are described, um, on the right hand side. And I suppose that the important background point here for mRNA Messenger, RNA vaccines, is that this actually is a, it's an interesting field. It's been going on for decades, um, and there's a few people in the world who've devoted their careers to this, but it only really achieved prominence when covid came along, as I'm sure lots of people will know. And the mRNA vaccines within months went from pretty much the drawing board to being delivered to people to, um, protect against covid. And that type of technology is being now applied to cancer as well. So what did this look like in this trial? This is a small trial, um, and the bottom line is people who are treated, um, with pembrolizumab. So that's the standard treatment in this situation. And then the line above that is the people who got the vaccine, uh, and pembrolizumab. And there's several caveats to this. One of them I've said already, and I've said, again, it's a small trial, so you need to be a bit careful. Uh, there's relatively limited follow up. The X axis here is in weeks, but nevertheless, you can see pretty clearly, um, that the chance of the cancer returning was significantly less with the vaccine and with the immunotherapy. And this has now led, um, to a bigger trial. Hopefully it'll be a confirmatory trial. So-called phase three trial, which is, uh, recruiting around the world. And certainly, um, we are part of that. So this is very exciting, and actually it hit the press, uh, when it came out. The way that we measure the difference between, uh, the two groups is, is the hazard ratio, and it's actually shown there for people that are interested. But again, it's a magnitude of benefit that we don't see very often. And I had actually lots of patients coming to my clinic saying, can I have this treatment? Because it, it featured in the press and it's promising, but again, it's a small trial and I think we need to see, uh, further data. So that's, uh, vaccines. Uh, what about cellular therapy? Um, well this isn't new either. Um, Steven Rosenberg, who's in his mid eighties now and still working, uh, at the NCI in the US has really been doing this since the 1990s with colleagues, and he's really the pioneer, I would say. Um, and really the idea, uh, with cellular therapies, you actually take immune cells outta the patient and then you manipulate them in the laboratory and then you give the product, and it's called a product rather than a drug back to the patient with the idea that you've, if you like, reinvigorated or rejuvenated, uh, those immune cells so that they can attack the cancer. So it sounds like a simple idea. Um, and historically over the last sort of 10, 20 years, there's been lots of reports of this type of, uh, therapy, uh, for treating cancers, not just melanoma, but various different cancers. It is logistically a complex treatment. I think it's fair to say that's one thing to say. Um, and the, the treatment that we give, and I'll show a bit more about this in a minute, to deliver the cellular therapy back for the patients is actually fairly intensive and people actually need to be pretty fit to be able to, um, receive this type of therapy in the last 10 or 20 years. The other problem with this was that actually the time taken to generate the product was often months, which is a long time if you've got a cancer that spread and it hasn't responded to other treatments and you know, you're not in the best of health. So the, the group of people that can benefit from that was relatively limited as a result of this. So those have been the, uh, the kind of the background issues, if you like. And I suppose that's what I'm saying there with that bottom bullet point, that the, you know, if your cancer's growing quickly and you are really ill, then actually you might not have months to wait for a cellular therapy product to be generated in a lab. So, um, this is a sort of a cartoon of how this works in practice. So at the left hand end, um, you take some tumor tissue, uh, so that's usually removed with an operation, um, that, that might be a centimeter or a centimeter and a half, uh, bit of tumor. Um, this, um, cartoon, this diagram, uh, refers to something called Lucile, um, which is a product that's generated, um, by a biotech company called Ivan in the us. And so then the product is generated, that's that box along the bottom. And the critical thing here for me at least, is that it's three weeks. So the product is generated in three weeks. Meanwhile, um, the patient who's gonna get the treatment comes into hospital and they have something, uh, that's called non myeloablative lymphodepletion. So what that means is giving chemotherapy, um, if you like to make space to give the immune cells, make space within the body back to the patient, you then give the uc infusion, that's number four. And then after that you give something called high-dose interleukin two, which I mentioned at the start. So this is a cytokine, um, so a potential stimulant of t-cells. And that's actually given in quite high doses and it has quite tough side effects and people need to be in hospital to have this treatment. And then when all of that is done, a patient gets discharged from hospital. And so typically people will be in hospital to have this treatment for a week or two, uh, for close monitoring and uh, uh, to make sure that the side effects, particularly of the interleukin two are managed properly. It's not an outpatient treatment at the moment. So what does this look like, this product life elusal, um, in melanoma? So, uh, a trial has been done over the last several years in people who've got melanoma that's spread, they've had treatment with checkpoint inhibitors, the treatment with checkpoint inhibitors hasn't worked, and then they're in a situation where there isn't really a well-defined treatment option. And with life elusal, this has got a waterfall plot. And if you imagine the horizontal line going through the middle below the line, uh, each of those lines is a patient who is treated with this. And it's a measurement of tumor reduction, basically. So you can see all of those bars below the line on the right hand side of people who experienced tumor reduction, uh, with this therapy. And this is just over a hundred patients, so it's not an enormous trial, but it's, it's still, for me at least, um, pretty compelling evidence of potential benefit from this treatment with the caveats that I've mentioned already. What about side effects? Well, I've sort of, um, said this already and, and you can read out the side effects on the right hand side, but actually, interestingly enough, most of the side effects with this treatment are associated with the side effects of being hospital, the chemotherapy that I mentioned in the interleukin two. And this graph on the left hand side is really showing you that all the side effects that that sort of bunch line, uh, are happening when the people are in hospital and once they've had the treatment, they're discharged from hospital. Actually the side effects are pretty rare. So one way to think about it, and I say this a lot, um, to patients if you're having this kind of treatment, is it's a bit like having a bone marrow transplantation. In other words, it's a tough intensive treatment right at the very start, but you're trying to do something with durable benefit and it's a one off treatment. This, it's delivered. Then again, it's a bit like a bone marrow transplantation. And that's, that's kind of how I think about it a little bit. So what about moving forwards with cellular therapy? Again, this is a, an another cartoon and in many ways the details of this don't matter, but from the perspective of molecular biology, there's all sorts of different ways that you can potentially improve on this treatment by re-engineering the treatment, making it smarter, making it kinder. So I think we're gonna see lots of this in the next five or 10 years, and there's enormous interest in this in academia and in industry around the world to try and develop this, uh, therapy, um, to make it work better. Is this just melanoma very reasonable question to ask? Well, we don't know at the moment 'cause I think it's too early to say, uh, but what I'm showing here is again, some waterfall plots. Uh, you'll gather, uh, from the thickness of the bars, that these are relatively small numbers of people in these trials. You can see that it's actually just a handful. But the point of this slide, the melanoma is on the left hand side so that you can see with melanoma treatment with pembrolizumab, anti PD one and uc altogether, pretty much everyone who was treated had tumor shrinkage. But more importantly, um, I would say as you move across the middle group is head and neck cancer. And then the group on the right is cervical cancer. So, um, these are both cancers and particularly cervical cancer where immunotherapy hasn't really had a particularly strong track record. So I think these are really potentially quite encouraging early data but require confirmation. So this is pretty much my final slide in bringing us, uh, right up to date. So I mentioned that Ivan Therapeutics make life elusal, um, uh, regulatory decision is expected from the FDA in the US uh, on the 24th of February, which is the end of next week. I dunno what that's decision's going to be. Um, but if the FDA do approve this for the treatment of refractory melanoma, uh, this will pretty much be the first regulatory approval that we've seen for a cellular therapy to treat a solid tumor. So I think all of us in the field are, are hotly anticipating, uh, and looking forward to this decision. So watch this space. So to summarize, um, historically I think it is fair to say that pretty much all metastatic solid tumors, um, were incurable, uh, checkpoints inhibitors are, I think, and I hope I've been able to show you are probably curative in some people who've got metastatic, um, melanoma. But in melanoma I still make the point that half of people will die from this disease. So there's still a lot of work for us to do. Those of us, um, who treat melanoma have genuinely been excited to see the vaccine data that I showed you and also the cellular therapy data over the last, um, few years. And perhaps the key point to make is the success of immune checkpoint inhibitors has really, I think, revitalized the field of cancer immunotherapy, not just in melanoma. And I hope, and I expect actually to see further progress in the next five years or so. Um, my acknowledgements are to our patients and their families, first and foremost, many of whom have participated in some of the clinical trials that I've shown you. I'd also like to thank, uh, my team at the Marsden who really do all the work. Carrying out clinical trials is an incredibly, uh, um, resource intensive, uh, activity. It's very tightly regulated. It really requires a big team of people to work together to do it best. Uh, and it's very much a multidisciplinary activity. So, um, uh, trials team is led by Ellie Carlisle, uh, in the office. And Kim Edmond, who's our lead research nurse, and Dr. Vu, one of our clinical fellows has, uh, helped me put the talk together this evening. So I'd like to thank her as well. And I'd also, uh, like to thank, um, collaborators and friends in the UK and internationally in industry, um, uh, in academia, um, in government as well, and also actually in advocacy groups. I haven't really mentioned anything at all about advocacy, uh, groups this evening, but it's been a critical, I think, piece of the jigsaw, uh, with trying to work out which trials to do and to sometimes generate, uh, pressure, uh, to help make things happen. Um, so I will thank you for attention and I think we've got some questions and answers next. So there's quite a, a detailed question that has lots of like extremes. So I'm gonna read it as it is. And then I think we might need to put it into layman's terms for, for the general audience. Could slash does using immunotherapy concurrently encourage tumor propagation due to cancer promoting immune cell phenotypes such as tumor associated macrophages? So in layman's terms, could we actually make the cancer grow faster because of the different environment that we're creating around about the tumor cells? Yeah, I mean, to to, to be blunt, I I think you could speculate almost anything, especially with the immune system 'cause it's so complicated and there's so many checks and balances. So it, it's difficult to refute that. But I think a lot of this will then come back to clinical trials and actually demonstrating benefit. Um, and I think if you are seeing benefit in clinical trials, it's really difficult to argue against that. But I think maybe the take home for me is that once you move, if you like, from preclinical models, the laboratory, that kind of thing into clinical trials, at the end of the day it's quite difficult to predict and one can almost make an argument in all sorts of different ways. And I'm sure lots of people know this, that this will, the other thing might happen, but I think you need to test it. And maybe the other point I would make there with, with clinical trials is it's really important when you're doing this to try and characterize as best you can the tumor from a biological perspective. Because, you know, in the old days, uh, and again, many people realize this, we, we tended to just do clinical trials and not really get that kind of in depth understanding. But I think it's bold on all of us to really try and do that academia and in industry. So that's how to answer that. I think Absolutely there is. Hello there. My name's Carmen Blair, I'm a hospital doctor in emergency medicine. And my question is about cost. I didn't hear you mentioning the cost of these drugs once the, you have mentioned the duration of the treatments one to two years and the patient gets severe side effects, hepatitis, pneumonitis, colitis, some permanent, and then the cost, the NHS is not in a state to provide these drugs once these manufacturers starts asking thousands of pounds to treat one patient. What about the cost of these Three? Yeah, so, um, in terms of reimbursement in publicly funded health systems, NHS and others, for example, in, in most of western Europe there are, um, HTAs health technology assessment panels. Ours is called nice, which takes into account the benefit and the cost and then makes a decision about whether it's felt to represent good value for money or not. And what I would say about, uh, nice, let's say in melanoma, which is what I treat over the last 10 or 15 years, is that pretty much every drug that I would wish to be available has been made available based on that type of equation. You know, what's the benefit and what's the cost, which is obviously great for patients in this country, but NICE doesn't always make positive decisions. Um, and you know, if you've got a treatment where really the benefit doesn't seem to be that much or you're not able to define clearly the group of people who are really gonna benefit from the treatment, then I think, you know, we all pay taxes that, that then it's not gonna be an appropriate use of of public funds. So I think it's, it's interesting perhaps a queen digression. So, you know, 15 years ago, uh, in the US people used to sort of laugh about nice and you know, there was quite a lot of negative publicity about that. But interestingly enough, even in the US in the last five or 10 years ago, this is very much, uh, you know, an agenda item, shall we say. And, and yeah, of course the cost needs to be justified. It's as simple as that. Um, side effects, I mean A-A-A-A-A, a brief note on that, I mean the cost of managing side effects, it's, it's rare for people to need to be hospitalized for long periods of time to manage side effects. It does happen, but it's quite rare. But, um, I think the problem with side effects, and I sort of hinted at as I went along is there hasn't really been that much effort honestly into really understanding the biology of side effects, the same way that we really understand the biology of cancer. And that's honestly a bit of a gap. Um, and you know, I think all of us who are in clinic would like to see a better understanding of side effects. So let's say we didn't just give steroids to everybody, we could say, well actually the colitis is being driven by such and such in this situation, we're gonna use this particular drug to manage it for a short period of time. So there's a lot to do there. Thanks James. Moving on to another one here. So why do you think that chemotherapy has stayed as the predominant form of cancer treatment, although it's so unspecific to the cancerous cells? Well, I would go back to some extent to the history books here with, um, traditional chemotherapy, cytotoxic chemotherapy, whatever you wanna call it. It was sort of developed late forties, early fifties, basically often out of their poisons. Basically a lot of these drugs that were refined for medical use, leukemia and lymphoma, incredibly sensitive to these drugs. So I really wouldn't belittle that in any way whatsoever. Uh, and those were at the time, I mean, I wasn't born then, but those are the tools that were available and some for some types of cancer, it's a really excellent treatment. Today. Chemotherapy can be a good treatment for breast cancer, ovarian cancer, bowel cancer. There are lots of examples. And so my take on that is that chemotherapy, cytotoxic chemotherapy probably hit its high watermark generally speaking about 20 years ago or something like that. And then the next thing that sort of came along was targeted therapy, which hasn't really been a, a subject for tonight. And that made a big difference for certain types of cancer, often, which were difficult to treat cancers as well. And then with checkpoint inhibitors, that for me would be the sort of the third big group of anti-cancer drugs. And again, we've seen in the last 10 or 15 years what checkpoints inhibitors can do. So I actually see this as, uh, a problem of picking the right treatment for the right situation. And I absolutely would not sort of do down on cytotoxic chemotherapy. It's just that some types of cancer, we weren't treating it in the right way, it's as simple as that. But at the time we didn't have the understanding and the technology, and now we do, Uh, sometimes when I was treating patient, I'm a oculoplastic surgeon from the states, I was treating patients with a uveal melanoma and unfortunately sometimes I noticed that there can be a long period of time between the, when they had primary tumor resection like a nucleation and the, the, the presentation of metastatic disease sometimes over a decade. Yeah, long period of time. I remember having a patient who has a long period of time called up my dad, who's a dermatologist, Dan. I had a patient, came into my office 15 years ago, removed his eye and AAG disease died in three months. He said, that's nothing. I had patients 25 years from continuous lymph noble. Have you noticed any correlation between the time period between primary tumor resection, presence of metastatic disease in response to immunotherapies? No, in a word. It's a good question though. But this, this idea of dormancy, if you want to call it that, there's load of, um, speculation, uh, about why it happens and, and melanoma, yeah, so, so par excellence, I mean we see it with skin melanomas as well. Um, and it happens sometimes in breast cancer as well, but you can go for long periods of time. It's not common, but it happens. Um, even with doing scans and following people up really carefully, everything's fine. And then you do the next scan and you can see spread of the cancer. So then the obvious question there is what triggers that if there is a trigger, and I certainly dunno, and I'm not sure we're close to understanding that at the moment. To me that speaks to the immune system honestly, that for some reason it was being controlled for a long period of time and why is it stopped being controlled? I don't think that's unraveled yet, but it's an important point. With that question. I think I've got a really good follow on question from that here. So with the survival curves shown in, for instance melanoma, is there a discernible difference between those patients who survive post three to five years versus those that pass away earlier? And if not, where would you like to look within the system to try and find those answers? Is there a difference? No, um, there's no easy a priori way honestly, to pick out the people who are really gonna get the most benefit from treatment, um, from those that don't, honestly, the kinds of, if you wanna call them prognostic factors, in other words, statistical factors that are associated with getting a better chance of, of treatment in melanoma. They're still really, frankly, quite old fashioned things, how well people are. We call that performance status, uh, the burden of the cancer. In other words, if you do scans, are there a few or lots of abnormalities? Um, and we use this blood test LDH that I mentioned at the beginning as well. But, but no, we don't have any sophisticated markers at the moment. It's a massively important question. I haven't really talked about PD L one expression. I'll just maybe say something a little bit about that now. Uh, 'cause it's important. So for some cancers, benefit from checkpoint inhibitors shown to be linked to PD L one expression. I think that lung cancer is the best example, PD L one expression, meaning the amount of the PD L one protein that's on the surface of tumor or nearby cells. But, um, it's a relatively crude marker and it varies over space and time. It can be induced or suppressed by various other things. And so, you know, I think no one would like it more than me if we had really good markers for using these treatments and a massive amount of effort's gone into it. But have we got anything that we can use in clinic to say, well, actually this treatment's really likely to work or not work now, I'm afraid not, not at the moment. Can you just give us a sense of when some of these drugs might be generally available in the UK subject to nice approval or, or, or, or similar processes, um, rather than having to be accessed as I understand it, through trials, which is the current position. Yeah, so the, the, the, the process there if you like, is that clinical trials need to recruit, which takes variable amounts of time, and then they need to be analyzed. And usually the analysis of a clinical trial will take minimum a year or two after it's ceased recruitment. Uh, once it's been analyzed, if the data look good positive, then it will go to regulators. So this is in the us the FDA in Europe, the EMA, and now for us, the MHRA, uh, post Brexit. And then the timeline to regulatory approval will typically be six to 12 months after the first readout of the trial. Uh, the regulators have an incredibly important responsibility, which is to determine that the efficacy, in other words, how well the drug works, uh, is justified in terms of the side effects and the risks of treatment. Because once they sign it off, it's, it's kind of out there, if you see what I mean. So it's a really really important decision and not to be taken lightly. And they put a lot of careful effort into this. And then you've got reimbursement, which is the final step. And we talked a little bit about that already. And so the reimbursement might then typically take, let's say another six to 12 months. So all of that is, um, and I'm incredibly impatient. It's probably my worst characteristic, actually. Um, uh, it can be frustrating at times. Um, but there's, there's no, I mean, the regulators really working hard to, and you know, it's, it's difficult. The FDA's actually quite quick at making decisions, but again, even with reimbursement, it might sound like it's a simple yes no thing. It's not, it's complicated. There's, you know, health economics to consider. And so, so that's the realistic timeline in general terms. Sometimes things are quicker, unfortunately, sometimes things are slower. I've been doing this a while and actually things are quicker now, uh, than they have been in the past. But I still really understand the frustration. And again, we have this in clinic most days. Um, but I would come back to the importance of doing clinical trials. Uh, you know, I, the, the progress that we've seen is because of doing clinical trials, and if we don't keep going on doing clinical trials, then progress will stall. It really is as simple as that. So another question right here at the front with Martin, and then I'll come back to the iPad if we have time. So, uh, this is a question for both of you. Oh, so, so we've got squillions of drugs being designed to attack the various, uh, molecules and receptors you've been designed. We've had a very good question about cost. Um, I think it would be interesting for people to hear how much it costs to make one of these drugs from thought up of drug to delivery and if you like, not just getting it to market, but the risk of getting it to market because some of this stuff must be a huge gamble for a company like yours. I think that's one for you to kick off with.<laugh>, uh, I'll certainly start the, the quick answer is it's a bit of a ballpark to be honest, because you start off with so, so many potential options. And then there's, there's considerable preclinical work that has to be done to identify if any of them could have utility within the clinical sphere. And then there's the varying different phases of clinical trials, which James showed you earlier. They take time to set up their global studies. They take a huge amount of money. I, I, I'm hesitant to put any kind of specific figures on this, but it's not just the time and years, it's the time in working with investigators such as James designing the studies and very frequently they fail. So what you see as a positive, with positive results is actually the abnormal result. Normally things fail in research and development, so that's why things take while that's why they come through and, and it's, it's trying to understand the, the cost effectiveness to your point earlier of, of the medicine within the, the clinical setting. But it's a huge amount of money globally to be able to invest in the development of medicines to try and get one to be successful in and move through. James, there Any does? Yeah, I mean it's, it's hundreds of millions of pounds, dollars, euros upward <laugh>. Yeah. You know, and um, I could do a talk about failed melanoma trials in the last five years, uh, but I haven't. Um, and if, if you, if you start from the, the very start of this process and then you go to the end of it for say 10 strong candidate drugs or a hundred, most of them will not succeed. So it's a high risk business, um, from the industry perspective as well. And you know, I'm, I'm sure the system if you like, isn't perfect, but at the end of the day it is delivering results And I think this probably feeds on where we have successes and failures. You alluded to earlier, do all the checkpoint inhibitors do the same function and therefore why are we seeing some successes and studies and Not Well that's, yeah, so that's a kind of an interesting question actually, and I, I didn't really talk too much about this. So in terms of CTLA four, ipilimumab being a CTLA four, anti CTLA four, which is the first one I showed you, if you remember, um, there's really only one other anti CTLA four, which is tremelimumab, which has sort of made it into regulatory approval and late stage development. Um, with the PD ones, there's probably dozens now they're not all necessarily got regulatory approval and without wishing to speak out of turn, I think most kind of large and medium sized pharma company have got a PD one or a PD L one drug. Several reasons for that I think because actually there's lots of different types of cancer where these drugs can show benefit. And so from an industry perspective they've really looked very hard at all the possible indications for that. Are there differences between the anti PD ones and anti PDL ones? That's kind of part of the thrust of this question as well. Um, not major differences in my opinions. People talk a lot about this. Are the side effects different? You know, does a PD one work a bit better than a than anti PDL one? There might be some minor differences, but for me they aren't major differences. They're relatively similar to each other. The bottom line often is they're made by different, um, pharmaceutical companies and they've been pursued in different cancer indications. One last question. There's quite a few questions in here, James, about specific cancer types and we don't have time to go into them all just now, but I think maybe the way to wrap them all up in one is we obviously see benefit through the clinical studies and clinical practice in melanoma and lung specifically and some other cancer types, but there are certain cancers where we have not seen the introduction of immunotherapies. Could you comment on why you think that is potentially PD one expression, et cetera, and whether we'll see developments that could potentially become agnostic? Yeah, so the first part of the question, so why do these drugs work in the first place in certain cancers? Well, for some cancers to some extent, I think we might understand that melanoma would be an example of that because it's in technical jargon, it's a cancer in general where there's a high mutational burden of the tumor. So it presents a better target. Same is true in lung cancer as well, probably in bladder cancer as well as that. But in kidney cancer, which I also treat, honestly, we don't really know why these drugs work well in kidney cancer. It doesn't have a high mutational burden. So we're still in the infancy of understanding that question in the first place. And then this idea about, um, tumor agnosticism, if we're gonna call it that. So that means actually if you know what the target is and you've got a drug, maybe it doesn't matter what tumor the target's on, you can use it anyway. There are beginning to be some examples of that. And there's one or two approvals where if you've got a particular abnormality, it doesn't matter what the type of cancer is, in principle you could use the drug. Will we see more of that? I think so, yes. Is the short answer to that. My kind of caveat to that would be that I think context is almost always important and it, you can probably illustrate this better with targeted therapy than with immunotherapy, but particular abnormalities within tumors, they don't always cut across. And it might be actually what's going in, what, what's around that abnormality in the tumor, the context that's really important for the benefit of the drug. So I think there's still a lot of work to do to really kind of get that nailed down actually. Thank you. I apologize if we've not had time to come to your questions either in the room or online. Um, professor Larkin will be part of the panel discussion on the 12th of March, so hopefully there will be the opportunity to answer then and obviously we'll follow up thereafter. Um, thank you so much James. I'll hand back over to, to Martin.