{"version":"1.0.0","segments":[{"startTime":5.195,"endTime":8.765,"body":"Immunotherapy cure for metastatic cancers."},{"startTime":8.785,"endTime":14.044,"body":"I'm gonna be thinking, um, a little bit about that, about what we've seen, particularly"},{"startTime":14.044,"endTime":14.394,"body":"in the last 10 or 15 years with immunotherapy to treat cancer, some of the"},{"startTime":14.394,"endTime":14.745,"body":"challenges, uh, and also what we might, um, expect to see, uh, over the next"},{"startTime":14.745,"endTime":25.965,"body":"five or 10 years."},{"startTime":27.575,"endTime":31.704,"body":"The Gresham College lecture that you're listening to right now is giving you knowledge and"},{"startTime":31.704,"endTime":31.98,"body":"insight from one of the world's leading academic experts, making it takes a lot of"},{"startTime":31.98,"endTime":32.255,"body":"time, but because we want to encourage a love of learning, we think it's well"},{"startTime":32.255,"endTime":40.515,"body":"worth it."},{"startTime":41.455,"endTime":44.635,"body":"We never make you pay for lectures, although donations are needed."},{"startTime":45.135,"endTime":48.435,"body":"All we ask in return is this, send a link to this lecture to someone"},{"startTime":48.435,"endTime":49.315,"body":"you think would benefit."},{"startTime":49.655,"endTime":53.305,"body":"And if you haven't already, click the follow or subscribe button from wherever you are"},{"startTime":53.305,"endTime":54.035,"body":"listening right now."},{"startTime":55.255,"endTime":57.035,"body":"Now, let's get back to the lecture."},{"startTime":59.695,"endTime":66.917,"body":"So, um, when I was at medical school, um, and to some extent when I"},{"startTime":66.917,"endTime":67.399,"body":"was training in oncology, I think many people thought that cancers that had spread metastatic"},{"startTime":67.399,"endTime":78.955,"body":"cancers were intrinsically incurable, uh, contrast, uh, with leukemia lymphoma."},{"startTime":78.955,"endTime":85.19,"body":"So-called hematological cancers, which we've known for decades, actually really since the 1950s, are potentially"},{"startTime":85.19,"endTime":90.595,"body":"curable often with traditional, so-called cytotoxic chemotherapy, even though the cancers have spread."},{"startTime":90.595,"endTime":95.875,"body":"But solid tumors really a different story altogether with one or two exceptions."},{"startTime":95.895,"endTime":100.826,"body":"So, for example, germ cell tumors, it's a rare type of cancer, are, uh, potentially"},{"startTime":100.826,"endTime":101.155,"body":"curable."},{"startTime":101.415,"endTime":105.795,"body":"Um, but most solid tumors were regarded historically as incurable."},{"startTime":106.415,"endTime":111.665,"body":"Uh, and I think that's one of the reasons perhaps, um, that oncology may not"},{"startTime":111.665,"endTime":112.015,"body":"have been considered necessarily an attractive career for, uh, doctors in training to go into,"},{"startTime":112.015,"endTime":119.715,"body":"which I think historically really was the case."},{"startTime":121.415,"endTime":125.283,"body":"Um, and an example of this would be melanoma, which is the type of skin"},{"startTime":125.283,"endTime":126.315,"body":"cancer that I treat."},{"startTime":126.485,"endTime":128.555,"body":"Metastatic means spread around the body."},{"startTime":128.555,"endTime":132.675,"body":"So melanoma spread around the body historically."},{"startTime":133.095,"endTime":136.555,"body":"Um, and these are some curves."},{"startTime":136.555,"endTime":140.755,"body":"I'll explain a a bit about that in a minute, um, from a paper about"},{"startTime":140.755,"endTime":142.435,"body":"10 or 15 years ago now."},{"startTime":142.815,"endTime":147.652,"body":"So these, uh, are called survival curves, and if you start at the top left"},{"startTime":147.652,"endTime":150.555,"body":"hand corner, um, that means that everybody's still alive."},{"startTime":150.555,"endTime":154.83,"body":"And then with the passage of time moving from left to right, and if you"},{"startTime":154.83,"endTime":155.115,"body":"look at the bottom, and you can see that's measured in years here, as people"},{"startTime":155.115,"endTime":161.955,"body":"die, um, from the disease, then the curve goes down."},{"startTime":162.015,"endTime":166.865,"body":"So if you, and I dunno how well this projects, but if you look at,"},{"startTime":166.865,"endTime":167.189,"body":"say, the five or the 10 year mark for people with metastatic melanoma, historically you"},{"startTime":167.189,"endTime":167.512,"body":"could see, uh, that only five or 10% of people were still alive reflecting, if"},{"startTime":167.512,"endTime":180.125,"body":"you like, the aggressiveness of this disease once it had spread."},{"startTime":180.745,"endTime":185.088,"body":"And also the fact that actually we didn't really historically have any effective treatment at"},{"startTime":185.088,"endTime":187.405,"body":"all for this disease once it had spread."},{"startTime":187.405,"endTime":192.041,"body":"And in fact, when I started as a consultant about 15 years ago, the same"},{"startTime":192.041,"endTime":192.35,"body":"drug was being used to treat melanoma that had spread, uh, as was first used"},{"startTime":192.35,"endTime":197.605,"body":"in the 1970s."},{"startTime":197.765,"endTime":203.555,"body":"So really in this disease, at least decades, uh, without seeing much progress, you may"},{"startTime":203.555,"endTime":203.941,"body":"be able to see there, um, that the different colored lines, uh, represent the fact"},{"startTime":203.941,"endTime":204.327,"body":"that according to which part of the body the cancer had spread to, and, uh,"},{"startTime":204.327,"endTime":220.925,"body":"a blood test, LDH lactate dehydrogenase, there'd be a little bit of variation in survival."},{"startTime":221.025,"endTime":225.744,"body":"But the general picture here is that unfortunately, most people with this disease, um, did"},{"startTime":225.744,"endTime":226.059,"body":"not survive long in the average, which it says in the title of the slide,"},{"startTime":226.059,"endTime":233.925,"body":"the average survival for this disease was six to nine months."},{"startTime":235.125,"endTime":239.038,"body":"Although you will see, uh, and I've said this already, that actually for reasons that"},{"startTime":239.038,"endTime":239.299,"body":"I'm still not sure we really understand that there is a group of people who,"},{"startTime":239.299,"endTime":246.605,"body":"despite the fact that cancer had spread, um, they survived in the long term."},{"startTime":248.065,"endTime":250.125,"body":"So what about cancer immunotherapy?"},{"startTime":250.825,"endTime":254.808,"body":"Uh, the first point I think I'd like to make is that this is not"},{"startTime":254.808,"endTime":255.605,"body":"a new idea."},{"startTime":256.625,"endTime":263.487,"body":"Um, I could have picked lots of examples historically, um, but I mention here William"},{"startTime":263.487,"endTime":263.945,"body":"Coley, who was a US surgeon, um, and actually he treated, uh, cancer patients with"},{"startTime":263.945,"endTime":274.925,"body":"bacteria, which is, uh, now known to be a streptococcus."},{"startTime":275.345,"endTime":281.264,"body":"And notice that in doing that and in a sense, um, uh, causing infections in"},{"startTime":281.264,"endTime":285.605,"body":"the patients, sometimes that was linked, uh, with cancers, uh, regressing."},{"startTime":285.605,"endTime":287.165,"body":"So that was well over a hundred years ago."},{"startTime":287.165,"endTime":290.205,"body":"And there are other examples on the right."},{"startTime":290.665,"endTime":292.565,"body":"Um, and this is out of date."},{"startTime":292.985,"endTime":298.971,"body":"Um, it's really a graph that's showing the interest in cancer immunotherapy over the last"},{"startTime":298.971,"endTime":301.765,"body":"10 or 15 years really has grown."},{"startTime":302.425,"endTime":304.445,"body":"So a couple of points to make there."},{"startTime":304.505,"endTime":308.07,"body":"One is that there's actually lots of different types of immunotherapy that have been looked"},{"startTime":308.07,"endTime":310.685,"body":"at in clinical trials over the last 10 or 15 years."},{"startTime":311.625,"endTime":316.389,"body":"And I would also make the point that prior to that, although there was interest"},{"startTime":316.389,"endTime":319.565,"body":"in cancer immunotherapy, uh, it really wasn't a major enterprise."},{"startTime":319.705,"endTime":323.402,"body":"And, um, I could probably use as an example of that sort of 20 years"},{"startTime":323.402,"endTime":323.649,"body":"ago, if you went to a, a big, uh, international cancer meeting and you went"},{"startTime":323.649,"endTime":323.895,"body":"to one of the immunotherapy sessions, that'd hardly be anyone in, in the room at"},{"startTime":323.895,"endTime":331.045,"body":"all."},{"startTime":331.505,"endTime":334.516,"body":"Uh, whereas now if you were to do that, it would be one of the,"},{"startTime":334.516,"endTime":336.925,"body":"the most popular sessions at the meeting, sort of standing room only."},{"startTime":336.985,"endTime":341.525,"body":"So it really has changed a lot in my working lifetime so far."},{"startTime":343.945,"endTime":349.626,"body":"So if you've got a good immunotherapy for cancer, what would it look like very"},{"startTime":349.626,"endTime":350.005,"body":"broadly?"},{"startTime":350.395,"endTime":352.605,"body":"Well, you would want long-term benefit."},{"startTime":352.745,"endTime":356.973,"body":"In other words, you'd want the treatment if you delivered it to have, um, durable"},{"startTime":356.973,"endTime":357.255,"body":"impact on the cancer, meaning over years, it's a treatment that you'd want to work"},{"startTime":357.255,"endTime":361.765,"body":"for years."},{"startTime":362.525,"endTime":364.085,"body":"I think that almost goes without saying."},{"startTime":365.185,"endTime":369.435,"body":"The driver for that, I think is the second point I make there duration of"},{"startTime":369.435,"endTime":369.718,"body":"response, meaning that if you give a treatment, you want it to work for a"},{"startTime":369.718,"endTime":377.085,"body":"long period of time, if the disease is gonna be well controlled"},{"startTime":378.955,"endTime":383.068,"body":"From the patient perspective, it would be good if you didn't need to give treatment"},{"startTime":383.068,"endTime":384.165,"body":"for a long time."},{"startTime":384.265,"endTime":388.072,"body":"In other words, if you could give treatment for a period of time, however long"},{"startTime":388.072,"endTime":388.325,"body":"that is, maybe weeks, months, something like that, stop the treatment, but then you would"},{"startTime":388.325,"endTime":394.925,"body":"want the cancer to still be controlled after the treatment has finished."},{"startTime":394.945,"endTime":396.405,"body":"So that's quite an important idea."},{"startTime":397.345,"endTime":400.658,"body":"And I would potentially contrast there some of the other treatments that we give for"},{"startTime":400.658,"endTime":402.205,"body":"cancer, some of the other drug treatments."},{"startTime":402.225,"endTime":406.571,"body":"So targeted therapy, for example, I'm not really gonna talk about that much, but typically"},{"startTime":406.571,"endTime":406.861,"body":"if we're giving targeted therapy for cancers that have spread, we will give it for"},{"startTime":406.861,"endTime":407.151,"body":"very long periods of time, sometimes even, sometimes even indefinitely, meaning as long as it"},{"startTime":407.151,"endTime":415.845,"body":"was working."},{"startTime":415.985,"endTime":421.549,"body":"So there's no real idea there actually with targeted treatment of the idea of stopping"},{"startTime":421.549,"endTime":421.92,"body":"the treatment and the benefit being maintained, generally speaking, safety of the treatment is obviously"},{"startTime":421.92,"endTime":427.485,"body":"important."},{"startTime":427.485,"endTime":432.475,"body":"This needs to be a treatment that you can deliver to patients and, um, ideally"},{"startTime":432.475,"endTime":434.805,"body":"not have too many serious side effects."},{"startTime":435.465,"endTime":439.902,"body":"And I think to some extent, all of those will go together, um, to generate"},{"startTime":439.902,"endTime":444.045,"body":"the maximum possible quality of life for patients, which is the final point there."},{"startTime":446.385,"endTime":449.045,"body":"So what does cancer immunotherapy mean?"},{"startTime":449.665,"endTime":455.778,"body":"Um, I would make the point that often, particularly in the last 10 or 15"},{"startTime":455.778,"endTime":461.485,"body":"years, uh, people will interchangeably use the term cancer immunotherapy with immune checkpoint inhibitors."},{"startTime":461.505,"endTime":463.165,"body":"And I'll say a bit more about that in a minute."},{"startTime":463.785,"endTime":469.205,"body":"Um, immune checkpoint inhibitors, uh, are listed at the bottom of this, um, slide."},{"startTime":469.715,"endTime":474.7,"body":"Sometimes the term immuno-oncology is also used, and you'll hear that being bandied about a"},{"startTime":474.7,"endTime":475.365,"body":"little bit."},{"startTime":475.425,"endTime":480.816,"body":"I'm not particularly fond of that if I'm honest, but I'm just making the point"},{"startTime":480.816,"endTime":481.176,"body":"with this non, uh, exclusive diagram, if you like, that there are lots of different"},{"startTime":481.176,"endTime":488.365,"body":"possible types of immunotherapy for cancer."},{"startTime":488.505,"endTime":490.165,"body":"It isn't just checkpoint inhibitors."},{"startTime":490.705,"endTime":499.925,"body":"So I've listed cytokines, uh, t-cell therapies, vaccines, dendritic cell therapies, and oncolytic viral therapies."},{"startTime":499.925,"endTime":505.063,"body":"As other examples, and I apologize to anyone who's listening, uh, if I haven't included"},{"startTime":505.063,"endTime":505.405,"body":"something, um, which is their particular interest, but it's a broad term and immunotherapy is"},{"startTime":505.405,"endTime":513.284,"body":"a broad term as well to treat human diseases."},{"startTime":513.345,"endTime":516.125,"body":"So I think that's, uh, worth bearing in mind."},{"startTime":517.225,"endTime":522.66,"body":"But I am going to spend at least, uh, the bulk of this talk thinking"},{"startTime":522.66,"endTime":523.023,"body":"about immune checkpoint inhibitors because, uh, I think that's what re really has brought immunotherapy"},{"startTime":523.023,"endTime":532.445,"body":"for cancer center stage, um, in the last 10 or 15 years."},{"startTime":532.505,"endTime":537.645,"body":"And we've seen real impact in clinic, uh, with immune checkpoint inhibitors."},{"startTime":538.465,"endTime":539.565,"body":"So what does this mean?"},{"startTime":539.875,"endTime":545.64,"body":"Well, this is a cartoon and that blue blob in the middle is a T-cell,"},{"startTime":545.64,"endTime":551.405,"body":"an immune cell, and at the top, uh, where it says interferon and interleukin two."},{"startTime":551.405,"endTime":552.765,"body":"So those are cytokines."},{"startTime":552.765,"endTime":557.592,"body":"They're actually substances, which our bodies are producing the whole time as part, if you"},{"startTime":557.592,"endTime":559.845,"body":"like, of normal life and normal physiology."},{"startTime":560.705,"endTime":565.242,"body":"And the idea with cytokines is that they give, if you like, a, what you"},{"startTime":565.242,"endTime":567.965,"body":"might call a non-specific stimulation to the immune system."},{"startTime":568.305,"endTime":572.921,"body":"And in fact, cytokines have been used therapeutically to treat cancer for a long time"},{"startTime":572.921,"endTime":573.845,"body":"now, really decades."},{"startTime":574.825,"endTime":579.947,"body":"And sometimes cytokines can work, uh, to treat cancer, although often the doses at which"},{"startTime":579.947,"endTime":584.045,"body":"they're given means that there are quite a lot of side effects."},{"startTime":584.625,"endTime":586.645,"body":"And interleukin two is a good example of that."},{"startTime":587.865,"endTime":593.422,"body":"The doses that are used to treat cancer are orders of magnitude greater than the"},{"startTime":593.422,"endTime":595.645,"body":"normal cellular doses at the bottom."},{"startTime":596.105,"endTime":598.565,"body":"Uh, I've shown immune checkpoint inhibitors."},{"startTime":598.665,"endTime":603.679,"body":"So rather than stimulating, uh, at the top, we're talking about removing a break from"},{"startTime":603.679,"endTime":605.685,"body":"the immune system at the bottom."},{"startTime":605.745,"endTime":608.685,"body":"And maybe that's the sort of critical concept to bear in mind here."},{"startTime":609.385,"endTime":614.892,"body":"And I've listed CTLA four and, uh, PD L one, which are probably at the"},{"startTime":614.892,"endTime":615.259,"body":"moment the best known immune checkpoint inhibitors and certainly the immune checkpoints, uh, that have"},{"startTime":615.259,"endTime":624.805,"body":"been targeted most with drugs over the last 10 or 15 years."},{"startTime":625.825,"endTime":631.836,"body":"But actually, and again, this is a T-cell in the middle, there's lots of possible,"},{"startTime":631.836,"endTime":636.645,"body":"uh, immune checkpoints which can be targeted with drugs on the right."},{"startTime":636.705,"endTime":638.445,"body":"And again, this is a non-exhaustive list."},{"startTime":639.145,"endTime":644.162,"body":"Um, there are inhibitory receptors and I would pick out CTLA four, uh, at the"},{"startTime":644.162,"endTime":648.845,"body":"top, and then PD one just underneath and perhaps lag three at the bottom."},{"startTime":649.745,"endTime":655.576,"body":"All of those targets have drugs, uh, which have got regulatory approval to treat cancer"},{"startTime":655.576,"endTime":655.965,"body":"globally."},{"startTime":657.465,"endTime":661.642,"body":"But if you look on the left and you look at some of the other,"},{"startTime":661.642,"endTime":661.921,"body":"um, targets that I've listed there, there's actually been intense activity over the last 10"},{"startTime":661.921,"endTime":668.605,"body":"years or so to develop drugs that target these molecules."},{"startTime":668.625,"endTime":672.658,"body":"But at least so far, I'm not really aware that any of those efforts have"},{"startTime":672.658,"endTime":675.885,"body":"actually resulted, uh, in drugs which have been approved to treat cancer."},{"startTime":675.985,"endTime":679.605,"body":"So this isn't a, uh, a straightforward, um, problem."},{"startTime":680.105,"endTime":684.365,"body":"Uh, and the immune system is par excellence, a complicated system."},{"startTime":687.315,"endTime":692.301,"body":"Just to take, uh, one final step back if you like, um, before I start"},{"startTime":692.301,"endTime":692.633,"body":"showing you some data and talking about the benefits of these treatments, I think it's"},{"startTime":692.633,"endTime":692.965,"body":"really important, uh, to note that the work, the scientific work that led to the"},{"startTime":692.965,"endTime":693.298,"body":"development of these drugs was recognized over five years ago now with the Nobel Prize"},{"startTime":693.298,"endTime":712.245,"body":"in physiology or medicine, uh, to Jim Allison and Suko Honjo who are shown there."},{"startTime":713.105,"endTime":717.914,"body":"And, uh, I'm not expecting anyone to read the small print at the bottom, but"},{"startTime":717.914,"endTime":718.234,"body":"perhaps you can read the headline, uh, discovery of Cancer Therapy by any emission of"},{"startTime":718.234,"endTime":723.685,"body":"negative immune regulation."},{"startTime":723.705,"endTime":726.485,"body":"So it was really their work and others around the world to scan."},{"startTime":726.485,"endTime":731.097,"body":"This has been a global effort that provided the basis for the development of these"},{"startTime":731.097,"endTime":731.405,"body":"drugs."},{"startTime":733.665,"endTime":737.925,"body":"So, uh, what are the benefits of immune checkpoint inhibitors?"},{"startTime":738.035,"endTime":744.112,"body":"Well, remember the curve that I showed you earlier on, which you could think about"},{"startTime":744.112,"endTime":744.517,"body":"as, uh, what metastatic melanoma looks like in terms of survival before we had any"},{"startTime":744.517,"endTime":751.405,"body":"potentially effective therapies."},{"startTime":752.115,"endTime":756.507,"body":"What I'm showing now is something similar, but this is a group of people who've"},{"startTime":756.507,"endTime":756.8,"body":"been with metastatic melanoma treated with a drug called ipilimumab, which is an anti CTLA"},{"startTime":756.8,"endTime":761.485,"body":"four drug."},{"startTime":761.505,"endTime":764.165,"body":"If you think to what I just showed you about immune checkpoint inhibitors."},{"startTime":765.145,"endTime":769.085,"body":"And this is the chances of surviving after treatment with ipilimumab."},{"startTime":769.265,"endTime":774.608,"body":"Now this is a drug, uh, that's given four times every three weeks as an"},{"startTime":774.608,"endTime":774.965,"body":"outpatient."},{"startTime":775.105,"endTime":777.085,"body":"So it's only three months of treatment."},{"startTime":778.225,"endTime":782.991,"body":"And we can see here, and this is, uh, a pooled analysis of just under"},{"startTime":782.991,"endTime":783.309,"body":"2000 patients that actually, if you look at the passage of time there, it looks"},{"startTime":783.309,"endTime":792.525,"body":"like there's about 20% of people who are long-term survivors after treatment with this drug."},{"startTime":794.035,"endTime":796.165,"body":"That is more than what I showed you before."},{"startTime":796.225,"endTime":799.893,"body":"In other words, the five or 10% of people who might be long-term survivors because"},{"startTime":799.893,"endTime":801.605,"body":"of the natural history of the disease."},{"startTime":802.785,"endTime":807.012,"body":"And also the other point I would make here is if you look at the"},{"startTime":807.012,"endTime":807.294,"body":"shape of that curve, let's, if we pick out 36 months, the curve's really quite"},{"startTime":807.294,"endTime":812.085,"body":"flat after that."},{"startTime":812.225,"endTime":815.847,"body":"So meaning that if you have this treatment and you're still alive after three years,"},{"startTime":815.847,"endTime":816.089,"body":"there's a good chance that you'll be alive at five years and there's also a"},{"startTime":816.089,"endTime":821.885,"body":"good chance that you will be alive at 10 years."},{"startTime":821.905,"endTime":826.391,"body":"And that's certainly something over the years that I've discussed with my patients in the"},{"startTime":826.391,"endTime":828.485,"body":"clinic, uh, when they're having this treatment."},{"startTime":828.505,"endTime":833.821,"body":"So for me, this was the first, um, clinical, uh, evidence if you like, that"},{"startTime":833.821,"endTime":837.365,"body":"this might be, uh, a treatment with potentially long-term benefit."},{"startTime":838.785,"endTime":844.127,"body":"So then if we come up to date or more up to date, at least,"},{"startTime":844.127,"endTime":848.045,"body":"this is another clinical trial, and again, I'm showing survival curves."},{"startTime":848.045,"endTime":852.125,"body":"And that black line at the bottom is the people who were treated with ipilimumab."},{"startTime":852.505,"endTime":854.925,"body":"But this trial actually looked at two other things."},{"startTime":855.025,"endTime":858.351,"body":"So ipilimumab was, if you like, the control arm at the time the trial was"},{"startTime":858.351,"endTime":860.125,"body":"done, and it started about 10 years ago."},{"startTime":861.225,"endTime":866.125,"body":"The green line in the middle is nivolumab, uh, so-called anti PD one drug."},{"startTime":866.425,"endTime":870.975,"body":"And the sort of orangey line at the top, um, is the combination of nivolumab"},{"startTime":870.975,"endTime":871.885,"body":"and ipilimumab together."},{"startTime":872.385,"endTime":875.165,"body":"So again, we've got over five years of follow up here."},{"startTime":875.735,"endTime":879.165,"body":"Again, you can see that the curves are flattening, as I showed you before."},{"startTime":879.865,"endTime":885.026,"body":"And for me, the real take home message here is that with treatment with nivolumab"},{"startTime":885.026,"endTime":885.37,"body":"or the combination of nivolumab and ipilimumab, around about 50% of people were alive at"},{"startTime":885.37,"endTime":891.565,"body":"five years and beyond."},{"startTime":892.305,"endTime":897.718,"body":"And, uh, for the record, I'm gonna say that pembrolizumab, uh, a very similar drug"},{"startTime":897.718,"endTime":900.245,"body":"to nivolumab actually shows very similar results."},{"startTime":900.265,"endTime":901.965,"body":"But I'm not gonna show you the data for that."},{"startTime":904.665,"endTime":905.925,"body":"So that was survival."},{"startTime":905.985,"endTime":909.445,"body":"In other words, the chances of, um, being alive."},{"startTime":910.225,"endTime":916.765,"body":"Um, but do we know what the chances are of actually, uh, surviving the melanoma?"},{"startTime":916.765,"endTime":919.605,"body":"In other words, if people are starting to die at these later time points, is"},{"startTime":919.605,"endTime":922.445,"body":"it because they've died of the cancer or they're beginning to die of other things?"},{"startTime":922.475,"endTime":924.005,"body":"It's a really important question to ask."},{"startTime":925.105,"endTime":929.365,"body":"And so from this trial, we actually analyzed melanoma specific survival."},{"startTime":929.465,"endTime":934.02,"body":"And actually you can see if you look at this, that the melanoma specific survival"},{"startTime":934.02,"endTime":934.324,"body":"is even better suggesting at least that once you control the melanoma in the very"},{"startTime":934.324,"endTime":942.525,"body":"long term, then it might be that people start dying of other causes."},{"startTime":944.225,"endTime":944.445,"body":"If"},{"startTime":944.445,"endTime":948.522,"body":"We move to kidney cancer, which is the other disease that I treat, and I"},{"startTime":948.522,"endTime":948.794,"body":"don't necessarily, uh, want you to focus too much on the specific shape of these"},{"startTime":948.794,"endTime":949.066,"body":"curves, but this is a kind of a similar trial to what I've just showed"},{"startTime":949.066,"endTime":959.125,"body":"you in kidney cancer of nivolumab and ipilimumab together."},{"startTime":959.145,"endTime":963.935,"body":"And actually these data were presented very recently in the last few weeks at a"},{"startTime":963.935,"endTime":968.725,"body":"meeting in San Francisco in the us again, with over five years of follow up."},{"startTime":969.465,"endTime":971.605,"body":"The shape of the curves is actually a little bit different."},{"startTime":971.605,"endTime":974.675,"body":"If you look at the left hand curve, there isn't that flattening at the early"},{"startTime":974.675,"endTime":975.085,"body":"time point."},{"startTime":975.105,"endTime":979.533,"body":"And you can see even at 5, 6, 7 years, the curve is still, if"},{"startTime":979.533,"endTime":982.485,"body":"you like, going downwards, meaning that people are still dying."},{"startTime":983.545,"endTime":987.902,"body":"The question though, for me, and I dunno, the answer to this question, is what"},{"startTime":987.902,"endTime":989.645,"body":"is the disease specific survival here?"},{"startTime":989.785,"endTime":992.885,"body":"Are these people at these late time points who are dying of kidney cancer?"},{"startTime":993.305,"endTime":997.525,"body":"Or is the kidney cancer still under control and are they dying of other causes?"},{"startTime":997.545,"endTime":1001.555,"body":"So I don't know the answer to this in kidney cancer, but for me it's"},{"startTime":1001.555,"endTime":1005.565,"body":"a really important question for these new treatments, what's really happening in the long term?"},{"startTime":1009.295,"endTime":1012.365,"body":"Which brings me to the question of how you define cure."},{"startTime":1013.445,"endTime":1018.457,"body":"I don't really have an answer to this, but one way to define it might"},{"startTime":1018.457,"endTime":1018.792,"body":"be to say, to return to normal life expectancy for your age and level of"},{"startTime":1018.792,"endTime":1023.805,"body":"health."},{"startTime":1024.944,"endTime":1029.881,"body":"Um, and so from a formal perspective, it's difficult to say that these drugs are"},{"startTime":1029.881,"endTime":1030.21,"body":"curative because we haven't really been using them for long enough, because we'd need decades"},{"startTime":1030.21,"endTime":1030.539,"body":"of follow up really to be able to say that with formal confidence, if you"},{"startTime":1030.539,"endTime":1040.085,"body":"like."},{"startTime":1040.305,"endTime":1045.422,"body":"But nevertheless, from what I've shown you and certainly from my experience in clinic, having"},{"startTime":1045.422,"endTime":1045.763,"body":"been using these drugs for 10 or 15 years, it does seem that people are"},{"startTime":1045.763,"endTime":1052.245,"body":"potentially cured with these drugs."},{"startTime":1052.265,"endTime":1055.125,"body":"And I've shown you the example of melanoma."},{"startTime":1056.075,"endTime":1058.125,"body":"I've shown you some data from kidney cancer."},{"startTime":1058.715,"endTime":1063.886,"body":"Obviously there's lots of other different types of cancer and certainly in lung cancer, uh,"},{"startTime":1063.886,"endTime":1064.231,"body":"for example, we can see what looks like to me at least, the possibility of"},{"startTime":1064.231,"endTime":1073.885,"body":"cure of people with lung cancer with these drugs, albeit a, a lower proportion."},{"startTime":1077.105,"endTime":1081.621,"body":"So the next, uh, point I want to make is that it's not just about"},{"startTime":1081.621,"endTime":1082.525,"body":"immune checkpoint inhibitors."},{"startTime":1082.545,"endTime":1086.395,"body":"And I've said a little bit about this already, but I think it's an important"},{"startTime":1086.395,"endTime":1087.165,"body":"point to make."},{"startTime":1087.165,"endTime":1092.64,"body":"And I'm just gonna show, uh, a couple of slides, um, for a drug called"},{"startTime":1092.64,"endTime":1093.005,"body":"tivas."},{"startTime":1093.825,"endTime":1100.713,"body":"Now, uveal melanoma, meaning melanomas that start in the eye, they're rare, but they behave"},{"startTime":1100.713,"endTime":1105.765,"body":"very differently from melanomas that start in the skin cutaneous melanomas."},{"startTime":1106.345,"endTime":1110.325,"body":"And they've been even more difficult to treat than skin melanomas in the past."},{"startTime":1110.505,"endTime":1116.092,"body":"And the drugs that I've just shown, immune checkpoints, inhibitors, nivolumab, ipilimumab, pembrolizumab really don't"},{"startTime":1116.092,"endTime":1119.445,"body":"work very well in uveal melanomas in many ways."},{"startTime":1119.685,"endTime":1119.765,"body":"Actually."},{"startTime":1119.815,"endTime":1124.285,"body":"Uveal melanoma biologically is a different disease from cutaneous melanoma."},{"startTime":1125.625,"endTime":1131.561,"body":"So, um, these data, uh, that I'm showing here, and this was presented at an"},{"startTime":1131.561,"endTime":1131.957,"body":"oncology meeting in Madrid, uh, within the last, uh, six months or so, uh, for"},{"startTime":1131.957,"endTime":1138.685,"body":"something called tifa."},{"startTime":1138.785,"endTime":1144.285,"body":"And that that diagram on the left may not, um, project particularly well."},{"startTime":1144.785,"endTime":1149.982,"body":"But the idea is that this is basically, uh, something t-cell receptor bispecific is the"},{"startTime":1149.982,"endTime":1150.329,"body":"technical term for it, but you can see at the top is the melanoma cell"},{"startTime":1150.329,"endTime":1158.645,"body":"at the bottom, uh, is a t-cell and immune cell."},{"startTime":1158.645,"endTime":1163.473,"body":"And what this is doing, this drug is to connect the two together connecting the"},{"startTime":1163.473,"endTime":1165.405,"body":"immune cell to the cancer cell."},{"startTime":1166.065,"endTime":1170.133,"body":"And the reason really to show this is actually it's working in a really different"},{"startTime":1170.133,"endTime":1172.845,"body":"way from the immune checkpoint inhibitors I've just shown you."},{"startTime":1172.845,"endTime":1174.165,"body":"This is a class of drugs."},{"startTime":1174.165,"endTime":1177.645,"body":"This is just one of a class of drugs that's being developed."},{"startTime":1178.225,"endTime":1182.365,"body":"And in uveal melanoma, this is another, um, survival curve."},{"startTime":1182.365,"endTime":1186.6,"body":"And this is with three years of follow up for the trial of tus and"},{"startTime":1186.6,"endTime":1187.165,"body":"uveal melanoma."},{"startTime":1187.835,"endTime":1192.608,"body":"This is actually the first ever treatment in this disease which has been shown to"},{"startTime":1192.608,"endTime":1193.245,"body":"prolong survival."},{"startTime":1193.345,"endTime":1194.765,"body":"So that's an important landmark."},{"startTime":1195.705,"endTime":1199.617,"body":"If you look at those two curves, the people with the tuss, but the top"},{"startTime":1199.617,"endTime":1199.878,"body":"and those who were in the control arm of the study, um, below you might"},{"startTime":1199.878,"endTime":1200.138,"body":"say, well, there isn't really that much difference and the curves are, are still dropping"},{"startTime":1200.138,"endTime":1208.485,"body":"off after three years."},{"startTime":1208.705,"endTime":1214.09,"body":"But prior to this trial, there had been dozens, hundreds of trials in this disease,"},{"startTime":1214.09,"endTime":1216.245,"body":"nothing had previously shown any impacts."},{"startTime":1216.265,"endTime":1219.698,"body":"So for me, that's the main important point that I want to make in showing"},{"startTime":1219.698,"endTime":1222.445,"body":"this, and I'm sure we'll see more of this in the future."},{"startTime":1225.105,"endTime":1226.885,"body":"So what about adjuvant treatment?"},{"startTime":1226.885,"endTime":1228.765,"body":"What does adjuvant treatment mean?"},{"startTime":1229.385,"endTime":1232.82,"body":"Um, I always forget \u003claugh\u003e, I say this in clinical lot to patients as well,"},{"startTime":1232.82,"endTime":1233.049,"body":"whether it's in the Latin or Greek, I'm sure most people in the room will"},{"startTime":1233.049,"endTime":1236.485,"body":"know."},{"startTime":1236.825,"endTime":1241.565,"body":"But the idea of adjuvant treatment is it helps the definitive treatment."},{"startTime":1241.665,"endTime":1246.567,"body":"So the definitive treatment usually being surgery or radiotherapy, sometimes the point being that someone"},{"startTime":1246.567,"endTime":1246.894,"body":"might have a cancer removed and then they may have an adjuvant treatment afterwards to"},{"startTime":1246.894,"endTime":1254.085,"body":"reduce the chance of the cancer coming back."},{"startTime":1254.085,"endTime":1259.651,"body":"So this idea of adjuvant treatment, um, is very commonplace in oncology, in breast cancer"},{"startTime":1259.651,"endTime":1260.765,"body":"and bowel cancer."},{"startTime":1260.765,"endTime":1262.645,"body":"People have been using adjuvant treatment for decades."},{"startTime":1262.705,"endTime":1266.516,"body":"It might be hormonal treatment, it might be chemotherapy, but the idea that you have"},{"startTime":1266.516,"endTime":1266.77,"body":"your surgery, then you might have drug treatment afterwards for a period of time, often"},{"startTime":1266.77,"endTime":1273.885,"body":"a year to reduce the chance of the cancer coming back in the future."},{"startTime":1274.785,"endTime":1276.765,"body":"So what does immunotherapy look like?"},{"startTime":1276.835,"endTime":1278.485,"body":"What do checkpoint inhibitors look like?"},{"startTime":1278.785,"endTime":1283.226,"body":"Um, in the adjuvant setting, the reason this is important is obviously if you can"},{"startTime":1283.226,"endTime":1283.522,"body":"prevent cancer spreading in the first place with adjuvant treatment, then it's a better place"},{"startTime":1283.522,"endTime":1283.818,"body":"to be in from the patient perspective and actually from the oncologist perspective than having"},{"startTime":1283.818,"endTime":1293.885,"body":"to treat cancers that have spread."},{"startTime":1293.945,"endTime":1299.599,"body":"So it's, it, it's an important concept, and again, this might not, uh, project particularly"},{"startTime":1299.599,"endTime":1299.976,"body":"well, but in melanoma until about five years ago, we had no evidence for the"},{"startTime":1299.976,"endTime":1300.353,"body":"benefit of using immunotherapy earlier in the disease stage three disease, which means involving lymph"},{"startTime":1300.353,"endTime":1311.285,"body":"nodes."},{"startTime":1311.905,"endTime":1316.593,"body":"And this is now around about five years of follow up from an immunotherapy trial,"},{"startTime":1316.593,"endTime":1316.905,"body":"um, in stage three melanoma showing very clearly that if you have a year of"},{"startTime":1316.905,"endTime":1317.218,"body":"immunotherapy after you've had surgery for stage three melanoma, there's a significant reduction in the"},{"startTime":1317.218,"endTime":1327.845,"body":"chance of the cancer coming back."},{"startTime":1327.845,"endTime":1332.89,"body":"And this is now a treatment that's been widely adopted, uh, from a regulatory perspective"},{"startTime":1332.89,"endTime":1335.245,"body":"and a reimbursement perspective around the world."},{"startTime":1335.345,"endTime":1339.782,"body":"So the point I'm making is that generally the way that anti-cancer drugs are developed"},{"startTime":1339.782,"endTime":1340.077,"body":"as they're initially treated in stage four or metastatic cancer, but the nature of it,"},{"startTime":1340.077,"endTime":1340.373,"body":"the nature of of this is that then we try and test them in earlier"},{"startTime":1340.373,"endTime":1340.669,"body":"stages of the disease to see if we can reduce the chance of the cancer"},{"startTime":1340.669,"endTime":1353.685,"body":"coming back."},{"startTime":1354.805,"endTime":1359.213,"body":"I show melanoma as an example here because I think we've got the most, uh,"},{"startTime":1359.213,"endTime":1361.565,"body":"mature follow up for melanoma at the moment."},{"startTime":1361.665,"endTime":1365.005,"body":"But actually this is a very widespread approach in lots of different types of cancer."},{"startTime":1367.865,"endTime":1372.685,"body":"So, uh, a couple of words about, so-called neoadjuvant, um, treatment."},{"startTime":1372.905,"endTime":1378.682,"body":"So, uh, I may have labored, uh, adjuvant treatment, uh, a little bit, but the"},{"startTime":1378.682,"endTime":1379.067,"body":"idea of neoadjuvant treatment is simply starting the adjuvant treatment before you actually do the"},{"startTime":1379.067,"endTime":1384.845,"body":"surgery."},{"startTime":1385.065,"endTime":1389.325,"body":"So the conventional approach would be do the surgery, then give the adjuvant treatment."},{"startTime":1389.745,"endTime":1393.835,"body":"And the idea of neoadjuvant treatment is really simple, is that you give that, you"},{"startTime":1393.835,"endTime":1397.925,"body":"start the adjuvant treatment and then you do the surgery after a period of time."},{"startTime":1398.065,"endTime":1404.326,"body":"So shown here in this, um, cartoon, um, is along the top, um, the conventional"},{"startTime":1404.326,"endTime":1404.743,"body":"approach to this that you remove the tumor, uh, and then you give the immunotherapy"},{"startTime":1404.743,"endTime":1411.005,"body":"afterwards."},{"startTime":1411.825,"endTime":1416.252,"body":"And then along the bottom you can see the idea, well, if you give the"},{"startTime":1416.252,"endTime":1416.547,"body":"immunotherapy first, perhaps you can stimulate any immune cells that are in the tumor, particularly"},{"startTime":1416.547,"endTime":1421.565,"body":"in lymph nodes."},{"startTime":1422.025,"endTime":1426.462,"body":"And maybe as a consequence of doing that, your immune system is activated better and"},{"startTime":1426.462,"endTime":1430.605,"body":"then it results in less chance of the cancer coming back in the future."},{"startTime":1430.755,"endTime":1433.005,"body":"Very, very, very simple idea."},{"startTime":1434.065,"endTime":1436.965,"body":"How does that translate into clinical practice?"},{"startTime":1436.995,"endTime":1441.199,"body":"Well, um, in the world of oncology, and I think probably in most branches of"},{"startTime":1441.199,"endTime":1441.479,"body":"medicine, our kind of gold standard, if you like for evidence for benefit, is doing"},{"startTime":1441.479,"endTime":1446.245,"body":"a randomized trial."},{"startTime":1446.275,"endTime":1447.645,"body":"This is a randomized trial."},{"startTime":1448.585,"endTime":1452.885,"body":"It is a US academic study, SWOG 1801 is the name of it."},{"startTime":1453.545,"endTime":1457.54,"body":"And again, it's this really, really simple idea shown here, uh, that you have the"},{"startTime":1457.54,"endTime":1459.405,"body":"standard approach, which is along the top."},{"startTime":1460.145,"endTime":1464.485,"body":"Um, and so the, the, the people in the trial had surgery for stage three"},{"startTime":1464.485,"endTime":1464.775,"body":"melanoma, and then they had a year of treatment with pembrolizumab, an anti PD one"},{"startTime":1464.775,"endTime":1469.405,"body":"immunotherapy drug."},{"startTime":1469.545,"endTime":1472.205,"body":"So that was the standard approach up until that point."},{"startTime":1472.865,"endTime":1476.205,"body":"And then at the bottom you have the neoadjuvant arm of the study."},{"startTime":1476.625,"endTime":1481.195,"body":"And the only difference here is that the treatment was started around about nine weeks"},{"startTime":1481.195,"endTime":1481.805,"body":"before surgery."},{"startTime":1482.195,"endTime":1485.556,"body":"Then the people went on to have their surgery and then they finished off their"},{"startTime":1485.556,"endTime":1486.005,"body":"treatment afterwards."},{"startTime":1486.025,"endTime":1491.405,"body":"So very, very, uh, simple and I would say powerful clinical trial design."},{"startTime":1492.425,"endTime":1497.782,"body":"And the, the headline here, and this is from a, a paper published in the"},{"startTime":1497.782,"endTime":1498.14,"body":"New England Journal of Medicine around about this time last year, is just from this"},{"startTime":1498.14,"endTime":1498.497,"body":"one very simple manipulation, the chances of the people being, uh, event free, which means"},{"startTime":1498.497,"endTime":1498.854,"body":"that basically the melanoma hadn't come back after two years of follow up was a"},{"startTime":1498.854,"endTime":1515.285,"body":"difference of over 20%."},{"startTime":1515.345,"endTime":1519.245,"body":"And again, you may or may not be impressed by that, but that's the kind"},{"startTime":1519.245,"endTime":1521.845,"body":"of level of benefit that we actually pretty rarely see."},{"startTime":1522.545,"endTime":1529.085,"body":"And so in melanoma, uh, there's various, uh, regulatory issues associated with this."},{"startTime":1529.425,"endTime":1532.6,"body":"But in melanoma, those of us in the community think that this is ideally a"},{"startTime":1532.6,"endTime":1535.565,"body":"treatment that we would want to use based on the results of this trial."},{"startTime":1535.625,"endTime":1540.53,"body":"So I really want to make the general point that actually it's not just about"},{"startTime":1540.53,"endTime":1542.165,"body":"having immunotherapy or checkpoint inhibitors."},{"startTime":1542.165,"endTime":1546.252,"body":"There's a lot about how you use them best to get the best outcomes for"},{"startTime":1546.252,"endTime":1546.525,"body":"patients."},{"startTime":1548.745,"endTime":1553.558,"body":"So moving on to challenges, I've talked about benefits, um, well this is probably the"},{"startTime":1553.558,"endTime":1556.125,"body":"subject of a talk in its own right."},{"startTime":1556.275,"endTime":1557.485,"body":"I've put a list here."},{"startTime":1558.425,"endTime":1560.925,"body":"Um, it's not an exhaustive list."},{"startTime":1560.935,"endTime":1564.977,"body":"Again, uh, I think first and foremost the challenge to is to increase the cure"},{"startTime":1564.977,"endTime":1566.325,"body":"rate from what we're doing."},{"startTime":1566.745,"endTime":1570.005,"body":"Um, and I wouldn't just apply that to melanoma, I apply that across the board."},{"startTime":1570.865,"endTime":1574.965,"body":"Do we really understand why the drugs work and why they don't work?"},{"startTime":1574.965,"endTime":1578.106,"body":"Well, I'm not really sure we do at the moment, although there's plenty of work"},{"startTime":1578.106,"endTime":1578.525,"body":"on that."},{"startTime":1579.465,"endTime":1584.593,"body":"If we did, could we develop useful biomarkers, in other words, markers of biology, that"},{"startTime":1584.593,"endTime":1584.935,"body":"it would allow us to select a particular treatment for a particular patient in a"},{"startTime":1584.935,"endTime":1590.405,"body":"particular situation?"},{"startTime":1591.045,"endTime":1593.245,"body":"I think that's still in its infancy, honestly."},{"startTime":1593.905,"endTime":1598.725,"body":"Um, can we combine these drugs to get more out of them?"},{"startTime":1600.825,"endTime":1602.405,"body":"Are we giving the treatments for too long?"},{"startTime":1602.685,"endTime":1606.533,"body":"I said at the beginning that one of the things about immunotherapy if it was"},{"startTime":1606.533,"endTime":1610.125,"body":"successful is that ideally you wouldn't give treatment for a long period of time."},{"startTime":1610.125,"endTime":1611.885,"body":"Perhaps you could give it a short period of time."},{"startTime":1612.415,"endTime":1616.062,"body":"Again, most of the clinical trials have used quite long periods of treatment a year"},{"startTime":1616.062,"endTime":1617.765,"body":"or two years or something like that."},{"startTime":1617.825,"endTime":1618.565,"body":"Is that too much?"},{"startTime":1618.595,"endTime":1623.026,"body":"Well, I suspect it is in certain situations, but we don't really have the tools"},{"startTime":1623.026,"endTime":1625.685,"body":"at the moment in clinic to work that out."},{"startTime":1627.165,"endTime":1631.586,"body":"I haven't really, uh, said much about, um, side effects, but I'll say a bit"},{"startTime":1631.586,"endTime":1632.765,"body":"about that later on."},{"startTime":1632.765,"endTime":1637.019,"body":"But again, the management, the dealing with side effects in my view for these drugs"},{"startTime":1637.019,"endTime":1637.303,"body":"is still, uh, relatively in its infancy in terms of trying to manage them as"},{"startTime":1637.303,"endTime":1642.125,"body":"best we can."},{"startTime":1643.265,"endTime":1648.301,"body":"Um, we tend to give people high doses of steroids to manage side effects, which"},{"startTime":1648.301,"endTime":1649.645,"body":"are powerful immunosuppressive drugs."},{"startTime":1649.705,"endTime":1651.045,"body":"Is that the best way to do that?"},{"startTime":1651.265,"endTime":1652.685,"body":"Is there a one size fits all?"},{"startTime":1652.705,"endTime":1653.845,"body":"We dunno the answer to that."},{"startTime":1654.545,"endTime":1659.485,"body":"And there's a quite a big question as well about understanding long-term side effects."},{"startTime":1659.545,"endTime":1663.24,"body":"So with checkpoints inhibitors, this is a new class of drugs that's only been used"},{"startTime":1663.24,"endTime":1664.965,"body":"in the last 10 years or so."},{"startTime":1665.355,"endTime":1668.045,"body":"What are the long-term consequences of these drugs?"},{"startTime":1668.105,"endTime":1670.045,"body":"We simply do not know at the moment."},{"startTime":1670.145,"endTime":1672.245,"body":"So that's a really important area of study."},{"startTime":1672.505,"endTime":1677.029,"body":"If we're saying that we're gonna be curing a group of people and returning them"},{"startTime":1677.029,"endTime":1680.045,"body":"to normal lives, are there any unexpected long-term side effects?"},{"startTime":1681.385,"endTime":1686.661,"body":"So just to pick up, um, a couple, uh, of those points for the purposes"},{"startTime":1686.661,"endTime":1687.365,"body":"of illustration."},{"startTime":1688.305,"endTime":1692.83,"body":"Uh, might there be new targets for checkpoint inhibition or, I've said a little bit"},{"startTime":1692.83,"endTime":1693.132,"body":"about this already and I've shown the cartoon again, but a massive amount of effort"},{"startTime":1693.132,"endTime":1693.433,"body":"has gone into this, um, certainly in industry and in academia over the last 10"},{"startTime":1693.433,"endTime":1693.735,"body":"or 15 years, and I'm not sure about that, whether we're gonna see more from"},{"startTime":1693.735,"endTime":1709.725,"body":"other immune checkpoint inhibitors in the next five or 10 years."},{"startTime":1710.745,"endTime":1714.872,"body":"Um, this point about biomarkers, I'm making it on this slide as well, if we"},{"startTime":1714.872,"endTime":1718.725,"body":"could rationally select who to treat with a particular drug, it might be different."},{"startTime":1718.725,"endTime":1722.437,"body":"But again, we haven't really got that, at least not in any detail at the"},{"startTime":1722.437,"endTime":1722.685,"body":"moment."},{"startTime":1723.825,"endTime":1728.005,"body":"Um, can we get more from the targets that we have at the moment?"},{"startTime":1728.105,"endTime":1730.485,"body":"So CTLA four and PD one, PD L one?"},{"startTime":1730.485,"endTime":1732.405,"body":"Well, that's a very interesting question actually."},{"startTime":1732.405,"endTime":1738.005,"body":"There's quite a lot of, uh, so-called second generation anti CTLA four drugs."},{"startTime":1739.595,"endTime":1741.765,"body":"Umab is, uh, an example of one of those."},{"startTime":1741.825,"endTime":1745.205,"body":"And so this is kind of a question of trying to re-engineer the drugs."},{"startTime":1745.225,"endTime":1749.777,"body":"So you're still hitting the target and potentially minimizing the side effects associated with that,"},{"startTime":1749.777,"endTime":1752.205,"body":"which is a problem for anti CTLA fours."},{"startTime":1752.665,"endTime":1757.471,"body":"Uh, and this again, may not project, but actually from some very preliminary data from"},{"startTime":1757.471,"endTime":1757.792,"body":"a couple of years ago, you can see activity for this drug really in, uh,"},{"startTime":1757.792,"endTime":1766.445,"body":"types of, uh, cancer that we haven't really seen much benefit from immunotherapy."},{"startTime":1766.585,"endTime":1771.165,"body":"So sarcoma, uh, and ovarian cancer, and also some colorectal cancer."},{"startTime":1771.305,"endTime":1776.205,"body":"So that, I would say watch this space in terms of second generation CTLA fours."},{"startTime":1778.665,"endTime":1780.365,"body":"So what about side effects?"},{"startTime":1782.195,"endTime":1787.49,"body":"Well, I'm talking about immune checkpoint inhibitors and, uh, par excellence, and I say this"},{"startTime":1787.49,"endTime":1787.843,"body":"to patients, almost any part of the body can be affected by side effects from"},{"startTime":1787.843,"endTime":1793.845,"body":"immune checkpoint inhibitors."},{"startTime":1793.845,"endTime":1795.245,"body":"And that's a really important point."},{"startTime":1796.675,"endTime":1801.829,"body":"This is a list of, its for want of a better word, meaning inflammation of"},{"startTime":1801.829,"endTime":1802.173,"body":"different parts of the body that the drugs can cause, uh, colitis, inflammation of the"},{"startTime":1802.173,"endTime":1810.765,"body":"colon causing diarrhea, pneumonitis, lungs, and so on and so forth."},{"startTime":1811.465,"endTime":1815.381,"body":"So the point is that some of these are more common than others, uh, on"},{"startTime":1815.381,"endTime":1815.642,"body":"the left of the vertical line, uh, but some of them are more serious than"},{"startTime":1815.642,"endTime":1821.125,"body":"others on the right of the line."},{"startTime":1821.145,"endTime":1827.005,"body":"So for example, uh, myocarditis inflammation of the heart is a particularly dangerous side effect."},{"startTime":1827.665,"endTime":1832.615,"body":"Um, and I would really make the point here that some of these side effects"},{"startTime":1832.615,"endTime":1833.605,"body":"can be permanent."},{"startTime":1833.625,"endTime":1838.125,"body":"And again, if we're thinking about curative treatment and people trying to return to a"},{"startTime":1838.125,"endTime":1839.925,"body":"normal life, that's obviously extremely important."},{"startTime":1841.105,"endTime":1845.872,"body":"We don't really have anywhere near the quality of evidence for managing side effects as"},{"startTime":1845.872,"endTime":1850.005,"body":"some of the evidence I've just shown you for benefit of the drugs."},{"startTime":1850.065,"endTime":1854.847,"body":"And again, if people are interested, we can talk about why that is, uh, in"},{"startTime":1854.847,"endTime":1855.485,"body":"questions afterwards."},{"startTime":1856.625,"endTime":1860.639,"body":"Um, and I've said this already, but a lot of the time we're using very"},{"startTime":1860.639,"endTime":1860.907,"body":"high doses of steroids like Prednisolone, uh, to manage these side effects, and certainly some"},{"startTime":1860.907,"endTime":1861.175,"body":"that's something that worries me, um, for various different reasons, not least the side effects"},{"startTime":1861.175,"endTime":1869.205,"body":"of steroids."},{"startTime":1871.305,"endTime":1877.98,"body":"So the final, um, segment, I would like to think a little bit about, um,"},{"startTime":1877.98,"endTime":1880.205,"body":"new Frontiers for cancer immunotherapy."},{"startTime":1881.145,"endTime":1887.165,"body":"Uh, back to my, uh, cartoon diagram about different types of cancer immunotherapy."},{"startTime":1887.185,"endTime":1890.605,"body":"And I'm just gonna pick out a a couple of things."},{"startTime":1891.825,"endTime":1895.965,"body":"One of them, um, is, uh, vaccine therapy."},{"startTime":1896.785,"endTime":1899.245,"body":"And this is one example in melanoma."},{"startTime":1900.185,"endTime":1906.808,"body":"And so, uh, basically this is a small randomized trial, uh, looking at, uh, a,"},{"startTime":1906.808,"endTime":1907.249,"body":"so-called individualized neoantigen therapy, INT at the top in combination with pembrolizumab, an anti PD"},{"startTime":1907.249,"endTime":1917.405,"body":"one drug, uh, in melanoma in the adjuvant setting."},{"startTime":1917.465,"endTime":1920.085,"body":"And I've explained what that means, um, already."},{"startTime":1920.745,"endTime":1925.428,"body":"So just to focus on how this works, and again, I apologize, this is a"},{"startTime":1925.428,"endTime":1926.365,"body":"little bit involved."},{"startTime":1926.845,"endTime":1932.375,"body":"I think the important point here is that this is individualized, and the reason for"},{"startTime":1932.375,"endTime":1932.744,"body":"that is that how this works is the tumor is sequenced and as a consequence"},{"startTime":1932.744,"endTime":1933.113,"body":"of sequencing the tumor, uh, proteins are defined and they are used to make a"},{"startTime":1933.113,"endTime":1947.125,"body":"vaccine, and then the vaccine is different for every patient."},{"startTime":1947.985,"endTime":1951.772,"body":"And so that's the sort of left hand side of this, and some of the"},{"startTime":1951.772,"endTime":1954.045,"body":"workings are described, um, on the right hand side."},{"startTime":1954.585,"endTime":1959.322,"body":"And I suppose that the important background point here for mRNA Messenger, RNA vaccines, is"},{"startTime":1959.322,"endTime":1962.165,"body":"that this actually is a, it's an interesting field."},{"startTime":1962.165,"endTime":1965.872,"body":"It's been going on for decades, um, and there's a few people in the world"},{"startTime":1965.872,"endTime":1966.119,"body":"who've devoted their careers to this, but it only really achieved prominence when covid came"},{"startTime":1966.119,"endTime":1971.805,"body":"along, as I'm sure lots of people will know."},{"startTime":1972.145,"endTime":1978.418,"body":"And the mRNA vaccines within months went from pretty much the drawing board to being"},{"startTime":1978.418,"endTime":1981.765,"body":"delivered to people to, um, protect against covid."},{"startTime":1981.905,"endTime":1984.925,"body":"And that type of technology is being now applied to cancer as well."},{"startTime":1986.865,"endTime":1988.605,"body":"So what did this look like in this trial?"},{"startTime":1988.605,"endTime":1994.371,"body":"This is a small trial, um, and the bottom line is people who are treated,"},{"startTime":1994.371,"endTime":1995.525,"body":"um, with pembrolizumab."},{"startTime":1995.545,"endTime":1997.605,"body":"So that's the standard treatment in this situation."},{"startTime":1997.605,"endTime":2002.142,"body":"And then the line above that is the people who got the vaccine, uh, and"},{"startTime":2002.142,"endTime":2002.445,"body":"pembrolizumab."},{"startTime":2002.445,"endTime":2003.845,"body":"And there's several caveats to this."},{"startTime":2003.905,"endTime":2006.236,"body":"One of them I've said already, and I've said, again, it's a small trial, so"},{"startTime":2006.236,"endTime":2007.325,"body":"you need to be a bit careful."},{"startTime":2008.065,"endTime":2010.525,"body":"Uh, there's relatively limited follow up."},{"startTime":2010.585,"endTime":2016.388,"body":"The X axis here is in weeks, but nevertheless, you can see pretty clearly, um,"},{"startTime":2016.388,"endTime":2016.775,"body":"that the chance of the cancer returning was significantly less with the vaccine and with"},{"startTime":2016.775,"endTime":2022.965,"body":"the immunotherapy."},{"startTime":2023.905,"endTime":2026.925,"body":"And this has now led, um, to a bigger trial."},{"startTime":2026.925,"endTime":2028.605,"body":"Hopefully it'll be a confirmatory trial."},{"startTime":2028.605,"endTime":2031.885,"body":"So-called phase three trial, which is, uh, recruiting around the world."},{"startTime":2031.905,"endTime":2034.125,"body":"And certainly, um, we are part of that."},{"startTime":2034.145,"endTime":2038.401,"body":"So this is very exciting, and actually it hit the press, uh, when it came"},{"startTime":2038.401,"endTime":2038.685,"body":"out."},{"startTime":2039.145,"endTime":2043.245,"body":"The way that we measure the difference between, uh, the two groups is, is the"},{"startTime":2043.245,"endTime":2046.525,"body":"hazard ratio, and it's actually shown there for people that are interested."},{"startTime":2046.585,"endTime":2051.364,"body":"But again, it's a magnitude of benefit that we don't see very often."},{"startTime":2052.025,"endTime":2055.148,"body":"And I had actually lots of patients coming to my clinic saying, can I have"},{"startTime":2055.148,"endTime":2055.565,"body":"this treatment?"},{"startTime":2055.565,"endTime":2059.718,"body":"Because it, it featured in the press and it's promising, but again, it's a small"},{"startTime":2059.718,"endTime":2062.764,"body":"trial and I think we need to see, uh, further data."},{"startTime":2063.824,"endTime":2065.885,"body":"So that's, uh, vaccines."},{"startTime":2066.625,"endTime":2068.885,"body":"Uh, what about cellular therapy?"},{"startTime":2069.625,"endTime":2072.324,"body":"Um, well this isn't new either."},{"startTime":2073.264,"endTime":2077.894,"body":"Um, Steven Rosenberg, who's in his mid eighties now and still working, uh, at the"},{"startTime":2077.894,"endTime":2078.202,"body":"NCI in the US has really been doing this since the 1990s with colleagues, and"},{"startTime":2078.202,"endTime":2084.685,"body":"he's really the pioneer, I would say."},{"startTime":2085.425,"endTime":2090.538,"body":"Um, and really the idea, uh, with cellular therapies, you actually take immune cells outta"},{"startTime":2090.538,"endTime":2090.879,"body":"the patient and then you manipulate them in the laboratory and then you give the"},{"startTime":2090.879,"endTime":2091.22,"body":"product, and it's called a product rather than a drug back to the patient with"},{"startTime":2091.22,"endTime":2091.561,"body":"the idea that you've, if you like, reinvigorated or rejuvenated, uh, those immune cells so"},{"startTime":2091.561,"endTime":2107.925,"body":"that they can attack the cancer."},{"startTime":2107.985,"endTime":2109.325,"body":"So it sounds like a simple idea."},{"startTime":2110.305,"endTime":2115.205,"body":"Um, and historically over the last sort of 10, 20 years, there's been lots of"},{"startTime":2115.205,"endTime":2115.531,"body":"reports of this type of, uh, therapy, uh, for treating cancers, not just melanoma, but"},{"startTime":2115.531,"endTime":2121.085,"body":"various different cancers."},{"startTime":2121.505,"endTime":2124.805,"body":"It is logistically a complex treatment."},{"startTime":2125.005,"endTime":2127.165,"body":"I think it's fair to say that's one thing to say."},{"startTime":2127.825,"endTime":2132.251,"body":"Um, and the, the treatment that we give, and I'll show a bit more about"},{"startTime":2132.251,"endTime":2132.546,"body":"this in a minute, to deliver the cellular therapy back for the patients is actually"},{"startTime":2132.546,"endTime":2132.841,"body":"fairly intensive and people actually need to be pretty fit to be able to, um,"},{"startTime":2132.841,"endTime":2144.645,"body":"receive this type of therapy in the last 10 or 20 years."},{"startTime":2144.645,"endTime":2148.525,"body":"The other problem with this was that actually the time taken to generate the product"},{"startTime":2148.525,"endTime":2148.784,"body":"was often months, which is a long time if you've got a cancer that spread"},{"startTime":2148.784,"endTime":2149.043,"body":"and it hasn't responded to other treatments and you know, you're not in the best"},{"startTime":2149.043,"endTime":2156.805,"body":"of health."},{"startTime":2156.945,"endTime":2161.318,"body":"So the, the group of people that can benefit from that was relatively limited as"},{"startTime":2161.318,"endTime":2162.485,"body":"a result of this."},{"startTime":2162.505,"endTime":2166.365,"body":"So those have been the, uh, the kind of the background issues, if you like."},{"startTime":2167.065,"endTime":2170.326,"body":"And I suppose that's what I'm saying there with that bottom bullet point, that the,"},{"startTime":2170.326,"endTime":2170.544,"body":"you know, if your cancer's growing quickly and you are really ill, then actually you"},{"startTime":2170.544,"endTime":2170.761,"body":"might not have months to wait for a cellular therapy product to be generated in"},{"startTime":2170.761,"endTime":2177.285,"body":"a lab."},{"startTime":2178.465,"endTime":2183.605,"body":"So, um, this is a sort of a cartoon of how this works in practice."},{"startTime":2183.625,"endTime":2188.465,"body":"So at the left hand end, um, you take some tumor tissue, uh, so that's"},{"startTime":2188.465,"endTime":2188.788,"body":"usually removed with an operation, um, that, that might be a centimeter or a centimeter"},{"startTime":2188.788,"endTime":2195.565,"body":"and a half, uh, bit of tumor."},{"startTime":2196.425,"endTime":2202.352,"body":"Um, this, um, cartoon, this diagram, uh, refers to something called Lucile, um, which is"},{"startTime":2202.352,"endTime":2207.885,"body":"a product that's generated, um, by a biotech company called Ivan in the us."},{"startTime":2208.825,"endTime":2212.925,"body":"And so then the product is generated, that's that box along the bottom."},{"startTime":2213.785,"endTime":2216.525,"body":"And the critical thing here for me at least, is that it's three weeks."},{"startTime":2216.865,"endTime":2218.965,"body":"So the product is generated in three weeks."},{"startTime":2219.875,"endTime":2225.581,"body":"Meanwhile, um, the patient who's gonna get the treatment comes into hospital and they have"},{"startTime":2225.581,"endTime":2228.245,"body":"something, uh, that's called non myeloablative lymphodepletion."},{"startTime":2228.785,"endTime":2233.463,"body":"So what that means is giving chemotherapy, um, if you like to make space to"},{"startTime":2233.463,"endTime":2233.775,"body":"give the immune cells, make space within the body back to the patient, you then"},{"startTime":2233.775,"endTime":2240.325,"body":"give the uc infusion, that's number four."},{"startTime":2240.865,"endTime":2244.553,"body":"And then after that you give something called high-dose interleukin two, which I mentioned at"},{"startTime":2244.553,"endTime":2245.045,"body":"the start."},{"startTime":2245.045,"endTime":2249.405,"body":"So this is a cytokine, um, so a potential stimulant of t-cells."},{"startTime":2249.785,"endTime":2253.604,"body":"And that's actually given in quite high doses and it has quite tough side effects"},{"startTime":2253.604,"endTime":2256.405,"body":"and people need to be in hospital to have this treatment."},{"startTime":2257.025,"endTime":2260.405,"body":"And then when all of that is done, a patient gets discharged from hospital."},{"startTime":2260.425,"endTime":2265.063,"body":"And so typically people will be in hospital to have this treatment for a week"},{"startTime":2265.063,"endTime":2265.372,"body":"or two, uh, for close monitoring and uh, uh, to make sure that the side"},{"startTime":2265.372,"endTime":2272.485,"body":"effects, particularly of the interleukin two are managed properly."},{"startTime":2272.485,"endTime":2274.365,"body":"It's not an outpatient treatment at the moment."},{"startTime":2276.505,"endTime":2281.485,"body":"So what does this look like, this product life elusal, um, in melanoma?"},{"startTime":2281.585,"endTime":2286.756,"body":"So, uh, a trial has been done over the last several years in people who've"},{"startTime":2286.756,"endTime":2287.101,"body":"got melanoma that's spread, they've had treatment with checkpoint inhibitors, the treatment with checkpoint inhibitors"},{"startTime":2287.101,"endTime":2287.446,"body":"hasn't worked, and then they're in a situation where there isn't really a well-defined treatment"},{"startTime":2287.446,"endTime":2297.445,"body":"option."},{"startTime":2298.425,"endTime":2301.725,"body":"And with life elusal, this has got a waterfall plot."},{"startTime":2301.725,"endTime":2305.925,"body":"And if you imagine the horizontal line going through the middle below the line, uh,"},{"startTime":2305.925,"endTime":2309.285,"body":"each of those lines is a patient who is treated with this."},{"startTime":2309.585,"endTime":2311.845,"body":"And it's a measurement of tumor reduction, basically."},{"startTime":2311.865,"endTime":2315.707,"body":"So you can see all of those bars below the line on the right hand"},{"startTime":2315.707,"endTime":2318.525,"body":"side of people who experienced tumor reduction, uh, with this therapy."},{"startTime":2318.985,"endTime":2323.561,"body":"And this is just over a hundred patients, so it's not an enormous trial, but"},{"startTime":2323.561,"endTime":2323.867,"body":"it's, it's still, for me at least, um, pretty compelling evidence of potential benefit from"},{"startTime":2323.867,"endTime":2330.885,"body":"this treatment with the caveats that I've mentioned already."},{"startTime":2333.115,"endTime":2334.165,"body":"What about side effects?"},{"startTime":2334.165,"endTime":2338.203,"body":"Well, I've sort of, um, said this already and, and you can read out the"},{"startTime":2338.203,"endTime":2338.472,"body":"side effects on the right hand side, but actually, interestingly enough, most of the side"},{"startTime":2338.472,"endTime":2338.741,"body":"effects with this treatment are associated with the side effects of being hospital, the chemotherapy"},{"startTime":2338.741,"endTime":2348.165,"body":"that I mentioned in the interleukin two."},{"startTime":2348.465,"endTime":2352.415,"body":"And this graph on the left hand side is really showing you that all the"},{"startTime":2352.415,"endTime":2352.678,"body":"side effects that that sort of bunch line, uh, are happening when the people are"},{"startTime":2352.678,"endTime":2359.525,"body":"in hospital and once they've had the treatment, they're discharged from hospital."},{"startTime":2360.165,"endTime":2361.845,"body":"Actually the side effects are pretty rare."},{"startTime":2362.065,"endTime":2365.837,"body":"So one way to think about it, and I say this a lot, um, to"},{"startTime":2365.837,"endTime":2366.089,"body":"patients if you're having this kind of treatment, is it's a bit like having a"},{"startTime":2366.089,"endTime":2370.365,"body":"bone marrow transplantation."},{"startTime":2370.365,"endTime":2374.672,"body":"In other words, it's a tough intensive treatment right at the very start, but you're"},{"startTime":2374.672,"endTime":2378.405,"body":"trying to do something with durable benefit and it's a one off treatment."},{"startTime":2378.405,"endTime":2379.685,"body":"This, it's delivered."},{"startTime":2379.685,"endTime":2381.845,"body":"Then again, it's a bit like a bone marrow transplantation."},{"startTime":2381.845,"endTime":2384.085,"body":"And that's, that's kind of how I think about it a little bit."},{"startTime":2385.425,"endTime":2387.925,"body":"So what about moving forwards with cellular therapy?"},{"startTime":2388.175,"endTime":2393.009,"body":"Again, this is a, an another cartoon and in many ways the details of this"},{"startTime":2393.009,"endTime":2393.331,"body":"don't matter, but from the perspective of molecular biology, there's all sorts of different ways"},{"startTime":2393.331,"endTime":2393.653,"body":"that you can potentially improve on this treatment by re-engineering the treatment, making it smarter,"},{"startTime":2393.653,"endTime":2403.645,"body":"making it kinder."},{"startTime":2403.645,"endTime":2408.165,"body":"So I think we're gonna see lots of this in the next five or 10"},{"startTime":2408.165,"endTime":2408.467,"body":"years, and there's enormous interest in this in academia and in industry around the world"},{"startTime":2408.467,"endTime":2416.605,"body":"to try and develop this, uh, therapy, um, to make it work better."},{"startTime":2420.145,"endTime":2423.565,"body":"Is this just melanoma very reasonable question to ask?"},{"startTime":2423.955,"endTime":2428.53,"body":"Well, we don't know at the moment 'cause I think it's too early to say,"},{"startTime":2428.53,"endTime":2431.885,"body":"uh, but what I'm showing here is again, some waterfall plots."},{"startTime":2432.025,"endTime":2435.953,"body":"Uh, you'll gather, uh, from the thickness of the bars, that these are relatively small"},{"startTime":2435.953,"endTime":2437.525,"body":"numbers of people in these trials."},{"startTime":2437.625,"endTime":2439.165,"body":"You can see that it's actually just a handful."},{"startTime":2440.185,"endTime":2445.423,"body":"But the point of this slide, the melanoma is on the left hand side so"},{"startTime":2445.423,"endTime":2445.772,"body":"that you can see with melanoma treatment with pembrolizumab, anti PD one and uc altogether,"},{"startTime":2445.772,"endTime":2453.805,"body":"pretty much everyone who was treated had tumor shrinkage."},{"startTime":2454.305,"endTime":2459.689,"body":"But more importantly, um, I would say as you move across the middle group is"},{"startTime":2459.689,"endTime":2461.125,"body":"head and neck cancer."},{"startTime":2461.705,"endTime":2464.365,"body":"And then the group on the right is cervical cancer."},{"startTime":2465.065,"endTime":2471.38,"body":"So, um, these are both cancers and particularly cervical cancer where immunotherapy hasn't really had"},{"startTime":2471.38,"endTime":2473.485,"body":"a particularly strong track record."},{"startTime":2473.665,"endTime":2478.525,"body":"So I think these are really potentially quite encouraging early data but require confirmation."},{"startTime":2481.865,"endTime":2485.933,"body":"So this is pretty much my final slide in bringing us, uh, right up to"},{"startTime":2485.933,"endTime":2486.205,"body":"date."},{"startTime":2486.225,"endTime":2492.533,"body":"So I mentioned that Ivan Therapeutics make life elusal, um, uh, regulatory decision is expected"},{"startTime":2492.533,"endTime":2492.954,"body":"from the FDA in the US uh, on the 24th of February, which is the"},{"startTime":2492.954,"endTime":2500.525,"body":"end of next week."},{"startTime":2500.725,"endTime":2502.685,"body":"I dunno what that's decision's going to be."},{"startTime":2503.225,"endTime":2508.133,"body":"Um, but if the FDA do approve this for the treatment of refractory melanoma, uh,"},{"startTime":2508.133,"endTime":2508.46,"body":"this will pretty much be the first regulatory approval that we've seen for a cellular"},{"startTime":2508.46,"endTime":2515.005,"body":"therapy to treat a solid tumor."},{"startTime":2515.065,"endTime":2520.18,"body":"So I think all of us in the field are, are hotly anticipating, uh, and"},{"startTime":2520.18,"endTime":2521.885,"body":"looking forward to this decision."},{"startTime":2522.025,"endTime":2523.445,"body":"So watch this space."},{"startTime":2525.185,"endTime":2531.866,"body":"So to summarize, um, historically I think it is fair to say that pretty much"},{"startTime":2531.866,"endTime":2532.311,"body":"all metastatic solid tumors, um, were incurable, uh, checkpoints inhibitors are, I think, and I"},{"startTime":2532.311,"endTime":2532.757,"body":"hope I've been able to show you are probably curative in some people who've got"},{"startTime":2532.757,"endTime":2546.565,"body":"metastatic, um, melanoma."},{"startTime":2548.345,"endTime":2551.786,"body":"But in melanoma I still make the point that half of people will die from"},{"startTime":2551.786,"endTime":2552.245,"body":"this disease."},{"startTime":2552.305,"endTime":2555.045,"body":"So there's still a lot of work for us to do."},{"startTime":2555.975,"endTime":2561.295,"body":"Those of us, um, who treat melanoma have genuinely been excited to see the vaccine"},{"startTime":2561.295,"endTime":2561.65,"body":"data that I showed you and also the cellular therapy data over the last, um,"},{"startTime":2561.65,"endTime":2567.325,"body":"few years."},{"startTime":2568.145,"endTime":2573.812,"body":"And perhaps the key point to make is the success of immune checkpoint inhibitors has"},{"startTime":2573.812,"endTime":2578.725,"body":"really, I think, revitalized the field of cancer immunotherapy, not just in melanoma."},{"startTime":2579.225,"endTime":2582.908,"body":"And I hope, and I expect actually to see further progress in the next five"},{"startTime":2582.908,"endTime":2583.645,"body":"years or so."},{"startTime":2584.825,"endTime":2590.214,"body":"Um, my acknowledgements are to our patients and their families, first and foremost, many of"},{"startTime":2590.214,"endTime":2594.885,"body":"whom have participated in some of the clinical trials that I've shown you."},{"startTime":2595.705,"endTime":2599.605,"body":"I'd also like to thank, uh, my team at the Marsden who really do all"},{"startTime":2599.605,"endTime":2600.125,"body":"the work."},{"startTime":2600.685,"endTime":2608.405,"body":"Carrying out clinical trials is an incredibly, uh, um, resource intensive, uh, activity."},{"startTime":2608.555,"endTime":2610.125,"body":"It's very tightly regulated."},{"startTime":2610.185,"endTime":2613.525,"body":"It really requires a big team of people to work together to do it best."},{"startTime":2614.345,"endTime":2617.485,"body":"Uh, and it's very much a multidisciplinary activity."},{"startTime":2617.625,"endTime":2622.805,"body":"So, um, uh, trials team is led by Ellie Carlisle, uh, in the office."},{"startTime":2622.865,"endTime":2626.045,"body":"And Kim Edmond, who's our lead research nurse, and Dr."},{"startTime":2626.705,"endTime":2630.248,"body":"Vu, one of our clinical fellows has, uh, helped me put the talk together this"},{"startTime":2630.248,"endTime":2630.485,"body":"evening."},{"startTime":2630.505,"endTime":2631.765,"body":"So I'd like to thank her as well."},{"startTime":2632.545,"endTime":2639.59,"body":"And I'd also, uh, like to thank, um, collaborators and friends in the UK and"},{"startTime":2639.59,"endTime":2640.06,"body":"internationally in industry, um, uh, in academia, um, in government as well, and also actually"},{"startTime":2640.06,"endTime":2648.045,"body":"in advocacy groups."},{"startTime":2648.165,"endTime":2652.547,"body":"I haven't really mentioned anything at all about advocacy, uh, groups this evening, but it's"},{"startTime":2652.547,"endTime":2652.839,"body":"been a critical, I think, piece of the jigsaw, uh, with trying to work out"},{"startTime":2652.839,"endTime":2653.131,"body":"which trials to do and to sometimes generate, uh, pressure, uh, to help make things"},{"startTime":2653.131,"endTime":2661.605,"body":"happen."},{"startTime":2662.025,"endTime":2665.241,"body":"Um, so I will thank you for attention and I think we've got some questions"},{"startTime":2665.241,"endTime":2665.885,"body":"and answers next."},{"startTime":2671.945,"endTime":2676.125,"body":"So there's quite a, a detailed question that has lots of like extremes."},{"startTime":2676.145,"endTime":2677.325,"body":"So I'm gonna read it as it is."},{"startTime":2677.345,"endTime":2680.861,"body":"And then I think we might need to put it into layman's terms for, for"},{"startTime":2680.861,"endTime":2681.565,"body":"the general audience."},{"startTime":2682.655,"endTime":2691.39,"body":"Could slash does using immunotherapy concurrently encourage tumor propagation due to cancer promoting immune cell"},{"startTime":2691.39,"endTime":2694.885,"body":"phenotypes such as tumor associated macrophages?"},{"startTime":2695.905,"endTime":2700.645,"body":"So in layman's terms, could we actually make the cancer grow faster because of the"},{"startTime":2700.645,"endTime":2703.805,"body":"different environment that we're creating around about the tumor cells?"},{"startTime":2704.555,"endTime":2709.865,"body":"Yeah, I mean, to to, to be blunt, I I think you could speculate almost"},{"startTime":2709.865,"endTime":2710.22,"body":"anything, especially with the immune system 'cause it's so complicated and there's so many checks"},{"startTime":2710.22,"endTime":2715.885,"body":"and balances."},{"startTime":2715.985,"endTime":2719.845,"body":"So it, it's difficult to refute that."},{"startTime":2719.945,"endTime":2724.261,"body":"But I think a lot of this will then come back to clinical trials and"},{"startTime":2724.261,"endTime":2725.125,"body":"actually demonstrating benefit."},{"startTime":2725.985,"endTime":2731.211,"body":"Um, and I think if you are seeing benefit in clinical trials, it's really difficult"},{"startTime":2731.211,"endTime":2732.605,"body":"to argue against that."},{"startTime":2732.745,"endTime":2737.233,"body":"But I think maybe the take home for me is that once you move, if"},{"startTime":2737.233,"endTime":2737.532,"body":"you like, from preclinical models, the laboratory, that kind of thing into clinical trials, at"},{"startTime":2737.532,"endTime":2737.832,"body":"the end of the day it's quite difficult to predict and one can almost make"},{"startTime":2737.832,"endTime":2748.605,"body":"an argument in all sorts of different ways."},{"startTime":2748.605,"endTime":2751.13,"body":"And I'm sure lots of people know this, that this will, the other thing might"},{"startTime":2751.13,"endTime":2752.645,"body":"happen, but I think you need to test it."},{"startTime":2753.145,"endTime":2757.662,"body":"And maybe the other point I would make there with, with clinical trials is it's"},{"startTime":2757.662,"endTime":2757.963,"body":"really important when you're doing this to try and characterize as best you can the"},{"startTime":2757.963,"endTime":2763.685,"body":"tumor from a biological perspective."},{"startTime":2763.685,"endTime":2767.585,"body":"Because, you know, in the old days, uh, and again, many people realize this, we,"},{"startTime":2767.585,"endTime":2767.845,"body":"we tended to just do clinical trials and not really get that kind of in"},{"startTime":2767.845,"endTime":2772.005,"body":"depth understanding."},{"startTime":2772.025,"endTime":2775.356,"body":"But I think it's bold on all of us to really try and do that"},{"startTime":2775.356,"endTime":2776.245,"body":"academia and in industry."},{"startTime":2776.265,"endTime":2777.405,"body":"So that's how to answer that."},{"startTime":2777.445,"endTime":2777.645,"body":"I think"},{"startTime":2778.285,"endTime":2779.005,"body":"Absolutely there is."},{"startTime":2779.055,"endTime":2779.605,"body":"Hello there."},{"startTime":2779.665,"endTime":2783.285,"body":"My name's Carmen Blair, I'm a hospital doctor in emergency medicine."},{"startTime":2783.825,"endTime":2785.405,"body":"And my question is about cost."},{"startTime":2785.645,"endTime":2790.53,"body":"I didn't hear you mentioning the cost of these drugs once the, you have mentioned"},{"startTime":2790.53,"endTime":2790.856,"body":"the duration of the treatments one to two years and the patient gets severe side"},{"startTime":2790.856,"endTime":2791.182,"body":"effects, hepatitis, pneumonitis, colitis, some permanent, and then the cost, the NHS is not in"},{"startTime":2791.182,"endTime":2791.507,"body":"a state to provide these drugs once these manufacturers starts asking thousands of pounds to"},{"startTime":2791.507,"endTime":2806.165,"body":"treat one patient."},{"startTime":2806.635,"endTime":2808.125,"body":"What about the cost of these"},{"startTime":2808.125,"endTime":2808.445,"body":"Three?"},{"startTime":2808.555,"endTime":2815.217,"body":"Yeah, so, um, in terms of reimbursement in publicly funded health systems, NHS and others,"},{"startTime":2815.217,"endTime":2815.662,"body":"for example, in, in most of western Europe there are, um, HTAs health technology assessment"},{"startTime":2815.662,"endTime":2822.325,"body":"panels."},{"startTime":2822.325,"endTime":2827.105,"body":"Ours is called nice, which takes into account the benefit and the cost and then"},{"startTime":2827.105,"endTime":2831.885,"body":"makes a decision about whether it's felt to represent good value for money or not."},{"startTime":2832.625,"endTime":2837.176,"body":"And what I would say about, uh, nice, let's say in melanoma, which is what"},{"startTime":2837.176,"endTime":2837.479,"body":"I treat over the last 10 or 15 years, is that pretty much every drug"},{"startTime":2837.479,"endTime":2837.782,"body":"that I would wish to be available has been made available based on that type"},{"startTime":2837.782,"endTime":2846.885,"body":"of equation."},{"startTime":2847.265,"endTime":2852.125,"body":"You know, what's the benefit and what's the cost, which is obviously great for patients"},{"startTime":2852.125,"endTime":2855.365,"body":"in this country, but NICE doesn't always make positive decisions."},{"startTime":2856.185,"endTime":2860.252,"body":"Um, and you know, if you've got a treatment where really the benefit doesn't seem"},{"startTime":2860.252,"endTime":2860.523,"body":"to be that much or you're not able to define clearly the group of people"},{"startTime":2860.523,"endTime":2860.794,"body":"who are really gonna benefit from the treatment, then I think, you know, we all"},{"startTime":2860.794,"endTime":2861.065,"body":"pay taxes that, that then it's not gonna be an appropriate use of of public"},{"startTime":2861.065,"endTime":2872.725,"body":"funds."},{"startTime":2872.985,"endTime":2876.765,"body":"So I think it's, it's interesting perhaps a queen digression."},{"startTime":2876.785,"endTime":2881.981,"body":"So, you know, 15 years ago, uh, in the US people used to sort of"},{"startTime":2881.981,"endTime":2882.328,"body":"laugh about nice and you know, there was quite a lot of negative publicity about"},{"startTime":2882.328,"endTime":2887.525,"body":"that."},{"startTime":2887.585,"endTime":2891.56,"body":"But interestingly enough, even in the US in the last five or 10 years ago,"},{"startTime":2891.56,"endTime":2895.005,"body":"this is very much, uh, you know, an agenda item, shall we say."},{"startTime":2895.145,"endTime":2897.445,"body":"And, and yeah, of course the cost needs to be justified."},{"startTime":2897.475,"endTime":2898.365,"body":"It's as simple as that."},{"startTime":2899.065,"endTime":2904.725,"body":"Um, side effects, I mean A-A-A-A-A, a brief note on that, I mean the cost"},{"startTime":2904.725,"endTime":2905.102,"body":"of managing side effects, it's, it's rare for people to need to be hospitalized for"},{"startTime":2905.102,"endTime":2913.405,"body":"long periods of time to manage side effects."},{"startTime":2913.465,"endTime":2915.205,"body":"It does happen, but it's quite rare."},{"startTime":2916.025,"endTime":2919.925,"body":"But, um, I think the problem with side effects, and I sort of hinted at"},{"startTime":2919.925,"endTime":2920.185,"body":"as I went along is there hasn't really been that much effort honestly into really"},{"startTime":2920.185,"endTime":2920.445,"body":"understanding the biology of side effects, the same way that we really understand the biology"},{"startTime":2920.445,"endTime":2928.245,"body":"of cancer."},{"startTime":2928.305,"endTime":2930.085,"body":"And that's honestly a bit of a gap."},{"startTime":2930.665,"endTime":2933.651,"body":"Um, and you know, I think all of us who are in clinic would like"},{"startTime":2933.651,"endTime":2935.245,"body":"to see a better understanding of side effects."},{"startTime":2935.305,"endTime":2939.255,"body":"So let's say we didn't just give steroids to everybody, we could say, well actually"},{"startTime":2939.255,"endTime":2939.518,"body":"the colitis is being driven by such and such in this situation, we're gonna use"},{"startTime":2939.518,"endTime":2946.365,"body":"this particular drug to manage it for a short period of time."},{"startTime":2946.705,"endTime":2947.805,"body":"So there's a lot to do there."},{"startTime":2949.385,"endTime":2950.085,"body":"Thanks James."},{"startTime":2950.085,"endTime":2951.565,"body":"Moving on to another one here."},{"startTime":2951.705,"endTime":2956.617,"body":"So why do you think that chemotherapy has stayed as the predominant form of cancer"},{"startTime":2956.617,"endTime":2959.565,"body":"treatment, although it's so unspecific to the cancerous cells?"},{"startTime":2961.275,"endTime":2966.306,"body":"Well, I would go back to some extent to the history books here with, um,"},{"startTime":2966.306,"endTime":2969.325,"body":"traditional chemotherapy, cytotoxic chemotherapy, whatever you wanna call it."},{"startTime":2969.325,"endTime":2973.845,"body":"It was sort of developed late forties, early fifties, basically often out of their poisons."},{"startTime":2973.845,"endTime":2979.245,"body":"Basically a lot of these drugs that were refined for medical use, leukemia and lymphoma,"},{"startTime":2979.245,"endTime":2981.045,"body":"incredibly sensitive to these drugs."},{"startTime":2981.065,"endTime":2983.525,"body":"So I really wouldn't belittle that in any way whatsoever."},{"startTime":2984.345,"endTime":2987.754,"body":"Uh, and those were at the time, I mean, I wasn't born then, but those"},{"startTime":2987.754,"endTime":2987.981,"body":"are the tools that were available and some for some types of cancer, it's a"},{"startTime":2987.981,"endTime":2991.845,"body":"really excellent treatment."},{"startTime":2992.415,"endTime":2992.765,"body":"Today."},{"startTime":2993.085,"endTime":2997.005,"body":"Chemotherapy can be a good treatment for breast cancer, ovarian cancer, bowel cancer."},{"startTime":2997.005,"endTime":2998.085,"body":"There are lots of examples."},{"startTime":2998.105,"endTime":3004.324,"body":"And so my take on that is that chemotherapy, cytotoxic chemotherapy probably hit its high"},{"startTime":3004.324,"endTime":3008.885,"body":"watermark generally speaking about 20 years ago or something like that."},{"startTime":3008.945,"endTime":3012.531,"body":"And then the next thing that sort of came along was targeted therapy, which hasn't"},{"startTime":3012.531,"endTime":3014.205,"body":"really been a, a subject for tonight."},{"startTime":3014.205,"endTime":3017.625,"body":"And that made a big difference for certain types of cancer, often, which were difficult"},{"startTime":3017.625,"endTime":3018.765,"body":"to treat cancers as well."},{"startTime":3019.625,"endTime":3024.05,"body":"And then with checkpoint inhibitors, that for me would be the sort of the third"},{"startTime":3024.05,"endTime":3025.525,"body":"big group of anti-cancer drugs."},{"startTime":3025.525,"endTime":3028.712,"body":"And again, we've seen in the last 10 or 15 years what checkpoints inhibitors can"},{"startTime":3028.712,"endTime":3028.925,"body":"do."},{"startTime":3028.985,"endTime":3035.235,"body":"So I actually see this as, uh, a problem of picking the right treatment for"},{"startTime":3035.235,"endTime":3036.485,"body":"the right situation."},{"startTime":3036.485,"endTime":3040.925,"body":"And I absolutely would not sort of do down on cytotoxic chemotherapy."},{"startTime":3040.955,"endTime":3043.632,"body":"It's just that some types of cancer, we weren't treating it in the right way,"},{"startTime":3043.632,"endTime":3044.525,"body":"it's as simple as that."},{"startTime":3044.665,"endTime":3048.621,"body":"But at the time we didn't have the understanding and the technology, and now we"},{"startTime":3048.621,"endTime":3048.885,"body":"do,"},{"startTime":3049.665,"endTime":3054.724,"body":"Uh, sometimes when I was treating patient, I'm a oculoplastic surgeon from the states, I"},{"startTime":3054.724,"endTime":3055.061,"body":"was treating patients with a uveal melanoma and unfortunately sometimes I noticed that there can"},{"startTime":3055.061,"endTime":3055.398,"body":"be a long period of time between the, when they had primary tumor resection like"},{"startTime":3055.398,"endTime":3069.565,"body":"a nucleation and the, the, the presentation of metastatic disease sometimes over a decade."},{"startTime":3069.795,"endTime":3071.525,"body":"Yeah, long period of time."},{"startTime":3071.925,"endTime":3075.135,"body":"I remember having a patient who has a long period of time called up my"},{"startTime":3075.135,"endTime":3076.205,"body":"dad, who's a dermatologist, Dan."},{"startTime":3076.245,"endTime":3079.559,"body":"I had a patient, came into my office 15 years ago, removed his eye and"},{"startTime":3079.559,"endTime":3080.885,"body":"AAG disease died in three months."},{"startTime":3081.825,"endTime":3082.565,"body":"He said, that's nothing."},{"startTime":3082.845,"endTime":3085.045,"body":"I had patients 25 years from continuous lymph noble."},{"startTime":3085.045,"endTime":3089.987,"body":"Have you noticed any correlation between the time period between primary tumor resection, presence of"},{"startTime":3089.987,"endTime":3091.965,"body":"metastatic disease in response to immunotherapies?"},{"startTime":3092.145,"endTime":3093.045,"body":"No, in a word."},{"startTime":3093.195,"endTime":3094.325,"body":"It's a good question though."},{"startTime":3094.545,"endTime":3099.074,"body":"But this, this idea of dormancy, if you want to call it that, there's load"},{"startTime":3099.074,"endTime":3099.376,"body":"of, um, speculation, uh, about why it happens and, and melanoma, yeah, so, so par"},{"startTime":3099.376,"endTime":3106.925,"body":"excellence, I mean we see it with skin melanomas as well."},{"startTime":3107.185,"endTime":3110.263,"body":"Um, and it happens sometimes in breast cancer as well, but you can go for"},{"startTime":3110.263,"endTime":3111.085,"body":"long periods of time."},{"startTime":3111.115,"endTime":3112.805,"body":"It's not common, but it happens."},{"startTime":3113.625,"endTime":3118.085,"body":"Um, even with doing scans and following people up really carefully, everything's fine."},{"startTime":3118.085,"endTime":3121.565,"body":"And then you do the next scan and you can see spread of the cancer."},{"startTime":3121.705,"endTime":3125.43,"body":"So then the obvious question there is what triggers that if there is a trigger,"},{"startTime":3125.43,"endTime":3125.679,"body":"and I certainly dunno, and I'm not sure we're close to understanding that at the"},{"startTime":3125.679,"endTime":3129.405,"body":"moment."},{"startTime":3129.505,"endTime":3133.115,"body":"To me that speaks to the immune system honestly, that for some reason it was"},{"startTime":3133.115,"endTime":3136.725,"body":"being controlled for a long period of time and why is it stopped being controlled?"},{"startTime":3136.725,"endTime":3139.805,"body":"I don't think that's unraveled yet, but it's an important point."},{"startTime":3139.875,"endTime":3140.645,"body":"With that question."},{"startTime":3141.285,"endTime":3143.445,"body":"I think I've got a really good follow on question from that here."},{"startTime":3143.585,"endTime":3148.626,"body":"So with the survival curves shown in, for instance melanoma, is there a discernible difference"},{"startTime":3148.626,"endTime":3148.963,"body":"between those patients who survive post three to five years versus those that pass away"},{"startTime":3148.963,"endTime":3154.005,"body":"earlier?"},{"startTime":3154.425,"endTime":3158.875,"body":"And if not, where would you like to look within the system to try and"},{"startTime":3158.875,"endTime":3159.765,"body":"find those answers?"},{"startTime":3161.265,"endTime":3162.165,"body":"Is there a difference?"},{"startTime":3162.545,"endTime":3167.857,"body":"No, um, there's no easy a priori way honestly, to pick out the people who"},{"startTime":3167.857,"endTime":3168.211,"body":"are really gonna get the most benefit from treatment, um, from those that don't, honestly,"},{"startTime":3168.211,"endTime":3168.565,"body":"the kinds of, if you wanna call them prognostic factors, in other words, statistical factors"},{"startTime":3168.565,"endTime":3183.085,"body":"that are associated with getting a better chance of, of treatment in melanoma."},{"startTime":3183.085,"endTime":3186.685,"body":"They're still really, frankly, quite old fashioned things, how well people are."},{"startTime":3186.685,"endTime":3189.885,"body":"We call that performance status, uh, the burden of the cancer."},{"startTime":3190.225,"endTime":3194.325,"body":"In other words, if you do scans, are there a few or lots of abnormalities?"},{"startTime":3195.185,"endTime":3198.503,"body":"Um, and we use this blood test LDH that I mentioned at the beginning as"},{"startTime":3198.503,"endTime":3198.725,"body":"well."},{"startTime":3198.745,"endTime":3203.085,"body":"But, but no, we don't have any sophisticated markers at the moment."},{"startTime":3203.275,"endTime":3205.125,"body":"It's a massively important question."},{"startTime":3205.885,"endTime":3208.485,"body":"I haven't really talked about PD L one expression."},{"startTime":3208.485,"endTime":3210.685,"body":"I'll just maybe say something a little bit about that now."},{"startTime":3210.825,"endTime":3211.845,"body":"Uh, 'cause it's important."},{"startTime":3211.985,"endTime":3217.543,"body":"So for some cancers, benefit from checkpoint inhibitors shown to be linked to PD L"},{"startTime":3217.543,"endTime":3218.285,"body":"one expression."},{"startTime":3218.285,"endTime":3222.949,"body":"I think that lung cancer is the best example, PD L one expression, meaning the"},{"startTime":3222.949,"endTime":3223.26,"body":"amount of the PD L one protein that's on the surface of tumor or nearby"},{"startTime":3223.26,"endTime":3227.925,"body":"cells."},{"startTime":3229.065,"endTime":3234.565,"body":"But, um, it's a relatively crude marker and it varies over space and time."},{"startTime":3234.865,"endTime":3237.725,"body":"It can be induced or suppressed by various other things."},{"startTime":3237.745,"endTime":3241.699,"body":"And so, you know, I think no one would like it more than me if"},{"startTime":3241.699,"endTime":3241.963,"body":"we had really good markers for using these treatments and a massive amount of effort's"},{"startTime":3241.963,"endTime":3246.445,"body":"gone into it."},{"startTime":3246.505,"endTime":3249.926,"body":"But have we got anything that we can use in clinic to say, well, actually"},{"startTime":3249.926,"endTime":3250.155,"body":"this treatment's really likely to work or not work now, I'm afraid not, not at"},{"startTime":3250.155,"endTime":3253.805,"body":"the moment."},{"startTime":3254.225,"endTime":3258.668,"body":"Can you just give us a sense of when some of these drugs might be"},{"startTime":3258.668,"endTime":3258.965,"body":"generally available in the UK subject to nice approval or, or, or, or similar processes,"},{"startTime":3258.965,"endTime":3259.261,"body":"um, rather than having to be accessed as I understand it, through trials, which is"},{"startTime":3259.261,"endTime":3268.445,"body":"the current position."},{"startTime":3268.995,"endTime":3274.012,"body":"Yeah, so the, the, the, the process there if you like, is that clinical trials"},{"startTime":3274.012,"endTime":3274.347,"body":"need to recruit, which takes variable amounts of time, and then they need to be"},{"startTime":3274.347,"endTime":3279.365,"body":"analyzed."},{"startTime":3279.625,"endTime":3283.967,"body":"And usually the analysis of a clinical trial will take minimum a year or two"},{"startTime":3283.967,"endTime":3285.125,"body":"after it's ceased recruitment."},{"startTime":3285.785,"endTime":3290.637,"body":"Uh, once it's been analyzed, if the data look good positive, then it will go"},{"startTime":3290.637,"endTime":3291.285,"body":"to regulators."},{"startTime":3291.745,"endTime":3296.387,"body":"So this is in the us the FDA in Europe, the EMA, and now for"},{"startTime":3296.387,"endTime":3298.245,"body":"us, the MHRA, uh, post Brexit."},{"startTime":3298.305,"endTime":3303.719,"body":"And then the timeline to regulatory approval will typically be six to 12 months after"},{"startTime":3303.719,"endTime":3305.885,"body":"the first readout of the trial."},{"startTime":3306.705,"endTime":3312.615,"body":"Uh, the regulators have an incredibly important responsibility, which is to determine that the efficacy,"},{"startTime":3312.615,"endTime":3313.009,"body":"in other words, how well the drug works, uh, is justified in terms of the"},{"startTime":3313.009,"endTime":3321.285,"body":"side effects and the risks of treatment."},{"startTime":3321.285,"endTime":3324.051,"body":"Because once they sign it off, it's, it's kind of out there, if you see"},{"startTime":3324.051,"endTime":3324.605,"body":"what I mean."},{"startTime":3324.605,"endTime":3328.045,"body":"So it's a really really important decision and not to be taken lightly."},{"startTime":3328.045,"endTime":3330.565,"body":"And they put a lot of careful effort into this."},{"startTime":3331.785,"endTime":3335.525,"body":"And then you've got reimbursement, which is the final step."},{"startTime":3335.525,"endTime":3337.445,"body":"And we talked a little bit about that already."},{"startTime":3337.505,"endTime":3343.205,"body":"And so the reimbursement might then typically take, let's say another six to 12 months."},{"startTime":3343.305,"endTime":3346.165,"body":"So all of that is, um, and I'm incredibly impatient."},{"startTime":3346.275,"endTime":3348.325,"body":"It's probably my worst characteristic, actually."},{"startTime":3348.945,"endTime":3352.125,"body":"Um, uh, it can be frustrating at times."},{"startTime":3353.105,"endTime":3357.605,"body":"Um, but there's, there's no, I mean, the regulators really working hard to, and you"},{"startTime":3357.605,"endTime":3358.805,"body":"know, it's, it's difficult."},{"startTime":3358.805,"endTime":3363.265,"body":"The FDA's actually quite quick at making decisions, but again, even with reimbursement, it might"},{"startTime":3363.265,"endTime":3365.645,"body":"sound like it's a simple yes no thing."},{"startTime":3365.645,"endTime":3366.725,"body":"It's not, it's complicated."},{"startTime":3366.725,"endTime":3368.445,"body":"There's, you know, health economics to consider."},{"startTime":3368.445,"endTime":3372.005,"body":"And so, so that's the realistic timeline in general terms."},{"startTime":3372.395,"endTime":3376.005,"body":"Sometimes things are quicker, unfortunately, sometimes things are slower."},{"startTime":3376.515,"endTime":3380.122,"body":"I've been doing this a while and actually things are quicker now, uh, than they"},{"startTime":3380.122,"endTime":3381.325,"body":"have been in the past."},{"startTime":3381.425,"endTime":3383.365,"body":"But I still really understand the frustration."},{"startTime":3383.365,"endTime":3385.645,"body":"And again, we have this in clinic most days."},{"startTime":3385.945,"endTime":3389.005,"body":"Um, but I would come back to the importance of doing clinical trials."},{"startTime":3389.185,"endTime":3393.875,"body":"Uh, you know, I, the, the progress that we've seen is because of doing clinical"},{"startTime":3393.875,"endTime":3398.565,"body":"trials, and if we don't keep going on doing clinical trials, then progress will stall."},{"startTime":3398.945,"endTime":3400.045,"body":"It really is as simple as that."},{"startTime":3401.665,"endTime":3404.569,"body":"So another question right here at the front with Martin, and then I'll come back"},{"startTime":3404.569,"endTime":3405.925,"body":"to the iPad if we have time."},{"startTime":3407.865,"endTime":3409.445,"body":"So, uh, this is a question for both of you."},{"startTime":3409.545,"endTime":3415.302,"body":"Oh, so, so we've got squillions of drugs being designed to attack the various, uh,"},{"startTime":3415.302,"endTime":3417.605,"body":"molecules and receptors you've been designed."},{"startTime":3418.135,"endTime":3421.125,"body":"We've had a very good question about cost."},{"startTime":3422.345,"endTime":3427.002,"body":"Um, I think it would be interesting for people to hear how much it costs"},{"startTime":3427.002,"endTime":3427.312,"body":"to make one of these drugs from thought up of drug to delivery and if"},{"startTime":3427.312,"endTime":3427.623,"body":"you like, not just getting it to market, but the risk of getting it to"},{"startTime":3427.623,"endTime":3427.933,"body":"market because some of this stuff must be a huge gamble for a company like"},{"startTime":3427.933,"endTime":3441.285,"body":"yours."},{"startTime":3442.605,"endTime":3444.045,"body":"I think that's one for you to kick off with."},{"startTime":3444.285,"endTime":3448.733,"body":"\u003claugh\u003e, uh, I'll certainly start the, the quick answer is it's a bit of a"},{"startTime":3448.733,"endTime":3452.885,"body":"ballpark to be honest, because you start off with so, so many potential options."},{"startTime":3453.385,"endTime":3458.485,"body":"And then there's, there's considerable preclinical work that has to be done to identify if"},{"startTime":3458.485,"endTime":3461.885,"body":"any of them could have utility within the clinical sphere."},{"startTime":3462.105,"endTime":3465.965,"body":"And then there's the varying different phases of clinical trials, which James showed you earlier."},{"startTime":3466.955,"endTime":3470.125,"body":"They take time to set up their global studies."},{"startTime":3470.675,"endTime":3472.205,"body":"They take a huge amount of money."},{"startTime":3472.285,"endTime":3476.531,"body":"I, I, I'm hesitant to put any kind of specific figures on this, but it's"},{"startTime":3476.531,"endTime":3476.814,"body":"not just the time and years, it's the time in working with investigators such as"},{"startTime":3476.814,"endTime":3483.325,"body":"James designing the studies and very frequently they fail."},{"startTime":3484.185,"endTime":3489.565,"body":"So what you see as a positive, with positive results is actually the abnormal result."},{"startTime":3490.085,"endTime":3495.385,"body":"Normally things fail in research and development, so that's why things take while that's why"},{"startTime":3495.385,"endTime":3495.738,"body":"they come through and, and it's, it's trying to understand the, the cost effectiveness to"},{"startTime":3495.738,"endTime":3504.925,"body":"your point earlier of, of the medicine within the, the clinical setting."},{"startTime":3505.305,"endTime":3510.135,"body":"But it's a huge amount of money globally to be able to invest in the"},{"startTime":3510.135,"endTime":3514.965,"body":"development of medicines to try and get one to be successful in and move through."},{"startTime":3515.575,"endTime":3516.125,"body":"James, there"},{"startTime":3516.125,"endTime":3516.445,"body":"Any does?"},{"startTime":3516.475,"endTime":3521.445,"body":"Yeah, I mean it's, it's hundreds of millions of pounds, dollars, euros upward \u003claugh\u003e."},{"startTime":3521.475,"endTime":3521.765,"body":"Yeah."},{"startTime":3522.905,"endTime":3528.673,"body":"You know, and um, I could do a talk about failed melanoma trials in the"},{"startTime":3528.673,"endTime":3531.365,"body":"last five years, uh, but I haven't."},{"startTime":3531.945,"endTime":3536.272,"body":"Um, and if, if you, if you start from the, the very start of this"},{"startTime":3536.272,"endTime":3536.561,"body":"process and then you go to the end of it for say 10 strong candidate"},{"startTime":3536.561,"endTime":3543.485,"body":"drugs or a hundred, most of them will not succeed."},{"startTime":3543.945,"endTime":3547.485,"body":"So it's a high risk business, um, from the industry perspective as well."},{"startTime":3547.985,"endTime":3551.322,"body":"And you know, I'm, I'm sure the system if you like, isn't perfect, but at"},{"startTime":3551.322,"endTime":3553.325,"body":"the end of the day it is delivering results"},{"startTime":3554.545,"endTime":3558.685,"body":"And I think this probably feeds on where we have successes and failures."},{"startTime":3559.025,"endTime":3563.812,"body":"You alluded to earlier, do all the checkpoint inhibitors do the same function and therefore"},{"startTime":3563.812,"endTime":3566.685,"body":"why are we seeing some successes and studies and"},{"startTime":3566.685,"endTime":3569.841,"body":"Not Well that's, yeah, so that's a kind of an interesting question actually, and I,"},{"startTime":3569.841,"endTime":3571.525,"body":"I didn't really talk too much about this."},{"startTime":3571.745,"endTime":3576.491,"body":"So in terms of CTLA four, ipilimumab being a CTLA four, anti CTLA four, which"},{"startTime":3576.491,"endTime":3576.807,"body":"is the first one I showed you, if you remember, um, there's really only one"},{"startTime":3576.807,"endTime":3577.123,"body":"other anti CTLA four, which is tremelimumab, which has sort of made it into regulatory"},{"startTime":3577.123,"endTime":3587.565,"body":"approval and late stage development."},{"startTime":3588.345,"endTime":3593.529,"body":"Um, with the PD ones, there's probably dozens now they're not all necessarily got regulatory"},{"startTime":3593.529,"endTime":3593.875,"body":"approval and without wishing to speak out of turn, I think most kind of large"},{"startTime":3593.875,"endTime":3594.221,"body":"and medium sized pharma company have got a PD one or a PD L one"},{"startTime":3594.221,"endTime":3604.245,"body":"drug."},{"startTime":3604.675,"endTime":3609.11,"body":"Several reasons for that I think because actually there's lots of different types of cancer"},{"startTime":3609.11,"endTime":3610.885,"body":"where these drugs can show benefit."},{"startTime":3611.545,"endTime":3615.828,"body":"And so from an industry perspective they've really looked very hard at all the possible"},{"startTime":3615.828,"endTime":3616.685,"body":"indications for that."},{"startTime":3617.225,"endTime":3620.485,"body":"Are there differences between the anti PD ones and anti PDL ones?"},{"startTime":3620.485,"endTime":3622.485,"body":"That's kind of part of the thrust of this question as well."},{"startTime":3623.025,"endTime":3625.525,"body":"Um, not major differences in my opinions."},{"startTime":3625.525,"endTime":3626.565,"body":"People talk a lot about this."},{"startTime":3626.585,"endTime":3627.965,"body":"Are the side effects different?"},{"startTime":3628.505,"endTime":3632.236,"body":"You know, does a PD one work a bit better than a than anti PDL"},{"startTime":3632.236,"endTime":3632.485,"body":"one?"},{"startTime":3632.485,"endTime":3635.725,"body":"There might be some minor differences, but for me they aren't major differences."},{"startTime":3635.725,"endTime":3637.285,"body":"They're relatively similar to each other."},{"startTime":3637.625,"endTime":3642.77,"body":"The bottom line often is they're made by different, um, pharmaceutical companies and they've been"},{"startTime":3642.77,"endTime":3644.485,"body":"pursued in different cancer indications."},{"startTime":3646.705,"endTime":3647.445,"body":"One last question."},{"startTime":3647.715,"endTime":3652.188,"body":"There's quite a few questions in here, James, about specific cancer types and we don't"},{"startTime":3652.188,"endTime":3652.486,"body":"have time to go into them all just now, but I think maybe the way"},{"startTime":3652.486,"endTime":3652.784,"body":"to wrap them all up in one is we obviously see benefit through the clinical"},{"startTime":3652.784,"endTime":3653.082,"body":"studies and clinical practice in melanoma and lung specifically and some other cancer types, but"},{"startTime":3653.082,"endTime":3669.485,"body":"there are certain cancers where we have not seen the introduction of immunotherapies."},{"startTime":3670.215,"endTime":3675.465,"body":"Could you comment on why you think that is potentially PD one expression, et cetera,"},{"startTime":3675.465,"endTime":3678.965,"body":"and whether we'll see developments that could potentially become agnostic?"},{"startTime":3680.595,"endTime":3684.03,"body":"Yeah, so the first part of the question, so why do these drugs work in"},{"startTime":3684.03,"endTime":3685.405,"body":"the first place in certain cancers?"},{"startTime":3685.405,"endTime":3689.697,"body":"Well, for some cancers to some extent, I think we might understand that melanoma would"},{"startTime":3689.697,"endTime":3689.983,"body":"be an example of that because it's in technical jargon, it's a cancer in general"},{"startTime":3689.983,"endTime":3696.565,"body":"where there's a high mutational burden of the tumor."},{"startTime":3696.705,"endTime":3698.165,"body":"So it presents a better target."},{"startTime":3698.475,"endTime":3702.234,"body":"Same is true in lung cancer as well, probably in bladder cancer as well as"},{"startTime":3702.234,"endTime":3702.485,"body":"that."},{"startTime":3702.505,"endTime":3706.776,"body":"But in kidney cancer, which I also treat, honestly, we don't really know why these"},{"startTime":3706.776,"endTime":3708.485,"body":"drugs work well in kidney cancer."},{"startTime":3708.545,"endTime":3710.525,"body":"It doesn't have a high mutational burden."},{"startTime":3710.585,"endTime":3715.085,"body":"So we're still in the infancy of understanding that question in the first place."},{"startTime":3715.785,"endTime":3720.125,"body":"And then this idea about, um, tumor agnosticism, if we're gonna call it that."},{"startTime":3720.145,"endTime":3724.195,"body":"So that means actually if you know what the target is and you've got a"},{"startTime":3724.195,"endTime":3728.245,"body":"drug, maybe it doesn't matter what tumor the target's on, you can use it anyway."},{"startTime":3728.245,"endTime":3730.325,"body":"There are beginning to be some examples of that."},{"startTime":3730.325,"endTime":3733.987,"body":"And there's one or two approvals where if you've got a particular abnormality, it doesn't"},{"startTime":3733.987,"endTime":3737.405,"body":"matter what the type of cancer is, in principle you could use the drug."},{"startTime":3737.755,"endTime":3738.805,"body":"Will we see more of that?"},{"startTime":3739.645,"endTime":3740.325,"body":"I think so, yes."},{"startTime":3740.385,"endTime":3741.565,"body":"Is the short answer to that."},{"startTime":3742.465,"endTime":3747.782,"body":"My kind of caveat to that would be that I think context is almost always"},{"startTime":3747.782,"endTime":3748.137,"body":"important and it, you can probably illustrate this better with targeted therapy than with immunotherapy,"},{"startTime":3748.137,"endTime":3756.645,"body":"but particular abnormalities within tumors, they don't always cut across."},{"startTime":3756.705,"endTime":3760.893,"body":"And it might be actually what's going in, what, what's around that abnormality in the"},{"startTime":3760.893,"endTime":3764.245,"body":"tumor, the context that's really important for the benefit of the drug."},{"startTime":3764.305,"endTime":3767.59,"body":"So I think there's still a lot of work to do to really kind of"},{"startTime":3767.59,"endTime":3768.685,"body":"get that nailed down actually."},{"startTime":3769.055,"endTime":3769.485,"body":"Thank you."},{"startTime":3770.005,"endTime":3772.805,"body":"I apologize if we've not had time to come to your questions either in the"},{"startTime":3772.805,"endTime":3773.365,"body":"room or online."},{"startTime":3773.745,"endTime":3778.07,"body":"Um, professor Larkin will be part of the panel discussion on the 12th of March,"},{"startTime":3778.07,"endTime":3778.359,"body":"so hopefully there will be the opportunity to answer then and obviously we'll follow up"},{"startTime":3778.359,"endTime":3782.685,"body":"thereafter."},{"startTime":3783.145,"endTime":3784.645,"body":"Um, thank you so much James."},{"startTime":3784.645,"endTime":3786.045,"body":"I'll hand back over to, to Martin."}]}