WEBVTT - Measles: The Cancer Killer?... from Incubation 0:00:15.356 --> 0:00:23.876 Pushkin. Hey, it's Jacob. There's another podcast that I host 0:00:23.956 --> 0:00:28.276 called Incubation. It's a show about viruses, and recently we 0:00:28.356 --> 0:00:31.796 did an episode that I thought would be particularly interesting 0:00:31.916 --> 0:00:35.356 to you, to people who listen to What's Your Problem, 0:00:36.076 --> 0:00:39.476 it's about measles. Measles turns out to be way more 0:00:39.516 --> 0:00:44.076 interesting and way more insidious than we thought, but also 0:00:44.436 --> 0:00:49.236 measles may be a new way to fight cancer. I 0:00:49.276 --> 0:00:51.356 hope you liked the episode. I really found it interesting. 0:00:51.916 --> 0:00:54.796 One last thing, we won't be publishing episodes of What's 0:00:54.836 --> 0:00:57.476 Your Problem over the next few weeks. We'll start up 0:00:57.516 --> 0:01:02.116 again in January. I thought I knew what I needed 0:01:02.156 --> 0:01:05.956 to know about what happens when you get measles. You 0:01:05.996 --> 0:01:09.836 get a fever and a rash. Maybe you get very sick. 0:01:10.396 --> 0:01:14.836 If you're really unlucky, you die. But chances are you 0:01:14.876 --> 0:01:17.316 get measles, you get better, and that's the end of 0:01:17.356 --> 0:01:21.556 it as it happens. I was wrong. I did not 0:01:21.756 --> 0:01:24.236 know what I needed to know about measles. Because a 0:01:24.276 --> 0:01:27.956 recent discovery has blown open our whole idea of what 0:01:27.956 --> 0:01:30.236 the measles virus does to our bodies. 0:01:30.596 --> 0:01:34.036 The world thought that measles was done being discovered and 0:01:34.076 --> 0:01:38.716 then boom, all of a sudden, there's this new idea 0:01:39.556 --> 0:01:43.676 of something that really had massive, massive consequences on humans 0:01:43.716 --> 0:01:45.036 that we didn't even realize. 0:01:45.876 --> 0:01:49.716 I'm Jacob Goldstein and this is Incubation, a show about viruses. 0:01:50.196 --> 0:01:53.596 Today on the show how measles attacks your immune system 0:01:54.196 --> 0:01:58.076 and how researchers are trying to use measles to cure cancer. 0:02:07.756 --> 0:02:09.956 My guest for the first half of today show is 0:02:10.036 --> 0:02:15.756 Michael Minna. He's an epidemiologist slash immunologist, slash physician, and 0:02:15.796 --> 0:02:18.756 he's kind of a measles superfan. He did a lot 0:02:18.796 --> 0:02:20.756 of work we'll talk about today while he was a 0:02:20.756 --> 0:02:24.756 professor at Harvard. He's now chief scientific officer at a 0:02:24.756 --> 0:02:28.676 company called emed. We started by talking about a surprising 0:02:28.716 --> 0:02:31.676 thing that happened after the measles vaccine was introduced in 0:02:31.716 --> 0:02:35.116 the nineteen sixties. As more and more kids were vaccinated 0:02:35.116 --> 0:02:38.476 against measles, the rate at which kids were dying of 0:02:38.516 --> 0:02:43.076 infectious disease went down way more than anybody expected. It 0:02:43.116 --> 0:02:45.836 went down so much that it couldn't be explained by 0:02:45.916 --> 0:02:47.516 measles alone. 0:02:47.636 --> 0:02:53.036 After the vaccine was introduced, we saw market reductions in 0:02:53.156 --> 0:02:58.956 childhood mortality overall following the vaccine, which drove a lot 0:02:58.956 --> 0:03:03.316 of questions, why did that happen? Is it the vaccine 0:03:03.356 --> 0:03:07.876 actually acting directly to somehow prevent other infections, or is 0:03:07.916 --> 0:03:09.636 there something else at play? 0:03:09.676 --> 0:03:12.716 Even if zero people died of measles, even if zero 0:03:12.876 --> 0:03:16.356 children died of measles, you wouldn't get that large of 0:03:16.356 --> 0:03:20.116 a reduction immortality. Right, some weird thing is going. 0:03:19.956 --> 0:03:21.636 On, that's exactly right. 0:03:21.756 --> 0:03:24.076 Weird good thing, weird usually. 0:03:23.876 --> 0:03:26.476 That's right, A very weird good thing was going on. 0:03:26.876 --> 0:03:30.196 So now we have this interesting kind of happy mystery 0:03:30.276 --> 0:03:33.596 in a way. Why are so few children dying of 0:03:33.596 --> 0:03:37.316 infectious disease after the rollout of the measles vaccine? What 0:03:37.396 --> 0:03:39.916 do you do to try and figure out what's going on? 0:03:40.436 --> 0:03:45.956 We said, well, maybe it's because measles had detrimental effects 0:03:45.996 --> 0:03:50.236 on somebody's immune memory that might be putting them at 0:03:50.316 --> 0:03:53.356 risk for other stuff, other infections. And so what we 0:03:53.396 --> 0:03:55.916 did was we said, well, if that's the case, then 0:03:55.956 --> 0:03:58.836 if we look at a lot of data, could we 0:03:58.916 --> 0:04:02.676 map the numbers of cases of measles to the numbers 0:04:02.716 --> 0:04:06.476 of deaths from other things besides measles from year to year? 0:04:07.596 --> 0:04:12.196 And what we found was prof boundly predictive. Is if 0:04:12.236 --> 0:04:14.876 you asked what were the number of measles cases in 0:04:14.996 --> 0:04:18.636 nineteen forty nine and what were the numbers of deaths 0:04:18.876 --> 0:04:23.836 from non measles infections from nineteen forty nine, nineteen fifty 0:04:24.236 --> 0:04:27.676 and nineteen fifty one. When you accrued all three years, 0:04:28.116 --> 0:04:32.516 it became extraordinarily predictive of how many children would die 0:04:33.396 --> 0:04:37.436 over the next three years of non measles infectious related deaths. 0:04:38.036 --> 0:04:40.196 So, just to be clear, what you found is that 0:04:40.516 --> 0:04:43.596 when there's a measle's outbreak in one year, the rate 0:04:43.636 --> 0:04:46.836 at which kids died from other infectious diseases went up 0:04:46.916 --> 0:04:47.996 in the next few years. 0:04:48.156 --> 0:04:49.156 That's exactly right. 0:04:49.276 --> 0:04:52.236 So you used in your answer just there this phrase 0:04:52.356 --> 0:04:55.916 that I just want to spend a moment on immune memory. 0:04:56.556 --> 0:04:57.956 What is immune memory? 0:04:58.556 --> 0:05:04.076 Immune memory is very similar to our regular memory. All 0:05:04.156 --> 0:05:08.316 of our body's memories, whether it be muscle memory, brain memory, 0:05:08.956 --> 0:05:12.276 or immune memory, is stored in cells. The way that 0:05:12.396 --> 0:05:16.996 immune memory works is when you bump up against a 0:05:17.036 --> 0:05:20.996 pathogen as let's say, a virus like measles or coronavirus, 0:05:21.036 --> 0:05:25.276 whatever it might be, your body actually sees it, it 0:05:25.876 --> 0:05:29.836 recognizes that virus. It learns from it, and it actually 0:05:29.916 --> 0:05:33.996 remembers it in B cells and T cells and plasma cells. 0:05:34.556 --> 0:05:38.116 And that's how our immune system works in terms of 0:05:38.156 --> 0:05:42.716 developing immune memory and utilizing it to combat infections that 0:05:42.756 --> 0:05:43.676 we see in the future. 0:05:44.356 --> 0:05:46.556 Is what you're finding that in some way measles is 0:05:46.636 --> 0:05:51.836 attacking the kid's immune memory. Is that the hypothesis that follows. 0:05:52.276 --> 0:05:55.996 That's exactly the hypothesis that follows. For example, if a 0:05:56.996 --> 0:06:01.876 six year old got measles, then maybe that measles infection 0:06:02.596 --> 0:06:06.116 could destroy some of the immune memory the defenses that 0:06:06.116 --> 0:06:10.156 that child gained over the last six years, and therefore 0:06:10.436 --> 0:06:13.636 when they are seven or eight years old, are actually 0:06:13.716 --> 0:06:18.036 more vulnerable than they otherwise would have been to those 0:06:18.076 --> 0:06:20.276 infections that they gained the immunity to when they were 0:06:20.276 --> 0:06:20.836 two or three. 0:06:21.916 --> 0:06:25.596 So, okay, you have this hypothesis, how do you test it? 0:06:25.716 --> 0:06:27.876 How do you investigate what's really going on? 0:06:28.396 --> 0:06:33.916 There's a long, rich history of how to predict where 0:06:33.996 --> 0:06:36.596 measles is going to go next. It's actually famous for 0:06:36.676 --> 0:06:40.836 how predictive it is because it is so infectious that 0:06:40.916 --> 0:06:43.516 you just need to know how many people are vaccinated 0:06:43.516 --> 0:06:45.956 in a community, and if there's any measles anywhere in 0:06:45.996 --> 0:06:49.876 the region, you can expect that pretty soon at below 0:06:49.916 --> 0:06:51.276 certain levels, there's going to be an. 0:06:51.196 --> 0:06:54.076 Outbreak below certain levels of vaccination. 0:06:53.996 --> 0:06:56.316 That's right, and that's why measles is considered the canary 0:06:56.356 --> 0:07:00.196 and the coal mine for vaccine rates. It's literally the 0:07:00.196 --> 0:07:02.636 thing that pops up on the radar when you say 0:07:03.036 --> 0:07:06.636 who's what communities are having trouble vaccinating their population, and boom, 0:07:06.636 --> 0:07:08.876 if you see measles, you know they're having trouble vaccinating 0:07:08.916 --> 0:07:12.796 their populations. And so what we can do is we 0:07:12.836 --> 0:07:18.076 can leverage everything we know about measles epidemiology to help 0:07:18.156 --> 0:07:23.356 identify where might outbreaks happen. And that's exactly what Rick 0:07:23.436 --> 0:07:27.156 de Swart and his team did. They are in the Netherlands. 0:07:27.236 --> 0:07:30.636 He's at Erasmus, which is in Rotterdam, and so he 0:07:30.716 --> 0:07:33.316 was able to say, hey, right in our backyard, there's 0:07:33.356 --> 0:07:37.756 a community that, for religious reasons, they chose not to 0:07:37.836 --> 0:07:41.196 vaccinate their children against measles. So they said, well, if 0:07:41.196 --> 0:07:42.716 you're not going to get a vaccine, would you be 0:07:42.836 --> 0:07:46.276 interested or willing to have us just draw a little 0:07:46.316 --> 0:07:50.356 sample of blood from your kids today and should measles 0:07:50.356 --> 0:07:52.436 catch up to them in the future. Could we come 0:07:52.476 --> 0:07:54.396 back and draw another sample of blood. 0:07:55.316 --> 0:07:58.796 You have the before measles blood samples, and you have 0:07:58.956 --> 0:08:02.716 from the same children the after measles blood samples. We 0:08:02.796 --> 0:08:05.716 have everything ready to go. What happens. 0:08:06.156 --> 0:08:09.396 There was a big outbreak, and almost immediately we aren't 0:08:09.436 --> 0:08:13.116 seeing that we can measure all of these antibodies in 0:08:13.156 --> 0:08:16.316 the blood samples. And then when we actually look at 0:08:16.316 --> 0:08:19.636 the blood samples from right before the kids got measles 0:08:19.636 --> 0:08:22.836 to those same kids blood samples that they collected after, 0:08:23.396 --> 0:08:27.716 we saw marked reductions. Not just in a couple antibodies, 0:08:28.196 --> 0:08:31.756 but some kids lost eighty percent of all of the 0:08:31.876 --> 0:08:36.556 diversity of their antibodies that existed in that blood sample 0:08:36.596 --> 0:08:39.396 before they got measles. And we compared it, we said, well, 0:08:40.076 --> 0:08:42.436 maybe that's normal. So we looked at kids who had 0:08:42.436 --> 0:08:45.276 gotten vaccinated for measles. We like the kids who just 0:08:45.316 --> 0:08:48.396 had no infections, And what we saw was the average 0:08:48.436 --> 0:08:52.356 person from any two time points, there'd be like five 0:08:52.436 --> 0:08:56.676 percent difference in their overall antibody repertoire. But the measles kids, 0:08:57.036 --> 0:09:00.636 the kids who got measles lost anywhere from twenty percent 0:09:00.676 --> 0:09:05.676 to eighty percent of their whole immunological memory pool. This 0:09:05.716 --> 0:09:10.716 is the whole lifetime of immune memory that they've spent 0:09:10.876 --> 0:09:14.956 years building up and building up, just poof wiped away 0:09:15.396 --> 0:09:18.836 because of this measles infection and these kids. What that 0:09:18.916 --> 0:09:21.636 means is now, across millions and millions of kids who 0:09:21.636 --> 0:09:25.716 were before the vaccines, almost every child got measles. And 0:09:25.796 --> 0:09:29.516 so at that scale, when you have so many people 0:09:29.556 --> 0:09:35.036 getting measles and this effect happening, which we call immunological amnesia, 0:09:35.156 --> 0:09:39.516 essentially they forgot their body, forgot because of the infection 0:09:40.516 --> 0:09:43.796 the immune memories that they formed before the infection. What 0:09:43.836 --> 0:09:45.956 that means is that you have all of these kids 0:09:46.036 --> 0:09:50.156 that are more susceptible to other infectious diseases. So most 0:09:50.596 --> 0:09:54.036 most kids would survive, but it turned out that of 0:09:54.076 --> 0:09:58.956 those kids who did die from other things, about half 0:09:59.036 --> 0:10:04.676 of those deaths could be attributed to the immune amnesia 0:10:04.716 --> 0:10:06.476 associated with measles. 0:10:07.316 --> 0:10:10.356 Is there something particularly insane if that happens at a 0:10:10.396 --> 0:10:13.596 population level. If you imagine a group of people in 0:10:13.596 --> 0:10:16.636 the absence of a vaccine entirely, where it's like, not 0:10:16.676 --> 0:10:20.076 only is each kid more vulnerable, but because all the 0:10:20.116 --> 0:10:23.196 other kids are more vulnerable, everybody is more vulnerable. Is 0:10:23.196 --> 0:10:24.836 there something like that that happens. 0:10:25.076 --> 0:10:27.556 I am so happy you asked that question. 0:10:28.396 --> 0:10:28.996 You're welcome. 0:10:29.916 --> 0:10:34.636 So, yes, it is. It's a much much harder thing 0:10:34.876 --> 0:10:35.556 to measure. 0:10:35.916 --> 0:10:37.756 I mean, it's sort of like the reverse of herd 0:10:37.756 --> 0:10:40.756 immunity in some weird broad spectrum way, right. 0:10:41.036 --> 0:10:43.956 So what's so interesting that you bring that up? Because 0:10:44.036 --> 0:10:47.156 before my musle's work, I was working on influenza and 0:10:47.196 --> 0:10:51.116 its impacts on other bacterial infections. And during my PhD, 0:10:51.196 --> 0:10:56.956 I coined a term called generalized herd effects, and I 0:10:57.196 --> 0:11:00.876 explicitly didn't call it herd immunity because maybe it's not 0:11:00.956 --> 0:11:03.836 going to reduce things, but maybe you could exacerbate things. 0:11:03.996 --> 0:11:07.156 Yeah, how about herd vulnerability. I want the opposite. What's 0:11:07.196 --> 0:11:08.276 the opposite of herd. 0:11:08.116 --> 0:11:11.636 Immunity, that's herd vulnerability is a great term, and so 0:11:11.716 --> 0:11:13.796 the idea there as well. If you have a pathogen 0:11:14.276 --> 0:11:18.476 that's impacting your susceptibility to a lot of other pathogens, 0:11:18.876 --> 0:11:22.956 you could, you know, create a herd vulnerability because of 0:11:22.996 --> 0:11:27.476 infections of that initial pathogen. And on the contrary, if 0:11:27.476 --> 0:11:30.476 you figure out a vaccine against that initial pathogen, like 0:11:30.476 --> 0:11:36.116 the measles vaccine, you create massive benefits in getting rid 0:11:36.156 --> 0:11:38.156 of that herd vulnerability. 0:11:38.836 --> 0:11:42.276 So what's going on on a cellular level. 0:11:42.916 --> 0:11:47.276 As far as we know, measles is unique in its class. 0:11:47.596 --> 0:11:49.916 It's actually it's an amazing story. So if you give 0:11:49.916 --> 0:11:52.596 me forty seconds to describe it. 0:11:52.516 --> 0:11:55.116 I will, oh go, you got a minute if you 0:11:55.236 --> 0:11:55.516 need it. 0:11:56.356 --> 0:11:59.516 So, every virus has a receptor that it binds to 0:11:59.596 --> 0:12:02.476 and needs to latch onto on a cell. For measles, 0:12:02.596 --> 0:12:06.716 it's this molecule that's called CD one fifty or it's 0:12:06.796 --> 0:12:12.396 called SLAM. SLAM stands for a signaling of Lymphocyte Activation molecule, 0:12:12.756 --> 0:12:17.796 and it's when somebody gets a measles infection. The virus 0:12:18.036 --> 0:12:21.036 comes into somebody's lungs and we have these cool dendritic cells. 0:12:21.036 --> 0:12:23.116 And dendritic cells are like these cells of big arms, 0:12:23.116 --> 0:12:25.356 and they go out and reach pathogens that they that 0:12:25.356 --> 0:12:28.196 they know shouldn't be there, and they capture them and 0:12:28.236 --> 0:12:31.236 bring them in and then they shuttle them into the 0:12:31.356 --> 0:12:34.276 lymphoid system, which is where all of our immune cells are. 0:12:34.716 --> 0:12:37.636 And so normally what would happen is the dendritic cells 0:12:37.716 --> 0:12:41.876 would say, hey, immune system, you know here's a pathogen, 0:12:42.316 --> 0:12:45.276 take it and develop immune memory against it. And so 0:12:45.316 --> 0:12:47.996 it literally hands it off to B cells and T cells. 0:12:48.796 --> 0:12:52.876 In this case, when the dendritic cell does exactly that 0:12:52.996 --> 0:12:56.796 same process, it hands off Measles virus to B cells 0:12:56.796 --> 0:12:59.396 and T cells. And this is a big mistake because 0:12:59.436 --> 0:13:02.076 now you have a virus that, instead of being handed 0:13:02.116 --> 0:13:03.876 off to a B and T cell and having that 0:13:03.916 --> 0:13:07.116 B and T cell you know ingest it and learn 0:13:07.196 --> 0:13:10.716 from it. The Measles flips on it receptor utilization and 0:13:10.796 --> 0:13:14.716 grabs city one point fifty or slam these molecules on 0:13:14.756 --> 0:13:17.396 the outside of the B cells and the T cells 0:13:17.956 --> 0:13:21.396 and it actually invades them like a trojan horse. 0:13:21.756 --> 0:13:24.996 Aha. So it's like a like a trick, right, Like 0:13:25.396 --> 0:13:29.276 Measles is there acting like a normal virus until it 0:13:29.356 --> 0:13:31.436 gets to the B cells in the T cells in 0:13:31.476 --> 0:13:34.356 the immune system. And normally the B cells in the 0:13:34.356 --> 0:13:37.836 T cells would destroy Measles, would destroy the virus. But 0:13:37.956 --> 0:13:41.116 in that case this doesn't happen, right, So what does happen? 0:13:41.556 --> 0:13:44.956 Now It's in the cushy lymphoid system and it's just 0:13:45.076 --> 0:13:49.276 full of food and it just replicates like crazy inside 0:13:49.356 --> 0:13:54.356 the immune system all the while cell by cell destroying 0:13:54.716 --> 0:13:58.516 the valuable immune memory is stored inside each of those 0:13:58.556 --> 0:13:59.676 cells that it's destroying. 0:14:00.156 --> 0:14:04.356 That is very compelling. That it's like a viralogical horror 0:14:04.356 --> 0:14:06.156 movie inside your body. 0:14:06.796 --> 0:14:10.756 It absolutely is. And what we see when we see 0:14:10.796 --> 0:14:14.436 the prototypic measles rash, which is like dots all over 0:14:14.516 --> 0:14:18.196 a child's body, red dots, it is truly the tip 0:14:18.236 --> 0:14:21.276 of the iceberg in terms of where the damage is 0:14:21.316 --> 0:14:25.676 being done. The real damage inside a child is much 0:14:25.796 --> 0:14:28.756 much deeper and much much more profound in terms of 0:14:29.636 --> 0:14:34.396 destroying a huge, huge population of very important cells inside 0:14:34.396 --> 0:14:34.996 of our body. 0:14:35.796 --> 0:14:39.836 So if you sort of step back and think about 0:14:39.876 --> 0:14:43.556 this idea that measles not only gives you measles but 0:14:43.676 --> 0:14:47.996 makes you vulnerable to lots of other infectious diseases, does 0:14:48.036 --> 0:14:51.556 it make you think differently about viruses, about the immune system, 0:14:51.636 --> 0:14:52.796 Like where do you land? 0:14:53.516 --> 0:15:00.156 Measles brings together for me mathematics, biology, ecology and evolution 0:15:01.116 --> 0:15:09.236 and vaccinology, And I love bringing those pieces together. It 0:15:09.236 --> 0:15:13.116 gives you a very deep appreciation for the delicate balance 0:15:13.156 --> 0:15:18.876 we have between infectious diseases, immunity, cancer, and autoimmune disease, 0:15:19.156 --> 0:15:23.196 and how those all interplay with each other. You know, 0:15:23.436 --> 0:15:26.876 the world thought that measles was done being discovered and 0:15:26.916 --> 0:15:32.036 then boom, all of a sudden, there's this new idea 0:15:32.876 --> 0:15:37.236 of something that really had massive, massive consequences on humans 0:15:37.236 --> 0:15:40.716 that we didn't even realize, and so it drives this 0:15:41.276 --> 0:15:45.156 renewed excitement around measles vaccination and the importance of it. 0:15:45.156 --> 0:15:48.316 It's not just a cool finding. It hopefully helps us 0:15:48.636 --> 0:15:52.356 move further and further towards eradication of the virus altogether. 0:15:55.316 --> 0:15:56.996 It was great to talk with you. Thank you so 0:15:57.116 --> 0:15:57.756 much for your time. 0:15:58.276 --> 0:16:00.076 Well, thank you so much. It was a lot of fun. 0:16:01.396 --> 0:16:05.276 Michael Minna is Chief science Officer at EMED Digital Healthcare. 0:16:05.596 --> 0:16:08.276 He was previously a professor at the Harvard School of 0:16:08.316 --> 0:16:13.116 Public Health. When we come back using measles to fight cancer, 0:16:23.756 --> 0:16:26.556 going back all the way to the eighteen hundreds, which 0:16:26.676 --> 0:16:30.116 was before anybody even knew what a virus really was, 0:16:30.716 --> 0:16:34.436 there have been occasional reports of cancer patients who get 0:16:34.476 --> 0:16:38.116 some kind of viral infection and then go into remission 0:16:38.236 --> 0:16:41.676 from cancer. And at a certain level, this makes sense. 0:16:42.156 --> 0:16:46.996 Viruses are highly evolved to enter and destroy cells. Normally 0:16:47.116 --> 0:16:49.156 we think of this as a bad thing, but if 0:16:49.156 --> 0:16:53.036 a virus is entering and destroying cancer cells, this ter 0:16:53.156 --> 0:16:55.996 a cell and destroy it property might be a very 0:16:56.076 --> 0:17:00.796 good thing. By the nineteen fifties, researchers were actively trying 0:17:00.836 --> 0:17:04.156 to figure out how to use viruses to treat cancer. 0:17:04.596 --> 0:17:09.116 But then new kinds of cancer drugs were discovered, basically chemotherapy, 0:17:09.796 --> 0:17:13.676 and researchers got less interested in that virus cancer link. 0:17:14.516 --> 0:17:16.956 My guest for this half of the show is Stephen Russell. 0:17:17.596 --> 0:17:21.036 Stephen has spent his career trying to use viruses to 0:17:21.116 --> 0:17:24.836 cure cancer, and as you'll hear, he and other researchers 0:17:24.836 --> 0:17:28.356 in the field have made real progress. When Stephen was 0:17:28.356 --> 0:17:31.356 starting his career in the nineteen eighties, he was interested 0:17:31.396 --> 0:17:35.716 in using retroviruses as possible cancer treatments. Then he told 0:17:35.796 --> 0:17:37.956 me he turned his attention to measles. 0:17:38.436 --> 0:17:40.676 Yeah, well, measles became the next love. 0:17:40.996 --> 0:17:44.036 You fell in love with measles? Yeah, of course, why 0:17:44.076 --> 0:17:46.556 do you fall in love with measles? Well? 0:17:46.596 --> 0:17:49.556 All viruses are quite beautiful, I have to say, and 0:17:49.916 --> 0:17:55.276 the life cycles are extraordinarily elegant. But measles I could 0:17:55.356 --> 0:17:58.836 do things with. I knew that there was a very 0:17:58.916 --> 0:18:04.156 remarkable case of a boy with a retro orbital Burkitt lymphoma, 0:18:04.196 --> 0:18:07.396 a very aggressive lymphoma that was sort of bulging his 0:18:08.596 --> 0:18:11.356 eye out, and he went to a clinic and was told, well, 0:18:11.396 --> 0:18:13.516 come back in a couple of weeks and we'll start 0:18:13.556 --> 0:18:16.476 the therapy. And he came back in a couple of 0:18:16.476 --> 0:18:20.396 weeks and the tumor had just resolved. But in the 0:18:20.476 --> 0:18:24.676 meantime he'd had a severe measles infection. Huh, And so 0:18:24.756 --> 0:18:27.756 it looked like it was pretty certain that the measles 0:18:27.796 --> 0:18:30.716 infection had driven this response that he had. 0:18:31.276 --> 0:18:35.676 Burko lymphoma also caused by a virus, right, the first 0:18:35.716 --> 0:18:37.916 tumor we knew was caused by a virus. 0:18:37.956 --> 0:18:42.596 Epstein By Yeah, so go on, I apologize. So anyway, 0:18:42.676 --> 0:18:45.636 I looking at measles, it seemed to tick a lot 0:18:45.676 --> 0:18:48.356 of boxes. But there was this whole history of the 0:18:48.396 --> 0:18:52.556 development of a vaccine strain of measles, and measles had 0:18:52.596 --> 0:18:56.516 been the vaccine had been created by taking a virus 0:18:56.556 --> 0:19:01.036 from the throat of a patient with measles. He was 0:19:01.036 --> 0:19:03.996 an eleven year old boy at the time, David Edmonstone 0:19:04.116 --> 0:19:08.036 in nineteen fifty four, and then growing that virus on 0:19:08.236 --> 0:19:12.436 cancer cells in tissue culture, and the virus had required 0:19:12.476 --> 0:19:17.116 the ability to propagate efficiently in cancer cells, but it 0:19:17.316 --> 0:19:19.636 lost the ability to cause measles. 0:19:20.036 --> 0:19:23.076 And wait, I just just to be clear, this was 0:19:23.196 --> 0:19:25.836 just they weren't trying when they were doing this to 0:19:25.916 --> 0:19:30.556 fight cancer. They were just trying to develop a measles vaccine. 0:19:30.556 --> 0:19:32.996 They were just saying, we're going to grow this measles 0:19:33.316 --> 0:19:36.276 in culture over time and make it be attenuator, make 0:19:36.276 --> 0:19:39.156 it be weaker. And it adapted in such a way 0:19:39.196 --> 0:19:42.476 that it preferred to infect tumor cells and not to 0:19:42.556 --> 0:19:43.876 infect non tumor. 0:19:43.636 --> 0:19:46.796 Cells because of the way they adapted it. Because remember 0:19:46.836 --> 0:19:50.236 that the cells that they were growing in the lab 0:19:50.396 --> 0:19:53.116 that they could put the measles virus on were basically 0:19:53.196 --> 0:19:54.036 cancer cells. 0:19:54.396 --> 0:19:56.436 And is that just because those are easy cells to 0:19:56.436 --> 0:19:57.996 grow because they liked to propagate. 0:19:58.156 --> 0:19:58.356 Yeah. 0:19:58.436 --> 0:20:01.916 Yeah, It's very, very difficult to grow non cancerous sects. 0:20:02.036 --> 0:20:04.476 Yeah, it's like the problem with cancer, right, it just 0:20:04.556 --> 0:20:06.276 loves to divide. 0:20:06.436 --> 0:20:10.116 Yeah. Yeah. So they put this virus on on the 0:20:10.276 --> 0:20:14.556 cells in culture, and the virus had actually adapted and 0:20:14.996 --> 0:20:19.516 it had learned to use a receptor that is more 0:20:19.556 --> 0:20:23.436 abundant on cancer cells than on normal cells, and it 0:20:23.516 --> 0:20:26.916 was losing all sorts of things that it needed in 0:20:27.036 --> 0:20:30.676 order to cause disease because it didn't need them to 0:20:30.796 --> 0:20:34.676 be able to propagate the cancer cells. So it spontaneously 0:20:34.716 --> 0:20:38.476 attenuated through a lot of mutations that arose in the 0:20:38.556 --> 0:20:42.076 viral genome. And so there it was and had been 0:20:42.116 --> 0:20:45.796 given to billions of people, and it looked like it 0:20:45.916 --> 0:20:53.156 was fairly well adapted to test in human studies against cancer. 0:20:54.316 --> 0:20:57.596 The measles virus used in the vaccine didn't make people sick, 0:20:57.836 --> 0:21:01.716 and it tended to attack cancer cells. So Stephen started 0:21:01.796 --> 0:21:04.476 using that form of the virus in studies to see 0:21:04.556 --> 0:21:08.436 if measles could treat cancer. Eventually he landed on a 0:21:08.516 --> 0:21:12.116 kind of cancer called multiple myeloma that can take hold 0:21:12.156 --> 0:21:15.356 in the bone marrow and suppress the immune system. And 0:21:15.516 --> 0:21:19.636 there was one multiple myeloma patient in particular who had 0:21:19.676 --> 0:21:23.036 a huge effect on how Stephen thought about using measles 0:21:23.036 --> 0:21:26.516 to fight cancer. The patient's name was Stacy. 0:21:26.316 --> 0:21:32.156 Erholtz, so Stacy. She had multiple myeloma. She had been 0:21:32.956 --> 0:21:37.836 on treatment for ten years, on and off, but probably 0:21:37.876 --> 0:21:40.796 more on than off treatment for the first ten years 0:21:40.836 --> 0:21:44.596 of her diagnosis, because every time she stopped the treatment, 0:21:45.396 --> 0:21:47.996 or even if she continued on it, the disease would 0:21:48.076 --> 0:21:51.516 come back and then she needs switch to something else. 0:21:52.076 --> 0:21:54.716 She had a large tumor on her forehead that was 0:21:54.796 --> 0:21:59.636 destroying the underlying bone and compressing her brain. She had 0:21:59.956 --> 0:22:03.556 four other solid tumors, and then her bone marrow was 0:22:03.636 --> 0:22:07.996 diffusely infiltrated with myeloma and it was moving fast, and 0:22:08.076 --> 0:22:10.516 she was out of treatment and options at the time. 0:22:10.556 --> 0:22:11.396 I mean, there was nothing. 0:22:11.476 --> 0:22:13.396 She was going to die soon. 0:22:13.516 --> 0:22:16.996 She was going to die, yeah, and she had three 0:22:17.076 --> 0:22:20.956 children still at school and everything to play for. She 0:22:21.036 --> 0:22:24.356 was fifty years old at the time. We'd moved up 0:22:24.396 --> 0:22:28.636 through every dose level that FDA had negotiated with us. 0:22:28.676 --> 0:22:32.076 Based on a starting dose level of a million, we'd 0:22:32.076 --> 0:22:35.516 gone up to just tenfold short of a billion. 0:22:36.036 --> 0:22:38.396 Like, how much did she get compared to how much 0:22:38.396 --> 0:22:40.276 somebody gets when they get the measles vaxing. 0:22:40.356 --> 0:22:44.316 It's about ten million doses of vaccine, okay. 0:22:43.956 --> 0:22:46.596 For this one person, So she's getting quite a lot. 0:22:47.156 --> 0:22:48.916 And what happens. 0:22:48.876 --> 0:22:53.876 Well as with other patients, she had a reaction to 0:22:54.036 --> 0:22:57.956 the infusion of virus. So she got the virus infused. 0:22:58.036 --> 0:23:02.236 She felt fine for a couple of hours, and then 0:23:02.396 --> 0:23:06.756 she started shivering and shaking, and her temperature rose and 0:23:06.796 --> 0:23:10.516 she felt pretty unwell overnight, but by the following morning 0:23:10.596 --> 0:23:11.716 it had settled down. 0:23:11.956 --> 0:23:15.196 And is that essentially like a response to a massive infection. 0:23:15.396 --> 0:23:17.276 She's essentially has this massive infection. 0:23:17.956 --> 0:23:22.996 Yes, it's similar to that, although it wasn't causing measles 0:23:23.036 --> 0:23:26.276 in her so it was it was more the body 0:23:26.356 --> 0:23:30.036 reacting to the foreign stuff in the blood and a 0:23:30.156 --> 0:23:33.956 very kind of rapid reaction. That settled down, and then 0:23:34.436 --> 0:23:39.316 she left hospital, went home and after a few days 0:23:40.036 --> 0:23:44.876 she started noticing that the tumor on her forehead she 0:23:44.996 --> 0:23:50.036 and her family had named it Evan, and this tumor Evan, 0:23:50.236 --> 0:23:54.876 started to shrink and actually melted away. And you know, 0:23:54.956 --> 0:24:02.596 we conducted thorough evaluations on her intervals thereafter, and we 0:24:02.596 --> 0:24:05.556 were staggered to see that she went into a complete 0:24:05.876 --> 0:24:10.916 disease remission. She felt fantastic. You know. We thought at 0:24:10.956 --> 0:24:13.556 the time, Okay, we've got it. This is the way 0:24:13.596 --> 0:24:18.316 to cure multiple myeloma, and so we gave it to 0:24:18.396 --> 0:24:21.996 a lot of other multiple myeloma patients and it didn't 0:24:22.036 --> 0:24:26.076 work nearly so well. There was some partial responses, but 0:24:26.156 --> 0:24:30.076 there was really nothing as dramatic as Stacy. So we 0:24:30.196 --> 0:24:34.836 studied Stacy pretty intensively. To try and understand what was 0:24:34.916 --> 0:24:38.996 special about her, because that would be the key to 0:24:39.276 --> 0:24:42.036 the success of virotherapy. I mean, what we knew from 0:24:42.076 --> 0:24:45.516 Stacy as wow, this can actually happen. You can give 0:24:45.516 --> 0:24:50.916 a virus systemically nothing else, and you can get a 0:24:50.996 --> 0:24:56.036