The Peter Attia Drive - #177 - Steven Rosenberg, M.D., Ph.D.： The development of cancer immunotherapy and its promise for treating advanced cancers

00:00:00.000 Hey everyone, welcome to the drive podcast. I'm your host Peter Atiyah. This podcast,

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00:00:42.520 peteratiyahmd.com forward slash subscribe. Now, without further delay, here's today's episode.

00:00:50.660 I guess this week is Dr. Steve Rosenberg. Steve is the chief of the surgery branch of the National

00:00:55.480 Cancer Institute, a position he has held continuously for the past 47 years. Some of you may have heard

00:01:02.800 of me talk about Steve Rosenberg in the past. He is unquestionably the most important mentor I've

00:01:09.140 ever had. Steve has received numerous awards, in fact, really too many to name. So it's probably

00:01:15.020 easier to explain it this way. He has received essentially every major award in science, except

00:01:21.160 for the Nobel Prize. He is one of the pioneers in the field of immunotherapy, dating back to his

00:01:27.000 early work in the 1970s and 80s with the discovery of interleukin-2 and its effect on lymphocytes in

00:01:35.140 mediating cancer regression in patients with metastatic cancer. In this episode, we talk about

00:01:40.860 his entire history from childhood basically until now. And it serves as effectively a roadmap for the

00:01:50.120 field of immunotherapy from the very nonspecific therapies such as interleukin-2 into the discovery

00:01:57.700 of tumor infiltrating lymphocytes up into checkpoint inhibitors, which many people have heard of in the

00:02:02.820 last decade, CAR-T cells and adoptive cell therapy. We talk about all of these things in detail. And perhaps

00:02:08.980 most importantly, we talk about his optimism for what lies ahead, especially in the face of some of

00:02:14.900 the more recent discoveries with respect to tumor antigenicity. We also talk about the human side of

00:02:21.840 cancer, which I think when you listen to this, just completely comes through him in every way, shape,

00:02:28.060 or form. He has really never lost sight of why he chose to become a physician basically at the age of

00:02:34.380 six years old and why he was so drawn to cancer. One other point I'll make, if you find this episode

00:02:40.760 particularly interesting, I would highly recommend going back and reading the book, The Transformed

00:02:46.720 Cell, which Steve wrote with John Barry about 30 years ago. It's one of the best books I've ever read

00:02:52.860 on the process of scientific discovery and the journey and the ebbs and flows of failures and successes.

00:02:58.520 It's really an amazing book for anyone who wants to understand how biomedical research is conducted.

00:03:04.280 So without further delay, please enjoy my conversation with Dr. Steve Rosenberg.

00:03:13.600 Dr. Rosenberg, thank you so much for making time. I know how busy you are. I know as much as anybody,

00:03:18.940 how busy you are because I've sat next to you and watched how hard you work and how tirelessly you

00:03:23.500 work. So it really means a lot that you would make any amount of time to sit and talk about what we're

00:03:27.720 going to talk about today. I almost don't know where to begin, but I can't help but want to begin

00:03:31.660 kind of chronologically with your life story because you're probably one of the most focused

00:03:36.840 people I've ever met, if not the most focused person I've ever met. And that focus seems to

00:03:41.200 have started at a very young age. Let's talk a little bit about your childhood. You grew up in

00:03:45.380 the Bronx, if I'm not mistaken, correct? That's correct. I was born in the Bronx.

00:03:50.500 If I recall, we're coming up to your 81st birthday. So you were born, I think it's August 1st,

00:03:56.120 August 2nd, 1940. Yeah. So what are your earliest memories of childhood as they pertain both to

00:04:05.740 your love of science and perhaps more importantly, your obsession with cancer?

00:04:10.720 So up until about the age of five or six, I wanted to be a cowboy. I have an older brother and we would

00:04:16.000 talk about going out West together and riding on horses and doing all kinds of exciting things.

00:04:22.300 But the first things I remember, other than wanting to be a cowboy, occurred when I was about five or

00:04:30.180 six years old. And I've given a lot of thought to how that came to pass. When I was about five or six,

00:04:39.540 living at home, right at the end of the Second World War, when all of the remarkable tragedies

00:04:47.960 of the Holocaust sort of came home as my parents got one postcard after another. I remember this

00:04:56.340 and their suffering as they got word of relatives that died in the death camps during the war.

00:05:05.120 And I remember being so horrified by that in terms of how evil people could be towards one another.

00:05:14.900 And somewhere around that time, I developed an almost spiritual desire to become a doctor,

00:05:24.420 to do research and make progress in helping people in alleviating suffering rather than causing

00:05:32.500 suffering. And that persisted as I began to keep scrapbooks about anything I could find about

00:05:43.160 medicine or research. And I think it was in response to the horrors of that particular time

00:05:52.020 that inspired me to not only become a doctor, but to become a doctor who not only helped alleviate

00:05:59.580 suffering now, but alleviate potential suffering in the future by doing research. And I stuck

00:06:06.240 with that right through my education. Now you did very well in high school because,

00:06:13.060 or at least we've never spoken about it, but I can only assume you did because you were accepted to

00:06:17.560 the best medical school. And not only that, but you did the combined bachelor's MD degree, which I

00:06:23.140 assume would have been very difficult to go straight into medical school from high school, but you somehow

00:06:27.340 managed to get into the six-year program. And what, so just talking about Hopkins for a moment,

00:06:34.280 what was the impression that that place left on you in what would have been, I guess, the late

00:06:39.340 fifties and early sixties?

00:06:41.300 So I went into this six-year program. It was three years of college and three years of medical school,

00:06:46.740 knowing that I would want to get further education, that I would take additional time. And I knew from

00:06:53.160 the very beginning that I would go on to get a PhD in one of the, in one of the sciences, it turned out to

00:06:59.780 be biophysics. And Hopkins was a very nurturing environment with respect to, respect to that. I, as soon

00:07:06.500 as I got to Hopkins, I started working in a biology laboratory in the afternoons and evenings doing some

00:07:13.080 very simple projects in the biology lab. But I, I knew from the very beginning that I wasn't just going to try to

00:07:22.900 practice today's science, practice today's medicine, but rather try to create the medicine of tomorrow.

00:07:28.900 And that stuck with me for these last 60 or 70 years or so.

00:07:35.020 Who was the chief of surgery when you were there? Was Blalock still the chief of surgery?

00:07:39.420 Yes. And a, uh, and it was, the medical school was not necessarily a terribly nurturing environment.

00:07:45.580 You were thrown in there and at rounds, there seemed to be a spirit of calling people to task,

00:07:52.660 uh, in front of others. It wasn't, uh, the way that I thought education should, uh, should happen, but

00:07:59.020 there were brilliant people around. And that's what I think is the most, probably one of the single

00:08:05.420 most important components of a good education. And that is being surrounded by people who

00:08:11.220 know a lot, you know, more than you can inspire you. And that kind of person was at Hopkins.

00:08:18.740 Now, I remember when I was in medical school, when I was spending time with you and we got talking one

00:08:24.180 night and you explained that the reason you chose to do your PhD at Harvard in biophysics, and this is,

00:08:30.680 this is as close to my remember as a direct quote as possible is you never wanted to be intimidated by

00:08:36.100 a differential equation, which presumably was, was a bit of a shortcut for you. You wanted the,

00:08:42.020 the, the biggest or the broadest education possible, but what led to that choice to, I mean,

00:08:48.440 at that point in time, for example, did you know you had an interest in immunology? Had that piqued

00:08:51.640 your curiosity yet, or were you still thinking just more broadly? I was somehow interested in the

00:08:57.380 mysteries of cancer through high school biology and in my college classes. I got a PhD because I wanted

00:09:07.260 more formal learning. I never wanted to be intimidated by what I did not know. I wanted to

00:09:15.080 be able to grasp any area of science and use it to answer questions. And maybe differential equations

00:09:25.440 were in the, in the source of that. I ended up doing a lot of math in graduate school, but it was more

00:09:30.220 than that. I wanted to have the feeling that I had a good enough broad background in the sciences,

00:09:36.780 because when I got that PhD in biophysics, I was doing physical chemistry, quantum mechanics,

00:09:43.080 thermodynamics. It was a lot of non-biology in biophysics. I wanted to have a background in the

00:09:50.700 sciences such that if I encountered a problem, I could get a good book, read some papers and

00:09:57.200 understand it. And it was that base of knowledge that I tried to acquire.

00:10:03.120 So when you were doing your PhD, had you already applied to residency or did you take time out

00:10:09.040 between medical school and the application to residency?

00:10:12.540 So I went immediately into the surgical residency at the Peterbent Brigham Hospital, right out of medical

00:10:18.620 school, and then took off four years to get a PhD in, uh, in biophysics. So it was a year of

00:10:25.420 internship, took off four years, and then went back to the residency and then came down to the NIH for

00:10:31.380 several years to join the immunology branch here. This was during the Vietnam war before going back to

00:10:38.840 actually finish the residency in 1974. Now, was Franny Moore sort of the most significant

00:10:45.500 figure in your life at that point in time as a mentor?

00:10:49.920 Franny Moore was the chief of surgery and an incredibly smart person. There are an awful lot

00:10:56.000 of smart people in that educational system, but Franny stood out in that discussing a problem,

00:11:02.900 discussing a patient, it wouldn't be at all surprising for him to come up with an idea or an

00:11:08.500 outlook or a perspective on a problem that most people had not, had not considered. So in that

00:11:14.840 sense, he was a, an important figure. He was not so much loved as respected, which is a feature that I

00:11:23.920 think is, can be very inspiring to young people. Was it unusual for someone to leave their internship

00:11:30.180 or leave after their internship and go into a PhD program at that time?

00:11:33.700 Well, it was, as a matter of fact, and the Brigham encouraged you to take off a year or sometimes

00:11:39.640 two years in the middle of the residency program, generally after two or three years. But I knew at

00:11:46.100 that point, I was just itching to learn more. I was just not satisfied after, after medical school,

00:11:52.000 the college and medical school that I really knew enough to do creditable, meaningful, impactful research.

00:11:58.600 And so, again, this was a real program. For two years, I did nothing but study, nothing but take

00:12:05.620 classes and study and learn. And then the latter two years, I spent in the research laboratory doing

00:12:12.720 basically physical chemistry and protein chemistry research of cell membranes.

00:12:17.820 And Franny was supportive of this?

00:12:20.180 He was to an extent. To take that time off after internship required a few meetings. And I,

00:12:25.760 ultimately, I remember sending him a note saying, look, I'm 23 years old. I've just finished the

00:12:31.560 residency. I need to do what I'm excited about. And he gave in. And I have enormous respect for him

00:12:38.480 for that. And he was quite patient because I came back for a year. And then I went down to the NIH.

00:12:43.920 It was part of the Vietnam draft obligation. And he kept taking me back each time, which is very,

00:12:50.680 very nice. But it turns out, I set some kind of record at the Brigham. It took me 11 years from

00:12:56.420 the time that I started my internship to the time I actually finished the residency, which was some

00:13:01.500 sort of record at the time.

00:13:03.500 So you would have been old for a chief resident at that time?

00:13:06.960 I guess. Yes, I was, what, I was 33, 34 by the time I had my first job.

00:13:14.480 But of course, you made up for it because you sort of progressed so early at the outset.

00:13:18.480 As you know, well, the book that you wrote with John Barry in 1992, The Transformed Cell

00:13:23.740 is a book, I may have the record for most times reading it. I may also possess the record for most

00:13:28.460 copies owned, which I know you get a kick out of that. Every time I say something to that effect,

00:13:32.480 you basically say, I'm one of the few people who's read it, which I know is not true.

00:13:36.400 But I still remember the first time I read it. And it's a remarkable story. I suspect many people

00:13:41.000 will go on to read it after this interview, because it is in many ways, one of the best books about

00:13:45.840 science, which I think was your motivation for writing it. And we'll come back to that. But

00:13:50.240 in it, you talk about an important moment in your training, which occurred in 1968 with a patient who

00:13:56.640 you met in the ER one day. Can you tell us a little bit about that story and why it altered the course

00:14:02.220 of your career? Well, there were actually two patients that I saw early on or was familiar with

00:14:08.120 early on that influenced my thinking about cancer. The first was a patient I saw when I was a junior

00:14:15.460 resident at the West Roxbury VA Hospital. We rotated through there three or four months at a time

00:14:21.280 during the residency. And it was a 68-year-old fellow who came in complaining of right upper

00:14:27.080 quadrant pain. It looked like a typical gallbladder attack. And I got pretty excited about it because it

00:14:32.860 might be a patient that I might be able to perform one of the first operations I was allowed to do.

00:14:39.660 And so I looked into his chart and a remarkable story was encountered. I looked into the chart and

00:14:48.540 it turned out that 11 or 12 years earlier, that patient had been seen at the West Roxbury VA Hospital.

00:14:54.740 He had had a gastric cancer, a stomach cancer. He had undergone a laparotomy. And I looked at the

00:15:02.880 surgeon's note saying that he opened the belly. He saw a tumor that was encompassing about three

00:15:08.640 quarters of the stomach. There were multiple liver metastases deposits that were biopsied shown to be

00:15:14.420 the gastric cancer that had spread, multiple enlarged hardened nodes. And he took out part of the

00:15:20.000 stomach, I guess, as a palliative measure, left the rest of the disease in place. And the patient

00:15:25.980 recovered and about a week later went home. Well, as I turned the page of the chart, patient comes back

00:15:31.360 three months later. Nobody had expected to see him. And he was doing fine. He was gaining weight. Six

00:15:37.100 months later, he was back working. And here he was 12 years later, having lived the past 10 or 11 years

00:15:43.900 completely normally. And so I took part in removing his gallbladder under supervision, of course.

00:15:51.080 And his belly was completely clean of cancer. There was no evidence of cancer of any kind. And we went

00:15:57.220 back and looked at his, be sure it was the same patient. We reviewed the pathology. Sure enough,

00:16:02.540 it was a cancer that had spontaneously disappeared over time in the absence of any therapy. One of the

00:16:10.560 rarest events in medicine. And that is to have the spontaneous regression of cancer without any

00:16:17.360 treatments being given. Somehow his body had rejected the cancer. And I then did what turned

00:16:25.360 out, of course, to be a very naive experiment. But I was wondering whether or not this patient who had

00:16:31.360 somehow cured his own cancer could be somehow taken advantage of to treat other patients. And it turned

00:16:37.740 out we had another patient in the hospital with a gastric cancer, a veteran, who happened to have

00:16:42.580 the same blood type. And so I called up the head of the surgery department, Brownie Wheeler, and said,

00:16:48.120 hey, I want to take a blood transfusion from this patient who spontaneously was cured and give it to

00:16:53.820 this other patient. And he said, okay, that was the IRB as it existed at that time. And so we actually

00:17:02.340 got blood from this one patient and infused it into the other veteran. But of course, it didn't do

00:17:06.640 anything. And the other patient ended up dying of his gastric cancer, but at least planted the seed

00:17:12.800 that, in fact, maybe there was something in the immune system that caused the rejection of that

00:17:19.800 cancer, much as you would a foreign transplant. And the body's major defense mechanism, of course,

00:17:28.300 against foreign invaders is the immune system. And it got me thinking about potential immune

00:17:34.080 manipulations. But there was a second patient that also influenced me a great deal. And that was a

00:17:41.480 patient that had been seen about a year before I came to the Brigham as an intern. And this was a

00:17:46.740 patient who had received one of the early kidney transplants that were developed and innovated at the

00:17:52.140 Brigham hospital. He had received a kidney from a young individual who died in a motorcycle accident.

00:18:00.000 And that kidney was transplanted into the recipient. And the recipient developed a widespread renal cell

00:18:07.660 cancer. And it turned out, after study, that the kidney that had been transplanted inadvertently

00:18:14.080 had contained a renal cancer that then in this other patient, under the influence of immunosuppressive

00:18:19.620 medications, had spread widely through his body. So in an attempt to control this,

00:18:28.100 the immunosuppressive medications were stopped. Of course, the kidney rejected and had to be removed.

00:18:36.260 But the patient's cancer then went away as well, because it too was allogeneic. It too came from

00:18:43.040 the genome of the original donor. So what did that teach one? Well, it showed that a large,

00:18:52.560 invasive, vascularized cancer could be caused to reject completely by the immune system if you had

00:19:01.640 a strong enough stimulus that could mediate that rejection. And so it was that spontaneous regression,

00:19:09.380 maybe this demonstration that the immune system more directly by removing immunosuppressive

00:19:14.420 medications could result in tumor collapse and regression that tended to put me on the path towards

00:19:21.720 cancer. But I was already pretty much there because of what I had seen as a doctor in cancer patients.

00:19:28.560 Now, in the late 1960s, what was understood about the human immune system as it pertained to even

00:19:36.640 viruses, let alone cancer? I mean, had MHC class one and class two been identified yet? I don't think

00:19:42.220 they were identified until the mid-70s, right?

00:19:44.140 Class one in the 70s and the early 80s, class two. But when I started in 1974,

00:19:52.100 the idea of immunotherapy was a dream. There were anecdotes way back to the late 80s of tumors going

00:20:00.820 away when people got an infection, but really nothing stable. There was no ability to measure

00:20:07.600 an immune reaction against any cancer. There was no such thing as a cancer antigen that had ever been

00:20:12.320 found. There were no manipulations you could give that might work. So it was sort of a dark period

00:20:18.220 when it came to knowledge about the immune system against cancer. It's a little hard to understand

00:20:23.520 just how frequent immunologic information developed. In the 1957 issue of the Journal of Immunology,

00:20:31.900 the word lymphocyte was not in the index. We did not understand what small lymphocytes did,

00:20:37.780 what they were doing and circulating in the 1950s. And so that information only came to pass in the

00:20:45.060 early 60s when it was clear that you could transfer immunity by transferring lymphocytes

00:20:50.520 in a way that you could not do by transferring blood or serum. And even in experimental animals,

00:20:58.840 there was no manipulation that could cause an existing cancer to disappear. You could immunize a mouse

00:21:04.760 against a tumor by letting it grow and then removing it and cause that mouse to resist an

00:21:12.080 implantation of the same tumor again. But once the tumor was growing, there was no maneuver that could

00:21:17.880 keep it from growing, no immunologic maneuver that could keep it from growing. So the field was

00:21:23.600 desperately in need of more information.

00:21:27.560 So before we get to how you arrived at the NCI, well, actually let's talk about that. It's a very

00:21:33.880 unusual first job. How did it come about? And what did you assume you would do at the completion of

00:21:39.840 this otherwise very long residency? So as you're indicating, I finished my residency June 30th,

00:21:50.060 1974. And the next day I was appointed chief of surgery at the National Cancer Institute, a position

00:21:57.400 that I still hold. I'm still chief of the surgery branch now, what, 47 years later, 46 years later.

00:22:03.880 The NIH, when I came here, I knew it was a remarkable place. It had

00:22:08.100 resources and a commitment, a mandate to make progress. It's a state-of-the-art hospital

00:22:16.660 that provides outstanding care to patients, but it exists again, not only to practice the best of

00:22:24.180 today's medicine, but to create the medicine of tomorrow. And that always intrigued me from my

00:22:29.780 first knowledge of the NIH when I came here in the midst of the residency during the Vietnam War.

00:22:36.620 Now, you did have an offer to stay at Harvard, correct? Was Dana-Farber still, was it in existence

00:22:42.240 at the time? Dana-Farber was just being built, the hospital that was just being built. Franny Moore,

00:22:49.000 who was chief of surgery, offered me a position as the head of surgery in that new Dana-Farber

00:22:54.400 institution. Emil Fry was the director of it and head of medical oncology, and he too offered me

00:23:01.580 the position. And I had tentatively accepted it, although we're in the midst of some negotiations

00:23:07.060 about whether there would be individual and independent operating rooms in the hospital and so

00:23:11.980 on. But in the course of that, I heard from one of the division directors here at the NIH,

00:23:18.280 who I'd gotten to know when I was a fellow, who came to the Brigham to interview me. He was wondering

00:23:25.420 whether I would be interested in the position. And so he interviewed me, and I was expecting to stay

00:23:32.520 at the Brigham at Harvard, but one day I got a phone call from him saying that the chief of surgery

00:23:37.880 offered Ketchum. I decided to retire, and the position was open July 1. Was I interested?

00:23:42.560 And I knew I was, but I had a call. My wife, Alice, told her about it. She said, just pack,

00:23:49.220 let's go. And off we went. Was Franny disappointed?

00:23:53.360 Oh, it was a really shocking encounter that I had with him. And then I went in to tell him I decided

00:23:59.860 to go to the NIH. I thought it was a place where I could best utilize my interests and knowledge. And

00:24:06.280 he said, no. And I said, look, I've decided to do it. He said, you have to stay here. It's too great

00:24:12.140 an opportunity to turn down. And I said, no. And he wasn't an easy guy to say no to.

00:24:18.540 But I knew I wanted to come back to the NIH. And finally, after almost an hour, I finally said,

00:24:25.200 Dr. Moore, I'm not, I'm going down to Bethesda, Maryland. And I offered my hand to shake his hand

00:24:32.420 as I was going to leave. And he refused to shake my hand, which was a little shocking. But he got over

00:24:38.520 it. Finally, I left. And we became good friends. And he said all kinds of nice things about me when

00:24:44.760 he needed to. So it worked out well. You see, at that point, I knew I wanted to study cancer. I had

00:24:53.960 already made that absolute commitment. And the National Cancer Institute seemed like the right

00:24:58.860 way to do it. And in some sense, it was a logical decision for me, given my childhood experience

00:25:07.300 that got me interested in medicine and science. Cancer is such a devastating disease. It attacks

00:25:14.780 innocent people through no fault of their own. It makes them and their families watch impotently

00:25:20.720 as they progress and then die. Cancer is a holocaust. And it just seemed like the kind of

00:25:29.380 thing I wanted to study. So it was around this time, I guess, a little bit before this time that

00:25:35.240 Richard Nixon and that administration had declared a war on cancer. I believe it was just a year prior

00:25:40.840 to that. How did that resonate with you? Did you view that with great optimism? Or did you think that

00:25:48.380 it was naive that, you know, in a matter of years, cancer would be eradicated in the same way that

00:25:54.300 man had gone to the moon? Well, I had great hopes for making progress, perhaps naively, even at that

00:26:01.260 point, not fully understanding all of the complexities. The National Cancer Act mainly influenced funding

00:26:08.540 outside of the NIH. The NIH was already, I thought, well-funded, had a building that had been built in 1953,

00:26:15.880 one of the largest buildings in this area, dedicated to doing research. It had hospital beds. And so

00:26:23.060 that National Cancer Act didn't have much impact on the intramural NIH that I could see. But again,

00:26:29.280 remember, I'm a worker bee. I became chief of the surgery branch and have never advanced in the

00:26:35.340 hierarchy. I was where I wanted to be, turned down a fair number of physicians. And so when it came to

00:26:42.720 the influence of the National Cancer Act on the country as a whole, I really wasn't involved with

00:26:48.740 that very much at all. I focused on the work that I wanted to do intramurally at the NIH.

00:26:55.760 So how did you lay out a research agenda when you arrived in 1974? You're now finally able to,

00:27:03.040 not only with the resources of money, but perhaps more importantly, with the resources of time,

00:27:07.800 lay out an agenda for hypotheses that you want to test to build effectively a program to systematically

00:27:17.600 narrow down the set of questions. So what was the process by which you went about doing that?

00:27:23.900 So when I came to the NIH, knowing I wanted to study cancer, I started reading everything I possibly

00:27:28.700 could about therapeutic approaches, which at that point were simply surgery, radiation therapy,

00:27:34.160 and chemotherapy, most used alone. And it was clear to me at that point that although incremental

00:27:43.460 advances had been made over the years, surgery 3,000 years old, radiation therapy began immediately

00:27:52.220 after Renkin discovered x-rays in 1895. And chemotherapy arose in biological and chemical warfare laboratories

00:28:02.820 here at Fort Detrick, in Detrick, Maryland, to attempt to develop these agents. And it was in laboratory

00:28:09.920 accidents in 1942 when nitrogen mustard was inadvertently exposed to laboratory technicians and found to

00:28:20.200 develop a lymphopenia throughout their body with their lymph nodes shrinking down that led a Yale physician

00:28:26.420 to attempt to attempt to attempt to attempt to use nitrogen mustard, now known as melphalan, as a chemotherapy

00:28:33.520 agent. And that was the birth of chemotherapy, 1942. And that started chemicals to treat, search for chemicals to

00:28:41.420 treat cancer. But the advances that were being made were slowly and tiny incremental. I wanted something that big

00:28:49.620 that would make a big difference. And as I began to read about the immune system, how little was known about it, but with

00:28:56.820 the examples that I had, the intuition that I had developed, which is so important in science, that this might be

00:29:02.960 something valuable that I decided to study immunology. Looked at everything I could read about, and it seemed

00:29:10.520 to me that the immune cells that were then being recognized as the mediators of organ rejection were the

00:29:19.420 agents that one needed to stimulate. And why not use an immune cell as a drug? That is, take advantage of a

00:29:29.820 patient's own immune reactions to try to treat the disease, immunotherapy. And I started with unbelievably naive

00:29:35.820 experiments. There was no way at that point to keep lymphocytes alive outside the body. We're talking

00:29:42.400 about 1974. You could take them out, and they would die in a day or two. And you had no way to keep them

00:29:48.600 alive. You could mix them with other cells, and they would stimulate for a few days, but then they would die

00:29:53.660 after about a week. And yet I was desperate to try to use lymphocytes with immune reactivity to treat

00:30:00.780 patients. And so I began implanting human tumors into the mesentery of mini pigs. A good friend of

00:30:11.660 mine, David Sachs, here had developed a mini pig colony that was partially inbred at MHC loci. And so I would

00:30:18.820 embed tumor in the mesentery of these mini pigs, wait about two weeks, operate and remove the inflamed 0.87

00:30:26.120 lymph nodes that were draining that tumor. And gave those lymphocytes to six patients. That is,

00:30:35.640 would take out their tumor, generate lymphocytes reactive against that tissue, and then harvest

00:30:40.260 lymphocytes from that pig and administer them intravenously to patients. And of course, nothing

00:30:45.740 happened. But it's just a sign of how desperate I was at that point to have some impact, to be doing

00:30:51.840 something. I have over the door of my lab, you probably remember it. When you were in the lab,

00:30:59.020 it said, it's a modification of a Louis Pasteur saying that said, chance favors the prepared mind.

00:31:06.680 And what I added to it was, chance favors the prepared mind only if the mind is at work. And so I was

00:31:13.660 trying things. And it was only with the discovery of T-cell growth factor in 1976 by Morgan Resetti,

00:31:21.840 Gallo, that opened the door to be able to manipulate lymphocytes outside the body by putting

00:31:28.000 them in a growth factor called interleukin-2. And that was something I began to study quite

00:31:33.740 intensively to see if one couldn't then grow lymphocytes that had anti-tumor activity and

00:31:40.600 would retain it as they grew. None of that was known, but those were the first experiments I was

00:31:45.620 doing along those lines. Now, before we go further, I think it's worth making sure people understand

00:31:52.420 some of the semantics because obviously you and I can take so much of this for granted. But

00:31:57.780 let's start with some basics about cancer. How does one define cancer? What separates a cancer cell

00:32:05.480 from a non-cancer cell? Well, if you look at the broadest properties, there are two properties

00:32:11.700 that separate cancer from other cells in the body. The first is uncontrolled growth. Virtually

00:32:18.980 all of the tissues we have, fingernails or eyebrows or you name it, they'll grow to a given amount and

00:32:24.820 then they'll stop. Well, cancers don't have that signal to stop. They'll keep growing. And the second

00:32:31.400 is it's the only cell that can arise in one part of the body and spread and live and divide and grow

00:32:40.840 in another part of the body. And that's not true of virtually any other kind of cell. So cells with

00:32:48.000 uncontrolled growth that can spread and grow elsewhere are the biologic properties. Now, we can dig down

00:32:54.700 layer by layer by layer and get to the point of, well, why does a normal cell ultimately become

00:33:01.340 a cancer cell? And we now understand that that's due to the accumulation of mutations in DNA of these

00:33:08.300 cells divide, which explains why it's the common organs of the body, all of which have ducts. The

00:33:15.700 lining of those ducts are constantly turning over. And as that DNA is turning over, mistakes are made

00:33:22.680 called mutations. And it's that accumulation of mutations that results in the cancer itself. So

00:33:27.620 we can take it all the way from the biology of uncontrolled growth, but down to the very molecules

00:33:32.920 that are involved. We can describe it. It doesn't mean we really understand it all, but we can describe

00:33:38.020 it. And let's also explain to people the difference between the epithelial tumors, the hematologic tumors,

00:33:46.200 tumors. And even let's frame it as it was in 1974, in terms of what was a person's odds of surviving?

00:33:54.080 So maybe tell folks what the common epithelial tumors are and explain a little bit about the,

00:34:01.300 we're not going to go into staging in great detail, but what's the difference between local tumor versus

00:34:07.340 metastatic tumor? And what's the impact that has on a person's survival at the time you arrived at NCI?

00:34:12.640 Right. So the hematologic cancers, of course, are the blood cancers, and they start from

00:34:17.580 progenitors in the hematopoietic system. Because after all, the hematopoietic system starts from an

00:34:23.380 individual stem cell that then divides into multiple different characteristics, much as we all grow from

00:34:29.720 a single fertilized egg from one cell that makes us what we are. So even back then, and a little more

00:34:39.940 so now, if you developed a cancer of the bloodstream, which were about 10% of all cancer deaths are due to

00:34:50.900 those, 90% of cancer deaths are due to the epithelial cancers. So these start in the solid

00:34:55.700 organs of the body. And that's all the way from the rectum up through the GI tract, through the stomach,

00:35:03.360 through the esophagus, the pancreas, the GU organs, the testis, the ovary, the prostate. All of these

00:35:10.920 solid organs have ducts. And as I've mentioned, it's the epithelial lining of the ducts that are

00:35:16.600 turning over that become the cancer. In blood cancers, it's the more primordial cells that develop

00:35:23.100 into neutrophils and lymphocytes and other types of cells. So let's talk about the solid tumors,

00:35:29.780 which are 90% of all cancer deaths. Last year in the United States, there were about 600,000 deaths

00:35:35.460 due to cancer. 550,000 were due to the solid epithelial cancers.

00:35:43.540 If you operate on a patient who develops a cancer to remove that cancer, then well over half the time

00:35:52.000 that patient will be cured. That is, go on and live their normal lifespan. But the half,

00:35:59.220 a little less than half of patients that cannot be cured result in this enormous tragedy of 600,000

00:36:06.060 innocent people dying of cancer every year. Once the cancer spreads, however, and this in my view is

00:36:13.480 a dirty little secret of oncology. And that is that if a cancer spreads from its local site and cannot be

00:36:24.160 surgically removed, then the death rate in that patient is 100%. That is, we have virtually no

00:36:34.780 treatments that can cure, systemic treatments that can cure a patient with a metastatic solid cancer

00:36:41.760 that is one that is spread to a different site that can't be surgically resected. Now, there are a

00:36:46.580 couple of exceptions to that. There are two solid tumor exceptions that have existed for several

00:36:52.360 decades. One is choriocarcinoma. These are cancers that start in the placenta of pregnant women that

00:36:58.220 then spread, and you can have 90% of the lung replaced by that tumor receive methotrexate,

00:37:03.780 a chemotherapy drug, and it will all disappear. Still don't understand exactly how. Germ cell tumors

00:37:10.800 in the male, tumors of the testis like Lance Armstrong, who had brain mets and lung mets,

00:37:17.100 no matter how much they've spread, if you give patients platinum-derived chemotherapy regimens,

00:37:25.420 you can cause complete durable regression of that metastatic disease.

00:37:30.920 Up until 1985, those were the only cancers that could be cured. We can now add to that list solid

00:37:37.280 cancers. We can now add to that list melanoma and renal cancer because interleukin-2 administered to

00:37:43.860 patients back in the mid-80s caused complete regressions of widely metastatic cancer in

00:37:48.120 patients that are still alive today. But that's it. Choriocarcinoma, germ cell tumors, melanoma,

00:37:55.080 renal cancer. Other than those four, everyone who develops a spread cancer will die of it despite all

00:38:02.520 the best treatments that we have. Well, you read in the paper that this celebrity has cancer and they're

00:38:10.580 going to fight it and they're going to beat it, but nobody beats it. We're in such desperate need

00:38:15.840 of better treatments for patients with metastatic cancers because we can beat them back a little

00:38:22.360 bit. We can improve survival by months and for some cancers, maybe a few years like breast cancer and

00:38:28.480 colon cancer, but everybody ultimately will succumb to the disease. And that's what I was actually going

00:38:34.620 to ask you about, which is if you think about the past 50 years in cancer and what you just said,

00:38:40.060 I still starkly remember having those discussions as a medical student with you. And the main point

00:38:45.780 was we've basically just extended median survival of metastatic cancer, but we haven't increased

00:38:52.500 overall survival. And what would be the extent to which even median survival has changed if we

00:38:59.100 are just talking about stage four of the common cancers, breast, colorectal, lung, pancreatic. How

00:39:06.240 much has the needle been moved with respect to median survival, notwithstanding the fact that overall

00:39:12.020 survival hasn't changed? Well, if you look at current papers and advertisements, most regimens that

00:39:21.560 ultimately get approved by the Food and Drug Administration prolong survival by months,

00:39:27.980 probably the best example in modern oncology is the treatment of metastatic colorectal cancer.

00:39:35.380 When I started, median survival would have been maybe eight to 10 months. Now it's two and a half

00:39:42.200 years. So there's an example where life has been extended by years. Breast cancer patients can go from

00:39:48.520 one regimen to another, each one causing some temporary regression of the cancer or limitation of its

00:39:56.020 growth, but the cancer will ultimately grow and the patient will have to move on to something else.

00:40:00.420 And that's why cancer care is so remarkably expensive because people just move from one

00:40:06.420 treatment that can prolong life by a few weeks, like erlotinib and pancreatic cancer, six-week

00:40:13.080 improvement in survival. For $40,000, right? For enormous toxicity and huge, huge life-altering expense.

00:40:21.580 Because the most frequently prescribed drug in oncology today is avastin, bevacizumab, which can

00:40:29.040 impact on blood vessels and tumors. And the trials of that regimen in combination with others will

00:40:38.140 prolong survival in patients with colorectal cancer by about four and a half months. But those are the

00:40:45.380 tiny increments, which can provide substantial, some can provide substantial benefit to patients,

00:40:51.260 but not a curative and people are always living under the cloud of that cancer that is going to

00:40:58.100 regrow. So we, we need something more dramatic than the application of surgery, radiation, and

00:41:07.000 chemotherapy, barring some enormous advances in those fields.

00:41:11.100 And I think one other point worth making for folks with respect to chemotherapy,

00:41:15.660 I was actually just on the phone yesterday with one of my patients whose wife is currently

00:41:20.340 recovering from surgery from a cancer. And, and he asked a question about the efficacy of

00:41:26.400 chemotherapy and how good is chemotherapy at killing cancer cells, which I thought was an

00:41:31.120 interesting question. And it led to a discussion where I said, the challenge with chemotherapy is not

00:41:37.800 finding chemotherapeutic agents that can kill cancer cells. Uh, you know, I made a point that

00:41:42.520 he probably had 20 chemicals in his home and in his garage that could kill every cancer cell remaining

00:41:48.760 in his wife. The issue is how can you do that selectively? How could you do that? And not at the

00:41:54.400 same time, kill the normal cells. And I, I think therein lies the arbitrage that needs to be exploited

00:42:00.900 with chemotherapy and ultimately what we're going to talk about, which is immunotherapy.

00:42:04.740 But I think that's an important point that many people don't understand, which is how difficult

00:42:09.840 it is to thread the needle of chemotherapy. It's not the killing of cancer. That's hard. It's the

00:42:14.280 killing of cancer and not killing the non-cancer. The point you make is incredibly important

00:42:20.380 because it's the selective killing of cancer without killing normal cells, which is not the case for

00:42:27.660 virtually any chemotherapy or radiation therapy. Even in surgery, you have to remove some normal tissue.

00:42:32.700 And so it's that selectivity against the cancer that's so important. And in fact, that's almost

00:42:41.000 the perfect explanation for another reason that I think immunotherapy has potential importance because

00:42:48.060 of its immense selectivity and sensitivity of recognition. Can recognize single amino acid changes

00:42:56.600 in a protein in a protein and develop an immune response against it. Trivial differences that can

00:43:02.780 distinguish normal from tumor, or if you get a viral infection, destroy the virus in the respiratory

00:43:09.840 system without destroying the respiratory epithelium. It's the exquisite sensitivity and specificity of

00:43:16.680 the immune reaction that I think makes it such a seductively interesting approach to trying to develop

00:43:23.460 new cancer treatments. Let's take a moment and have people get a little bit deeper on how the immune

00:43:29.460 system works. I remember for me personally in medical school, it was one of the most interesting

00:43:36.000 sets of courses we took were the courses in immunology in particular, how T cells worked was

00:43:42.100 fascinating. It seemed to lend itself to a story almost and with generals and soldiers and all of these

00:43:49.680 things. So explain to people, let's maybe start with a virus as the example, because obviously in the

00:43:55.840 era of coronavirus, that's on everybody's mind. And we can talk about how the body defeats a virus,

00:44:01.980 but then pivot to then how in the case of cancer, that exact same immune system can accomplish what you

00:44:09.600 just said. So let's take viral infection as an example, whether it's a common cold or coronavirus.

00:44:15.180 The virus comes into the body and infects the respiratory epithelium in the pharynx and the

00:44:25.940 bronchi and the lung. And as that virus then infects those respiratory epithelium, the virus replicates

00:44:35.720 and the infected cells then express the viral proteins. The immune system has evolved to detect

00:44:43.820 proteins or other molecules that are not part of the normal self of the body. As the immune system

00:44:52.000 evolves, cells that can recognize foreign invaders get spared, whereas cells that can attack normal

00:45:01.320 tissue get eliminated in the thymus. And so except for autoimmune diseases, we don't have cells that can

00:45:08.300 recognize normal tissues. They've been eliminated in the evolution of our immune systems. So you have

00:45:16.160 lymphocytes, B cells that make antibodies, T cells that act directly by interacting with other tissues.

00:45:24.400 And so the immune system via antibodies or T cells recognizes viral protein that's now being expressed

00:45:32.420 by the respiratory cell. The lymphocytes are constantly patrolling the body. Every 14 or 15 seconds,

00:45:39.100 your heart's pumping out these lymphocytes that are circulating through the vascular system,

00:45:44.660 sometimes extravasating into tissues, coming back into the lymphoid system and returning to the heart

00:45:49.840 via the thoracic duct. Well, when the lymphocyte encounters a foreign antigen to which it can have

00:45:56.920 reactivity, that's not self. And define an antigen for folks. Tell people what an antigen is. How long

00:46:03.000 is it? What's it made of? So an antigen is a molecule in the body that is not normally being expressed

00:46:10.000 in the body by tissues. They're generally proteins, but they can be carbohydrates. And what makes that

00:46:17.380 molecule an antigen is its ability to be recognized by a T lymphocyte or a B lymphocyte. That is a T

00:46:25.300 lymphocyte that can directly recognize an infected cell or a B lymphocyte that can make antibodies

00:46:30.360 against it, plasma cells. And so if a molecule is recognized as foreign, the immune system can

00:46:37.360 recognize that antigen. Well, lymphocytes are patrolling the body. They encounter this viral

00:46:43.720 antigen in the respiratory epithelium. They stop at that location, and you can visualize this in mouth

00:46:48.920 ears with something called two-fotile microscopy. They stop at that location, and you can see them

00:46:54.640 extravasate into the tissue. When they're there, they then begin to divide. As they divide, the

00:47:01.940 dividing cells can further recognize the viral protein and starts making molecules that can

00:47:07.780 destroy the infected cells, but also call other cells into that arena, macrophages, neutrophils,

00:47:14.160 and so on. And that's what an immune reaction is. As the antigen is eliminated by these mechanisms,

00:47:21.000 lymphocytes, other cells. There's no reason for those cells to stay around anymore. They're not

00:47:26.100 stimulated. They enter the circulation. But now you have patrolling the body for the rest of your life,

00:47:31.740 long-lived lymphocytes that can recognize those foreign molecules. And that's why when you get

00:47:37.540 immunized against smallpox, you have that immunization for the rest of your life, and hopefully

00:47:41.860 for coronavirus, although we don't know that, we don't know the extent to which those cells survive.

00:47:46.320 Now, at the outset, you said there are two things about cancer that make it different from self. It

00:47:53.140 has these two properties that individually wouldn't be the end of the world, but when you combine them,

00:47:59.300 they're devastating. It's this failure to respond to cell cycle signaling, which results in unregulated

00:48:05.660 growth. And it's this capacity to leave the site of origin and grow in an unregulated manner

00:48:12.240 elsewhere. And you also mentioned that this is the result of, although you didn't use the word,

00:48:18.600 somatic mutations. And we can clarify for people, these aren't typically mutations that people are

00:48:23.960 born with, although in diseases like Lynch syndrome, that might be the case, that it leads to that. But

00:48:29.300 these are acquired mutations. So the natural question would be, why is it that a cell that has these

00:48:38.400 acquired mutations that clearly produce a phenotype that is different from self, why wouldn't that be

00:48:45.920 foreign enough for the immune system to act? In other words, why does cancer even exist in the first

00:48:52.500 place? Why doesn't it get squashed out in its infancy? These mutations, these changes in DNA that are

00:49:00.660 random events as the cell is dividing, can produce proteins that can be recognized or other molecules

00:49:09.640 recognized by the immune system. And they do it in complex ways by breaking down small molecule peptides

00:49:16.080 and putting it on the cell surface. But the immune system can recognize these mutations. And it's only

00:49:23.860 been in the last, I'd say, three or four years that we now recognize these mutations as commonly

00:49:34.500 recognized by the immune system. And about 80% of patients with the common epithelial cancers, it turns

00:49:41.060 out, as a result of the research done in recent years, do exist and can recognize the products of the

00:49:48.420 mutations. But the immune system against them is too small, it's not vigorous enough. What does that

00:49:55.860 mean? Create enough cells, create receptors that have a high enough avidity for recognition to the tumor.

00:50:02.840 The immune reaction is not very strong. And the growth of the tumor can overcome the small impact that an

00:50:10.820 immune reaction might have in killing some tumor cells. Plus, for a tumor cell to survive and grow,

00:50:17.660 it develops certain properties that can suppress the local immune reaction. It can make molecules like

00:50:26.560 transforming growth factor beta, TGF beta. It can make cytokines like interleukin-10. It can cause

00:50:34.520 the development of cells, lymphocytes that inhibit immune reactions. I mean, virtually every physiologic

00:50:43.100 system in the body has stimulatory elements and inhibitory elements. You have hormones that can

00:50:50.540 increase gastric secretion, some that can decrease it. You have a sympathetic nervous system, a

00:50:55.440 parasympathetic nervous system. Well, the immune system is the same. It has effector cells that can

00:51:01.340 be very aggressive in recognizing antigens, and it has regulatory T cells that deliberately suppress

00:51:08.420 immune reactions. And that's one of the things that keeps us from developing autoimmune disease.

00:51:13.500 But there are many of these regulatory elements. Recently described, myeloid-derived suppressor cells

00:51:19.220 can suppress immune reactions. And so it's the balance of the aggressive immune reaction against

00:51:25.700 the inhibitory molecules that can prevent that immune reaction that is the holy grail of trying to

00:51:34.180 find effective treatments. And effective treatments come in both directions. Interleukin-2 stimulates

00:51:39.920 immune reactions. And we now have checkpoint modulators like ipilimumab or PD-1 inhibitors

00:51:46.520 that can inhibit these inhibitory factors and thereby stimulate the immune reaction by taking away the

00:51:53.460 brakes on the immune system. So the more we understand, the more we can take advantage of the biology.

00:51:59.000 So let's go back to the first of those, because that seems to have been the first big break you got

00:52:04.860 at NCI after Gallo's discovery was interleukin-2. So now you had both a cytokine that could allow you

00:52:13.360 to grow lymphocytes in vitro, but also something that could be given to patients in vivo to stimulate

00:52:20.640 the immune system. So how did that sort of propel your work? Well, with the advent of interleukin-2,

00:52:28.340 what had been shown was that there were some bone marrow cells could make a substance which would

00:52:35.660 keep lymphocytes alive outside the body. But the minute I heard about that, there were a series of

00:52:42.400 questions that arose. Well, if it kept lymphocytes alive, would it keep lymphocytes alive and dividing

00:52:49.520 in a format that enabled them to have all of their immune recognition? That is, as they grew,

00:52:57.280 would they just lose that property? And so we try to demonstrate that by developing cells that could

00:53:03.780 recognize what we call alloantigens, that is very strong antigens that are present in one person

00:53:08.940 that inhibit the ability to transplant organs, for example. And so our initial studies were to see

00:53:15.780 whether or not we could develop lymphocytes, grow them in culture, and cause experimental skin grafts in

00:53:24.500 mice to disappear faster. We're not talking about tumor, that's normal tissue. And we showed that,

00:53:29.640 in fact, we could grow lymphocytes that retain their function in the laboratory and then retain

00:53:34.240 their function in vivo. Well, with that knowledge, we didn't want to cause skin grafts to disappear more

00:53:42.060 quickly. With that knowledge, we had to try to develop cells that could react against the cancer.

00:53:47.320 And very early on, when we grew cells in interleukin-2, we found that, in fact, they could

00:53:53.800 destroy tissue-cultured cancer cells, have some impact on normal cultured cells as well,

00:54:00.700 just by virtue of exposure to interleukin-2. And we call them LAC cells, lymphocytes activated killer

00:54:06.760 cells. And we studied them for three or four years. Turned out to be a false alarm because they could

00:54:12.380 impact on tiny little tumors in mice before they became vascularized. But by the time they were

00:54:17.840 vascularized, they would not work in mice at all. But interleukin-2 seemed like a molecule that might

00:54:25.960 be able to stimulate those rare cells in the body that could recognize the cancer as foreign or develop

00:54:32.160 cells in the laboratory that could do that recognition. And that then led us to many years

00:54:37.500 of experiments in the laboratory, but also clinical trials trying to see whether or not either interleukin-2

00:54:45.120 administration alone or cells that you could devise in vitro that could recognize the tumor and

00:54:51.060 administer those. And that was a very frustrating time. It wasn't until 1984 that we finally figured

00:55:01.120 out a way to use interleukin-2 to mediate regression. We treated over 70 patients with either interleukin-2

00:55:09.460 or cells that we grew in interleukin-2 and administered to patients without seeing a response

00:55:16.140 until we modified the schedule of interleukin-2 administration, knowing it's pharmacokinetics

00:55:23.540 that is only after half-life inside the body of about seven minutes. So we had to alter the schedule.

00:55:29.240 We had to give higher and higher doses, which mediated toxicity, until finally a patient that

00:55:35.200 we treated in 1984 who had widespread melanoma, was administered interleukin-2, and was the first

00:55:41.820 patient finally, after over 70 other patients, to show us a tumor regression. The first time that a

00:55:50.100 deliberate immunologic maneuver could reproducibly cause cancer regression. It was one of the few eureka

00:55:56.620 moments that I've had in doing research, but the realization finally that after all of those

00:56:01.400 patient deaths, everybody had advanced cancer or would go on to die of their cancer, survived in that

00:56:08.540 patient, now alive over 35 years later, free of disease. You know, it reminds me a lot of

00:56:15.500 the Thomas Darzel's work in the 1960s with liver transplantation, where the number of patients who died,

00:56:23.500 it was hard to keep track of before finally achieving the technical success that was necessary.

00:56:31.560 Both the perioperative care and the postoperative care and the technical skill necessary, plus the

00:56:37.420 immunosuppressive regimen, all of those four things had to be firing on all cylinders for patients to

00:56:42.540 finally undergo liver transplantation. And this patient in 1984, if I recall, was the 67th patient

00:56:51.420 treated, meaning 67 consecutive patients died of metastatic cancer and were unresponsive to

00:56:59.700 interleukin-2. The first question is really just a logistics question. How many different histologies

00:57:05.280 were in that group? How many different types of cancers were you treating at that time?

00:57:09.720 We were treating all cancers, metastatic cancers, with the idea that although they each arose from

00:57:16.240 different organs, had somewhat different properties and methods of spread, they would be commonalities

00:57:20.500 that could be attacked. And so we were treating all kinds of histologies. It was the first patient

00:57:28.400 that we treated with this revised regimen happened to have a melanoma. The third and fourth patients

00:57:33.760 had renal cancer. And as we continued to use interleukin-2, we found that those two histologies,

00:57:39.980 patients with those two histologic types of cancer could respond. And ultimately, response rates in those

00:57:45.680 two diseases turned out to be about 15% to 20% of patients, with about a third of those patients having

00:57:51.360 complete durable, durable regressions. But it was a little different than the liver transplant

00:57:57.480 situation. Because in that situation, there were technical problems that had to be overcome. And it was

00:58:04.460 a genius of Tom Starzl to stick with it and to figure out those technical problems. When it came to

00:58:10.400 immunotherapy for cancer, it was a little different. We didn't know that it would ever work. We didn't

00:58:17.040 know that there was ever going to be an immune system that could cause the cancer to disappear.

00:58:22.560 In contrast to, if, well, you could work the technical problems out, if so, the vessels together,

00:58:26.880 you could get this thing to work. And so that first patient had an enormous impact on me and on the

00:58:33.480 field because it showed that it was possible. And until you know it's possible, you never know that

00:58:40.040 it's ever going to occur. And so that changed everything because it showed that simply

00:58:46.760 administering this one molecule, a T-cell growth factor, could cause a cancer regression in a patient.

00:58:53.960 And that then led us to studies to understand how that was occurring. And that then led to a lot of

00:58:59.100 different directions, cell transfer, gene modification, and so on.

00:59:03.600 How did you keep going in the face of all of those failures up until this patient's miraculous

00:59:14.440 remission in 1984? Because again, if you were working as a surgical oncologist at the time,

00:59:22.020 you would not have been exposed to that death. The surgical oncologist's work would have been done

00:59:28.380 after the primary resection. Typically, the medical oncologist would be the one that would be

00:59:33.260 at that patient's bedside as they progress through treatment. But you were seeing something that you

00:59:40.240 would not have seen had you chose a different arc to your surgical career. And I just, I wonder how

00:59:46.620 you coped with that. What were those drives home? You know, what was it like to be alone in your

00:59:50.880 thoughts? Well, you know, as I look back on it, it seems remarkable that there were so many patients,

00:59:57.160 one after another. Everyone died eventually of their cancer because we did not have any impact in

01:00:03.200 the manipulations that we're applying. And, you know, you're a doctor and you know that it's not

01:00:09.120 the patients that do well that you remember. It's the patients that you fail to help that you

01:00:15.040 remember. And it was just a remarkable number of tragedies, young people dying of cancer, people of

01:00:21.760 all ages. But I had this intuition based on everything I knew about biology and everything

01:00:29.680 I had studied in biophysics. I had an intuition and also influenced by these inklings of the first

01:00:37.780 two patients I mentioned that this would work. You know, I recently saw a quote by Abraham Lincoln

01:00:45.220 that said, success consists of moving from failure to failure without loss of enthusiasm.

01:00:57.360 And that actually happened to me. I actually just saw that quote a few months ago. But I always felt it

01:01:04.700 was going to work. And it did eventually. And a small number of patients, still a long way to go.

01:01:12.300 But at least now we have effective immunotherapies for a variety of diseases that can be effective.

01:01:17.900 And when that first patient responded, it all exploded in my brain. It does work. This can work.

01:01:24.720 And we'll figure out now ways to make it better.

01:01:28.280 And I imagine Alice was a big part of that support for you. Again, I know I have the privilege of knowing

01:01:35.100 her and knowing how important she is. Do you think you could have got through this alone without

01:01:40.300 the support of your family? I mean, you had to do this very difficult thing, which was

01:01:45.400 basically have this remarkable obligation to your family, which every father does.

01:01:50.620 And at the same time, you felt like you were carrying the weight of the world on your shoulders

01:01:55.680 trying to take care of these patients who were otherwise really left with no hope. Do you see

01:02:00.780 that as sort of a synergy between those two?

01:02:04.560 There were probably, and I'm not exaggerating, 40 days in the first 40 years of my work here

01:02:12.300 that I was in town, not traveling, that I was not in this hospital.

01:02:20.100 I would come in every day, of course. I would come in every Saturday, Sundays. I would come in to

01:02:25.480 go over research with some of the fellows. You probably remember that or see some patients.

01:02:31.640 And that kind of life requires support of some kind. And there are not a lot of

01:02:39.720 wives who I think would tolerate that kind of commitment outside the home. 1.00

01:02:46.660 And Alice was such a person. Never hassled me about it. Always understood that. I remember once

01:02:54.740 she said, look, I know what you're doing is important. And so what I'm going to do as much

01:02:59.420 as I can is relieve you of the burdens that we commonly face as part of daily living. She handles,

01:03:05.500 I haven't written a check in 20 years. Alice pays our bills and really takes care of so much that

01:03:11.280 enabled me to work at that level. But it was a family thing. I have three daughters who are growing up

01:03:16.620 as all of this was happening. And I remember when my oldest daughter applied, my first daughter

01:03:21.380 applied to college, Beth, she opened her college essay with a sentence somewhat along the lines of,

01:03:28.440 at our dinner table at home, we're much more likely to be talking about cancer and AIDS

01:03:34.640 than the Washington Redskins. And it made me understand how much the kids had been affected by

01:03:42.300 all of this talk of death and suffering from these diseases. So it takes a family. And I doubt I

01:03:49.640 could have done it without that kind of support. So once you identified this patient, patient number

01:03:56.440 67, did you have an inkling what it was about melanoma and renal cell cancer that made them

01:04:03.800 particularly immunogenic relative to this whole host of other epithelial cancers that were less reactive?

01:04:11.400 The answer is no. But the answer would be yes, 35 years later. But I think now we do understand

01:04:21.180 what's different about melanoma. But we didn't at the time. We were seeing responses to interleukin-2

01:04:27.500 in patients with melanoma and kidney cancer. But no other diseases would respond to interleukin-2. And

01:04:33.300 we learned that the hard way, treating over 600 patients with interleukin-2 here at the clinical

01:04:38.560 center, it turns out those two diseases were uniquely responsive. And we now know, at least

01:04:45.760 for melanoma, why that's the case. And that is the immune system is recognizing the products of

01:04:52.740 mutations. And melanoma, if one looks at the number of the frequency of mutations among different cancer

01:05:00.400 types, melanoma has more mutations than any other cancer type, with the exception of lung cancer.

01:05:07.600 They're about equivalent, about 400 mutations per tumor as a median. And that's very likely because

01:05:14.120 melanoma, induced by a carcinogen, ultraviolet light, lung cancer by the carcinogens largely in

01:05:21.680 cigarette smoke or the environment, that leads to an increased number of mutations. And that,

01:05:26.880 at least, is part of the answer. And that is, the more mutations you have in the cancer,

01:05:32.240 the more likelihood that you'll develop a particular protein, foreign protein, that can

01:05:37.680 be recognized by the immune system. Did you ever see patients with Lynch syndrome response? They

01:05:42.900 would typically have many mutations as well, wouldn't they? You're exactly right. So there are some

01:05:46.660 situations like the microsatellite unstable cancers, colon cancer, other kinds of cancer types,

01:05:54.140 Lynch syndrome. But we didn't understand that it was mutations that were involved at that point.

01:06:00.280 And I don't remember ever treating a patient with Lynch syndrome. You're right. They would have

01:06:03.700 a very large number of mutations. So for comparison, if we talk about a standard,

01:06:11.400 you can't even use the word standard. There's no such thing as a standard cancer, right? Now we know so

01:06:15.400 much about cancer that every cancer is different. But what would be the median number of mutations in a

01:06:21.720 metastatic breast cancer, colon cancer, or pancreatic cancer?

01:06:25.860 You would probably encompass 80% of these common cancers if you considered mutation frequency between

01:06:33.720 60 to 70 and 150. That would be the major. The median would probably be somewhere about 110,

01:06:43.060 but it would vary from cancer type to a cancer type. Some pediatric cancers have very few mutations.

01:06:48.520 Some cancers have more, but about, I'd say the median would be very likely to be about 110.

01:06:56.860 How many of those mutations would be driver mutations? So they are oncogenes, tumor suppressor

01:07:03.920 genes. They are playing a functional role in the cancer versus what we might call passenger mutations

01:07:10.260 that can still produce antigens. They would still generate a peptide that could be recognized by MHC,

01:07:16.920 but they're not playing a functional role in those two properties of cancer that we spoke about.

01:07:23.260 So about six years ago, we described an assay that would enable us to actually identify the exact

01:07:30.680 molecular nature of these antigens that are recognized by T cells. And that came from, again,

01:07:39.040 the understanding that it was the products of these unique cancer mutations that were being

01:07:45.100 recognized by the immune system. Well, it turns out that some of these antigens that are recognized

01:07:51.440 by T cells are recognizing the proteins that derive from driver mutations, that is, that cause the

01:07:58.540 cancer in the first place, like P53, present in half of all cancers, but only about 2% of patients

01:08:06.000 develop immune reactions against it. KRAS, about 90% of pancreatic cancers will have that as a driver

01:08:12.980 mutation. But what's stunning to me about oncology and the biology of cancer, and that is how few

01:08:20.360 of these shared cancer mutations exist. There's P53, there's KRAS, to some extent PIK3CA in breast cancer,

01:08:30.960 maybe BRAF mutations in melanoma. Other than that, the incidence of driver mutations as a cause of cancer

01:08:38.960 is low single digits. You'd think there would be many mutations that would change the cell so

01:08:45.340 dramatically. But it turns out it's not only those few driver mutations, but the accumulation of

01:08:52.900 mutations, each with its own property that in and of itself appears unlikely to cause cancer. But in

01:08:59.000 concert with the action of other genes, other mutations does cause a cancer. And we've, you know,

01:09:05.300 more recently shown in a breast cancer patient that we published a few years ago, that we could

01:09:10.900 mediate complete durable regression, now over six years later, by targeting four what appeared to be

01:09:16.980 random somatic mutations, none of which had a driver function, but in concert caused the cancer. And by

01:09:23.980 attacking them, you could cause cancers to disappear. I mean, I still, I'm struggling to understand

01:09:30.960 why it is that a P53 mutation or a KRAS mutation is not immunogenic. Is that simply due to the evolution

01:09:39.680 of cancer, that because of the ubiquity of these mutations in cancer, cancer has come up with enough

01:09:46.520 evolutionary tricks to evade detection of those mutations? I mean, that's a teleologic question,

01:09:53.280 but I mean, do we have any biologic insight into this?

01:09:55.820 So you have to get a, have to dig a little deeper into the biology. For a mutation gives rise to a

01:10:04.700 molecule, a protein, right? It's DNA, RNA transcribed, translated into a protein. For that protein, even

01:10:12.940 though it has now a mutation, a string of amino acids that are not seen as normal by the body,

01:10:18.860 that mutation, that abnormal amino acid called a non-synonymous mutation is only recognized by

01:10:26.540 the immune system. If the molecule in which it occurs is broken down inside the cell into small

01:10:34.540 peptides, that is small sequences of amino acids, or the tumor cell or the antigen presenting cell takes

01:10:42.860 an antigen, a protein from the outside of the cell into the cell and breaks it into small peptides,

01:10:49.740 strings of amino acids. Well, that has to happen. And then one of those strings of amino acids

01:10:55.820 has to fit onto the surface of the patient's own HLA molecule. That is the kind of molecules that we call

01:11:04.260 transplantation molecules. And so for a mutation to be recognized by the immune system, it has to be

01:11:11.620 broken into these 9 to 11 amino acid peptides and fit on that patient's own transplantation molecule.

01:11:20.020 And that transplantation molecule is highly polymorphic. There are hundreds of them.

01:11:25.460 And so if you had a mutation and your cells made small peptides, but it didn't fit on your HLA molecule,

01:11:34.440 it wouldn't be recognized by the immune system. And so as we've learned more in the last five to six

01:11:40.980 years about what cancer antigens are, it's these mutations that are broken down and put on the

01:11:49.140 surface of a patient's presenting cells or tumor cells. And that turns out to be

01:11:57.700 between one and a half and 2% of all mutations. And when you look at melanoma, it's 1.3%.

01:12:04.740 When you look at the gastrointestinal cancers, 1.6%. Breast cancer, 2.1% of mutations are immunogenic

01:12:14.180 because they happen to fit into that individual patient's HLA molecule. And the most stunning finding

01:12:21.860 of recent years, in my view, in this field is that virtually every patient recognizes a unique

01:12:31.860 antigen. And so we're in the process of writing a paper now on 195 consecutive patients that we've

01:12:40.980 identified the exact antigenic nature of what the T cell can recognize. And it can recognize in about

01:12:47.780 80% of all histologies. And that turned out to be 363 individual antigens that were recognized in these

01:12:56.480 995 patients. And no two patients shared the exact same antigen, with the exception of two patients

01:13:06.640 that had a KRAS mutation that was recognized on a very rare class 1 molecule, CW0802 HLA molecule.

01:13:15.360 So just to make sure I understand that, you're saying that in this series of nearly 200 patients,

01:13:23.760 the first interesting finding is each of them produces at least one neoantigen that is immunogenic.

01:13:32.480 80% of patients will, yes.

01:13:34.480 Okay, 80%. And secondly, outside of the KRAS overlap, they were novel across the board.

01:13:43.360 That's right. Of those 393 antigens, 392 of them were unique, not shared by any patients with the

01:13:54.000 exception of KRAS. That's not to say that P53 or other driver genes can't recognize it, but they

01:14:02.480 don't naturally recognize it. You might be able to raise those very rare cells, but that's correct.

01:14:09.120 It's good news and it's bad news. Explain why that is to people, because I was just about to say,

01:14:15.440 that's really good and creates a huge problem for scale.

01:14:19.040 You got it. That's exactly right. It's good news because we finally understand after all of these

01:14:26.400 decades what a cancer antigen is. Back in 1985, I knew one existed. I didn't know what it was,

01:14:32.960 whether it would be shared. And we spent an enormous amount of time trying to identify shared antigens,

01:14:38.880 especially in melanoma, these melanocyte antigens shared by normal pigment-producing cells.

01:14:43.920 But now that we understand what an antigen is, and we understand that most cancers contain multiple

01:14:53.840 mutations, which give rise to the antigens, well, since almost all cancers have mutations,

01:15:01.520 if we can figure out ways to target these mutations that are foreign, we potentially have a treatment

01:15:08.720 applicable to all cancer histologies. Since almost all cancers have mutations, let's recognize them.

01:15:14.560 And now you don't have to worry whether it's a breast cancer or a colon cancer or a brain tumor.

01:15:20.880 The T cells are there. So the possibilities of developing broadly applicable treatments exist.

01:15:28.640 The bad news is, as you point out, it's going to have to be, as you target these mutations, highly individualized treatments.

01:15:39.760 Unless you can fully unleash the immune system against even the most minor of antigens, which we can't do now,

01:15:46.000 checkpoint modulators have virtually no impact on the overwhelming majority of the solid epithelial cancers.

01:15:51.520 It means that if you're going to stimulate immune reactions via a vaccine or a T cell as a drug,

01:15:59.280 it has to be individualized to target that cancer, because that antigen is present only in that patient,

01:16:07.520 but not in any other patient. And that's going to make it very complex to develop. But when we

01:16:14.880 developed this other form of T cells, CAR T cells, a whole other story, people said that it could never be

01:16:20.640 applied. But in fact, if you have something that works and can cure people, the genius of modern

01:16:26.080 industry will figure out ways to make it available. Well, I wanted to go back to 1985 to pick up the

01:16:31.680 story with both Ronald Reagan and Tittle, unrelated, but temporally related. But before we do, because

01:16:37.440 you brought up CAR T cells, let's, let's tell the story about the diffuse B cell lymphomas that

01:16:43.520 ultimately led to kite, because it's a great way to, I think most people listening to this will have heard of

01:16:48.080 a CAR T. This is an illustrative case to explain how they came about, how they differ, of course,

01:16:54.000 from a regular T cell receptor. And as you said, how industry basically came in to solve a problem

01:17:00.960 that at the outset looked pretty daunting. So pick it up wherever it makes sense with respect.

01:17:06.000 So again, you have to understand the biology. You have to go back to the biology that normal T cells have

01:17:11.360 receptors that can recognize antigens on the surface of a cancer cell, right? These tiny peptides that

01:17:17.600 are put on the surface. Those alpha beta chains are expressed by a lymphocyte and that's how the

01:17:24.960 immune system recognizes antigens. Well, there's a way to create an alternate way for a lymphocyte to

01:17:31.440 recognize an antigen that was created by some scientists at the Weizmann Institute about 10 or 12

01:17:36.080 years ago, Zelegashar and Gideon Gross. They took advantage of antibody recognition. Now,

01:17:42.960 antibody recognition is very different than that of T cell recognition. Antibodies recognize the

01:17:49.440 three-dimensional structure of a molecule on the surface of a cancer cell or of any cell. Not a

01:17:56.320 processed peptide brought to the surface, but an actual molecule on the surface. And that antibody,

01:18:01.760 like a lock and a key, will latch onto that antigen and recognize it. Well, T cells can't do that, but

01:18:11.200 by creating a chimeric T cell, you put antibody recognition domains into a lymphocyte that converts

01:18:19.520 the lymphocyte from its normal recognition, from its own receptor, into the recognition of this antibody

01:18:26.640 that you've put into the lymphocyte. And that expands the number of molecules that can be recognized by

01:18:34.080 T cells. And so it's this chimeric antigen receptor, which is part receptor, normal receptor,

01:18:42.160 but with antibodies attached to it that enables the lymphocyte to recognize now molecules that it never was

01:18:48.880 able to recognize in the course of evolution based on antibody recognition. And it turns out

01:18:55.680 that there are very few molecules on the cell surface, very few, like I could name the few I know

01:19:02.480 of in the fingers of one hand, that are unique to a cancer that are not on normal cells. And we learned

01:19:11.600 the hard way that the immune system will destroy a normal cell just as quickly as it will a cancer cell.

01:19:18.240 And we've mediated cancer deaths by targeting antigens that are present even in very low levels on

01:19:25.200 normal cells. Well, it turns out there's a molecule on B lymphocytes called CD19. We don't exactly know

01:19:32.880 what its function is, but when B cells turn into lymphomas and leukemias, they continue to express CD19.

01:19:40.400 And so with this understanding, and as soon as I heard about these chimeric T cells,

01:19:48.000 I invited Zelig Eshar to come to a sabbatical in my lab. He came the next day, the next year,

01:19:53.360 and spent three years working in the surgery branch. And we worked out ways to use CAR T cells to attack

01:19:59.280 cancers, but we could never get them to disappear because the molecules that we were giving could not

01:20:04.480 be used in large enough in numbers because of their ability to recognize normal. Well, CD19 expressed

01:20:11.440 by leukemias and lymphomas, they developed from normal B cells, expressed CD19. And we developed a

01:20:21.600 technique to introduce these anti-CD19 CAR molecules, chimeric antigen receptors, into T cells to create a CAR

01:20:30.400 T cell that when we administered to patients would kill every cell in the body that expressed CD19.

01:20:36.960 So all the normal B cells were eliminated, but so too were lymphomas and leukemias. And that became the

01:20:47.440 first actual cell and gene therapy ever approved by the FDA. So how did that happen? Well, we studied the

01:20:55.120 ability of these anti-CD19 CAR T cells to kill cells in experimental animals, and they did. They wiped out

01:21:02.000 normal B cells, but you can live without normal B cells. Of course, you can give antibodies by giving antibody

01:21:08.240 infusions. We used these CAR T cells to treat the first patient ever to receive a CAR T cell. This was in 2009.

01:21:19.440 This was a patient that had a lymphoma that had spread throughout its chest. It had been through four different

01:21:24.640 chemotherapy regimens. It had enormous kilogram tumor burdens in its body. We treated with

01:21:31.680 CAR T cells that could recognize a CD19 molecule on the surface of normal B cells and tumor,

01:21:38.240 and all this tumor disappeared. And he's, well, we treated him in 2009. He's 12 years later and

01:21:44.880 completely disease-free. We published a series of those

01:21:49.200 over the course of the next two years. And we had seven or eight patients who had a complete

01:21:56.080 disappearance of all of their lymphoma. Diffuse large B cell lymphoma is the most aggressive form

01:22:01.680 of and lethal form of lymphomas that people develop. And they developed complete regressions that were

01:22:08.720 ongoing for at least seemed like several years. Well, once we did this, and incidentally, all the

01:22:16.000 patients' normal B cells disappeared. But again, you can live without B cells.

01:22:22.400 And so in 2011, two years later, after we had published several of these papers, and a year

01:22:28.400 after we published that work, Carl June at the University of Pennsylvania used these CD19 CAR T cells

01:22:34.080 to treat leukemia patients. And so two years after our description of multiple lymphoma patients undergoing a

01:22:41.200 complete regression, I was contacted by a former fellow named Ari Belderan, who had worked in my

01:22:46.400 lab 25 years earlier. He was just finished his urology training, became a professor of urology at UCLA.

01:22:55.040 And he, we had become friends. And he came to see me in 2011 saying, hey, you're treating patients with

01:23:02.800 these T cells, these chimeric T cells, these CAR T cells, and successfully treating

01:23:10.240 lymphoma patients. I want to commercialize this. I want to start a company to do this.

01:23:15.680 And we had had several companies come through, like Johnson & Johnson brought in 12 people,

01:23:20.000 examined everything we had done, said, hey, if we have a lymphoma, we'll come back and get treated by

01:23:24.800 you. But we don't see how we can make any money doing this at Johnson & Johnson. Well,

01:23:28.320 Ari Belderan had a different vision. He said, we can figure out a way to make this available.

01:23:33.280 And in 2012, we formed what's called a CRADA, Cooperative Research and Development Agreement,

01:23:39.120 that enabled us in the lab to work with this company. This biotech company started Kite Pharma.

01:23:45.200 They were able to give us funds to help support the research. And so we started that in 2012.

01:23:52.160 We signed the CRADA. We worked together. We treated over 50 patients, showed that this

01:23:58.080 could happen in over half of patients will undergo durable regressions. He then did a

01:24:05.040 multi-institutional study. And Novartis was doing this in leukemia patients almost simultaneously.

01:24:10.560 His multi-institutional study reproduced the results exactly about a 70% objective response

01:24:17.200 rate with 50% durable complete regressions. And in 2017, five years after Kite started working

01:24:26.240 with us on this, Kite was sold to Gilead for $11.9 billion. And that all happened in the course

01:24:35.120 of those five years. And that treatment is now available thanks to Kite and Novartis,

01:24:40.240 available for use in patients in the United States and Europe and parts of Asia,

01:24:45.680 that can effectively treat these B cell lymphomas and leukemias. So really a pretty incredible story

01:24:55.600 that evolved so rapidly. Yeah, it is. I mean, do you think that CAR T cells can have efficacy against

01:25:05.440 non-hematologic cancers? Right now, the answer is no. We have no way to use them against solid

01:25:13.360 cancers. Again, because the solid cancers, to be treated with a CAR T cell, you have to have a

01:25:18.400 molecule on the cell surface that's unique to cancer. We originally didn't fully realize quite

01:25:25.520 how sensitive they could be. And when we targeted molecules that were on normal cells, patients died,

01:25:31.360 devastating events in the development of the treatment. But monoclonal antibodies were first

01:25:38.320 described about 45 years ago. And no one has found unique monoclonal antibodies against molecules

01:25:48.960 uniquely on cancer cells and not normal cells. And that's what you need to make a chimeric T cell

01:25:55.520 receptor. You need an antibody that you can put into a lymphocyte that has specificity. And antibodies

01:26:03.280 just have not evolved to recognize individual cell surface molecules on cancer, which are shared by

01:26:08.880 normal cells. Whereas conventional T cells do, because internal proteins then get digested and

01:26:15.280 brought onto the surface. So right now, there's very little prospect for CAR T cells being useful

01:26:21.440 for the treatment of solid tumors. But that's not to say that some brilliant ideas will come forth in the

01:26:28.000 years to come that will make them available. Right now, they're not useful.

01:26:31.360 Now, what about for organs that are not essential? So where you could waive the need to recognize or

01:26:39.040 differentiate between cancer and non-cancer? So for example, breast or even pancreas. I mean,

01:26:43.840 if a person had metastatic pancreatic cancer and you were willing to completely lose both normal and

01:26:49.040 non-normal pancreatic cells and render that person a type one diabetic, it would still be worth it. So are there

01:26:55.280 any antigens that are present on exclusively pancreas or exclusively breast or colon? Obviously,

01:27:02.400 this wouldn't work for liver and lung, but is that a slightly easier problem to solve or is it just as

01:27:07.600 hard? Well, it's just as hard because for the past 45 years, some of the best immunologists in the world

01:27:12.880 have tried to develop these monoclonal antibodies that can uniquely recognize cancer and they have not

01:27:18.160 found any. Either, of course, they haven't done it right or there just aren't these molecules on the

01:27:23.680 cell surface. And even very recently, last several months, you probably heard about this T-immunity,

01:27:30.640 these two deaths for patients that were targeting what was thought to be a prostate-specific molecule,

01:27:35.360 PSMA, but it's not. It was present on normal cells and that can result in death of patients. And so,

01:27:44.960 yes, if you could find a molecule unique to prostate cancer, breast cancer, that is expendable organs,

01:27:51.200 you could develop more effective cell-based therapies against them. But right now,

01:27:57.440 none of those molecules have been identified. So let's now go back in time to

01:28:02.640 post the IL-2 insight. You have this other amazing realization, which is there are certain types of

01:28:11.920 lymphocytes that manage to track to tumors, these T-cells that infiltrate the tumor, and they're called

01:28:18.720 TIL. How did you come to understand these and understand the efficiency with which they could

01:28:24.160 identify tumors? So things seem to move very slowly, although we had an explosion of ideas. But looking

01:28:31.760 back on it, when it comes to scientific advance, it actually moved along pretty quickly. Because IL-2,

01:28:39.440 as a T-cell growth factor, was mediating reproducible regressions, it seemed reasonable

01:28:44.240 that it is being mediated by the ability of interleukin-2 to stimulate lymphocytes in vivo.

01:28:50.720 And so, in melanoma patients, we looked for T-cells that could recognize the tumor

01:28:57.120 deposit itself. We didn't know what it was recognizing. And what better place intuitively

01:29:02.480 to look for a cell doing battle against the cancer than within the cancer stroma itself.

01:29:07.520 And so we grew those cells, one out of peripheral blood, but we also grew cells invading into tumor,

01:29:13.920 called tumor-infiltrating lymphocytes, or TIL cells. We grew them in vitro.

01:29:19.680 And in animal, and then very quickly in human experiments, grew those lymphocytes to large

01:29:27.040 numbers in vitro and administered them to patients with metastatic melanoma. And now,

01:29:35.280 instead of the 15% response rate that we got from giving interleukin-2 alone, by giving lymphocytes

01:29:42.560 that we grew in interleukin-2, these TIL cells, we got response rates 30-35% in melanoma patients.

01:29:51.200 And so it represented a substantial improvement, but they were pretty short durations. They were real,

01:29:56.560 but they did not appear to be durable. But it was the first demonstration that lymphocyte transfer,

01:30:04.400 as a sole modality, could cause tumor regression in patients with melanoma. And to some lesser extent,

01:30:12.400 kidney cancer was mediated by lymphocytes. So that intuition then became a reality of a biologic

01:30:20.800 finding. And that is, lymphocytes were the cause of these regressions, or could be the cause of

01:30:27.280 regressions. And then things moved along fairly, well, slowly and quickly, depending on your point

01:30:34.000 of view. It immediately became apparent that if we had these lymphocytes naturally, maybe we could

01:30:41.200 genetically modify them to be more potent. That is, if they were making factors that drew other cells

01:30:47.440 in, well, let's introduce that gene into them. But no one had ever introduced a gene into human cells.

01:30:54.400 And so I teamed up with two scientists at the NIH, French Anderson and Mike Blaze, who were trying to

01:31:00.800 develop gene therapies to replace adenosine deaminase deficiencies, a lethal deficiency

01:31:09.520 in young children, to see if they couldn't introduce those genes. But of course,

01:31:14.000 no genes had ever been introduced into people. We decided to see if we could break the ice about putting

01:31:21.600 foreign genes into humans by putting a marker gene into the lymphocytes we were administering to patients.

01:31:27.280 We picked the gene, a bacterial gene called neomycin phosphatransferase, inserted that gene into a

01:31:34.000 patient's normal lymphocytes. And our plan was to administer them so we could track where these

01:31:41.600 lymphocytes were going inside the body, because they would have this unique bacterial gene that were

01:31:46.160 being expressed. And so we proposed that to investigational review boards. At that point,

01:31:52.640 the government had established what's called the recombinant DNA advisory committee, the RAC,

01:31:58.160 adequately named, who had to review any clinical proposals. We went through, we tabulated one,

01:32:04.720 17 different review groups, having to go back and forth as they made changes until the RAC

01:32:10.240 finally voted. It was a painful time, 13 to 4, to allow us to do it. But the director of the NIH,

01:32:16.080 James Weingarten, insisted that before we would start tampering with the human genome, we needed

01:32:21.040 unanimous consent back and forth making changes. Finally, there was a vote of the RAC, 13 to nothing,

01:32:28.480 to zero with one abstention, which was unanimous. And so we got permission to proceed with the clinical

01:32:35.600 trial. Biotechnology activists and filed lawsuits against the NIH saying we shouldn't be tampering

01:32:41.120 with the human genome. It was immoral. It was ungodly. But we finally got permission to do it and

01:32:46.560 inserted these lymphocytes that were genetically modified with this bacterial gene that did enable

01:32:52.080 us to track the cells inside the body when we did biopsies. It was a paper we published in the

01:32:56.480 New England Journal of Medicine. And that then led to the gene modifications of lymphocytes that we

01:33:02.880 attempted to use to improve them. We put in the gene for interleukin-2. That didn't improve them

01:33:07.120 because we couldn't regulate it. But it just started our endeavors to genetically modified cells that 0.75

01:33:14.080 finally came to their fruition in the CAR T cells by inserting the genes that would insert these new

01:33:19.920 receptors that could recognize molecules on lymphomas and leukemias. So that started us on the track of

01:33:28.400 trying to improve the cells. And then there were a variety of advances. We learned that you had to first

01:33:34.480 wipe out all of these inhibitory T cells, regulatory cells, before you gave the administered cells.

01:33:40.960 And that then jumped the response rates up to 55% in melanoma patients, with about 25% being durable,

01:33:49.920 complete remissions. We then started developing ways to use T cells to do cancer treatment. And in 2013,

01:33:59.840 finally realizing that it was unique mutations, we developed techniques that

01:34:06.000 enabled us to develop T cells specifically targeting mutations and published the first

01:34:12.640 paper on that in 2014. It was a patient with a bile duct cancer, a cholangiocarcinoma,

01:34:19.280 that was widespread in the lungs and liver. We gave her bulk TIL cells did not work. We gave cells that 1.00

01:34:25.760 were uniquely directed against her mutations, and she's undergone a dramatic regression. It's now

01:34:32.320 disease-free. But those were TIL that were not genetically modified?

01:34:37.040 Those were the natural. So our work went in two directions, genetically modifying TIL

01:34:41.360 or figuring out ways to use natural TIL. And these were natural TIL that were selected for mutation

01:34:49.600 reactivity and given to a patient and whose natural immune system was temporarily eliminated.

01:34:56.160 And she's living disease-free now. Eight years later, all of her liver and lung disease is gone.

01:35:02.080 And we subsequently now have published on these T cells that recognize unique mutations in their

01:35:08.400 ability to cause regression in cervical cancer induced by human papillomavirus,

01:35:14.960 by colon cancer. That patient recognized KRAS. Breast cancer recognized four random somatic mutations.

01:35:23.600 We're now struggling to figure out ways to more efficiently target the products of unique

01:35:30.400 mutations that cause the cancer. Sort of ironic that the Achilles heel of the cancer is going to be the

01:35:35.840 very abnormalities that caused it in the first place. And so that brings us up to 2021. Can we now take

01:35:43.600 advantage of all this new biologic information about the role of mutations and T cells that target them,

01:35:50.640 about the ability to genetically modify cells in large numbers using retroviruses? Can we take

01:35:55.840 advantage of that technology, that biologic information to develop more effective immunotherapies

01:36:02.080 in the years to come? And that's what we're working on today. That's what we're working on in the lab

01:36:06.960 as we speak. Well, I want to go back a little bit and talk about a few other things, both for

01:36:11.680 posterity, I suppose, and also because I think there were some other things we've glossed over quickly.

01:36:15.920 But in 1985, you had this opportunity to operate on the then president of the United States who had

01:36:22.240 developed colon cancer. Why is it that you were a part of the team that would take care of the president?

01:36:28.080 Why is it that the chair of the National Cancer Institute would be involved in the president's care?

01:36:33.120 Is that something that's sort of mandated at the federal level?

01:36:37.360 No, it's part of the aberrancy involved in treating high government officials. It turns out

01:36:45.280 that there is a set of modules in Walter Reed or Bethesda Naval Hospital that are set aside for the

01:36:54.560 treatment of the president. It's an isolated set of rooms. I learned this as it happened. I didn't know

01:37:01.120 it ahead of time, where the kinds of equipment and availability of technologies was available so

01:37:07.200 the president could actually run the country from his hospital bed. But it turned out that

01:37:14.800 it was the physicians in this particular case at Bethesda Naval Hospital, and they have marvelous

01:37:19.760 doctors there, that would be treating the president. And it turned out that the chief of surgery at

01:37:27.280 Bethesda Naval Hospital had just rotated off an aircraft carrier to be the chief of surgery at

01:37:33.280 Bethesda Naval. It would change very commonly as officers in the Navy had different assignments.

01:37:40.400 And he happened to be an expert in vascular surgery, not oncology. And he was the one responsible for

01:37:47.280 calling the shots about the patient's cancer. And it turned out he was an excellent doctor,

01:37:51.920 an excellent vascular surgeon, but not an oncologist, never really was operating on cancer patients in

01:37:59.760 any volumes. And so they needed an expert in oncology to take part. And just out of the blue,

01:38:07.280 on one Friday evening, I got a call saying, will you come over to Bethesda Naval Hospital? We have

01:38:11.520 a patient we need your help with. And it turned out to be President Reagan. And it was simply because

01:38:15.920 I was nearby. I had previously gotten a security clearance because I had tentatively been assigned

01:38:23.840 to be part of a medical team that would take care of high government officials in the case of

01:38:28.400 calamitous nuclear emergencies. So it was because the vascular surgeon was in charge, and I was across

01:38:36.960 the street that I got called and took part in that surgery. And if I recall, at the press conference

01:38:43.760 following the surgery, you explained point blank that the president had colorectal cancer. And

01:38:51.120 if I recall, Nancy Reagan wasn't too pleased about that, right?

01:38:55.040 No. And I'm not telling stories out of school here about a patient because it was public information.

01:39:00.880 And he later wrote a memoir that describes some of this. But Nancy Reagan, when we had to have a

01:39:06.800 press conference and they were a little concerned about having a vascular surgeon handle the questions,

01:39:11.840 and I had been in and as an operating surgeon as part of the operating team.

01:39:19.040 She, before I went on to hold the press conference, I remember standing backstage

01:39:25.200 and she said, you cannot use the word cancer in describing this because if foreign officials know,

01:39:32.640 think the patient has cancer, the president has cancer, they won't pay any attention to him anymore,

01:39:36.800 thinking he would not be around. And I said, I'm sorry, I can't do that. You know, if I have to,

01:39:43.760 I go out, I have to just tell the truth. And it was Don Regan, who was the chief of staff,

01:39:50.400 who finally talked her off that ledge and said, look, we've just got to let him do what he wants to do.

01:39:56.080 So we went out and the surgeon who led the discussion just basically read off the PATH report.

01:40:04.400 There's an adenocarcinoma, just a portion of the colon and so on. And nobody understood what he said.

01:40:10.960 And so they asked me to explain it. So I said, the president has cancer, which got me into all

01:40:18.480 kinds of trouble. I later learned that when Vince DeVita, who is the director of the NCI,

01:40:26.160 resigned to become chief at Memorial Sloan Kettering, I was on a short list to become the

01:40:30.800 director of the NCI, not a position I would have thought of accepting. And I was told at that point,

01:40:36.880 when I actually wrote this book in 1992, that my name get taken off the list as someone who would

01:40:42.880 become the director of the NCI. She was very upset that I used the word has cancer and not had cancer,

01:40:51.280 that is past tense. But we got over it and the president did very well and recovered and never

01:40:58.960 recovered from his early colon cancer. You mentioned it in passing earlier that

01:41:04.800 although you've been in the post you're in now for 47 years, along the way, you've had a few

01:41:11.040 job offers that have tempted you. I'm sure you've had many job offers. What are some of the other ones

01:41:15.760 that tempted you, at least where you thought you could even do better work or continue your work?

01:41:21.760 Because obviously you're so mission focused. It would be a special opportunity that I would imagine

01:41:28.240 would get you to leave NCI. But what were some of those other opportunities that you even contemplated?

01:41:33.920 There were only three that I looked at once. One was here at Georgetown because of a relationship

01:41:41.600 I had with a surgeon in terms of collaborating things. And it was sort of a favor to him

01:41:46.560 to look at the job. I was also invited to look at the job as chief of surgery at Hopkins.

01:41:55.520 And ultimately, I was told it got boiled down to John Cameron and me on the shortlist. But

01:42:00.240 I went back a second time, but refused to go back a third time because I knew I would not go to Johns

01:42:05.440 Hopkins and leave the NIH. I was also asked to look at the job at the Brigham where Mari Brennan, a friend

01:42:11.680 of mine, and I were again being pursued to accept that position. But again, I backed out. I knew that I didn't

01:42:20.720 want to take an administrative job. I wanted to be in the lab. I wanted to be mentoring fellows. I wanted to be

01:42:29.040 trying to make progress. I didn't want to guide other people making it. I wanted to be there. I wanted to

01:42:33.360 be doing it. I wanted to be guiding it because I thought I could do it well. So I actually refused

01:42:41.760 any of those offers and never looked at another job and actually turned down opportunities to advance

01:42:48.560 in the hierarchy here at the NCI because I wanted to remain at the level that I'm at. The

01:42:55.120 control of resources that enabled me to pursue the kinds of research that I thought needed to be done

01:43:02.080 in an environment of enormous resources.

01:43:04.880 So let's talk a little bit about checkpoint inhibitors. They've come up now a couple of times

01:43:10.400 in this discussion. You've mentioned anti-CTLA-4 and anti-PD-1. Certainly my time at the NCI,

01:43:18.640 my second stint, got me very familiar with anti-CTLA-4 and it was an exciting time. And of course,

01:43:26.000 James Allison would go on to receive the Nobel Prize a couple of years ago for his work in the discovery

01:43:32.160 of this. Maybe go back and explain how that system works, how the removal of breaks works.

01:43:40.560 And of course, as part of the undercurrent of this, it only works if there's a tumor

01:43:45.920 antigen to be recognized. In other words, taking the breaks off when there's no stimuli

01:43:50.320 doesn't do anything. But how does that system work and how is it a two-edged sword?

01:43:55.120 Dr. So again, there are stimulants and there are inhibitors of virtually every physiologic system

01:44:02.560 that we have. And one of the inhibitors are molecules on the cell surface, on the surface

01:44:09.840 of a lymphocyte that when engaged by a receptor, will inhibit a lymphocyte from developing an immune

01:44:20.960 reaction. And surprisingly, there are two molecules that have been found on the cell surface, now many

01:44:27.920 more, that when targeted by an antibody, will not kill the cell, but actually turn off

01:44:36.320 the breaks that are keeping that cell's activity from exhibiting itself. So it's releasing the breaks.

01:44:45.200 And it turns out to have a very important function in the body because there are some cells that can

01:44:51.840 react against normal tissues that do not react because they're being inhibited by these breaks.

01:44:58.800 And when you release those breaks, now the T cell can be very active. And it turns out that cancer has

01:45:06.080 manipulated those. And by taking the breaks off, you can attack certain cancers. And it explains why

01:45:12.400 melanoma is one of the more common cancers to be attacked because it has so many antigens, so many

01:45:18.480 mutations. And it was a startling discovery that simply attacking a molecule, a single molecule on

01:45:26.320 the cell surface, could take the breaks off a lymphocyte and let it attack cancer. And when it comes to

01:45:31.920 melanoma, kidney cancer, cancers that have large numbers of mutations because they have

01:45:38.880 mismatched repair gene mutations, Lynch syndrome, the MSI, the microsatellite unstable tumors, they can

01:45:48.720 very strongly react against cancer. But the common epithelial cancers that result in 90% of deaths in

01:45:54.880 patients have very little reactivity against the checkpoint modulator. So although they can be

01:46:00.480 life-saving and very likely, although it's been too soon, curable for some cancer patients,

01:46:06.240 patients, the overwhelming majority of cancer patients just do not respond to taking off the

01:46:12.160 brakes. Because when you take off the brakes, there's not a strong enough reaction to take

01:46:16.720 advantage of. But hopefully, combinations of treatments using checkpoint modulators will be

01:46:23.840 more effective in the future. But it was a major step forward. And the beauty of it, easy to apply,

01:46:30.000 because all it required was the injection of an antibody. So when you think about these

01:46:37.280 amazing conceptual advances in the field, the ability of CAR T cells to recognize CD19 on B cells

01:46:46.800 and eradicate any lymphoma originating from that lineage, the checkpoint modulators, anti-CTLA-4,

01:46:54.560 anti-PD-1, and the durable effect that they can have on patients in whom you have enough mutagenic

01:47:03.760 burden that relieving the checkpoint is enough to initiate it. Obviously, what you've alluded to

01:47:09.680 earlier with IL-2, high-dose IL-2, I don't want to at all sound disparaging, but just for the lack of,

01:47:18.080 let's just call that the low-hanging fruit of immunotherapy, which is, of course,

01:47:21.680 completely ridiculous given that that's 50 years of work and countless lives. But if for the sake

01:47:27.440 of being cheeky, the low-hanging fruit of immunotherapy are those pillars, do you believe

01:47:33.520 that the final frontier to go from where we are in 2021 until the point where all of those, let's just

01:47:42.240 call the 550,000 patients with solid organ metastatic cancer who have neoantigens, or 80% of them have

01:47:50.880 neoantigens that are unique to them, but not occurring in high enough frequencies that they

01:47:57.440 will respond to a checkpoint inhibitor in isolation and or in combination with cytokines? Do you believe

01:48:05.440 that there is a path for these people to be cured using adoptive cell therapy, either genetically or

01:48:13.920 naturally occurring in some sort of a customized format? Do you think that that is the path forward from here?

01:48:19.520 My intuition is very strong that the answer to that is yes, for a variety of reasons. One,

01:48:27.280 we know it can work from multiple tumor types. And as I've mentioned, we've described it and published

01:48:35.600 treatment of liver tumors, bile duct cancers, breast cancer, colon cancer, cervical cancer. We have

01:48:42.000 responses in ovarian cancer that we've published. And so it's no longer a question of can it work in these

01:48:48.960 other cancers? The answer is yes, it can work. And that's a world of difference. Like before IL-2,

01:48:54.720 we never knew that immunotherapy would work. But once it did, we knew the immune system could do it.

01:48:59.840 Now we know that antigens recognized by T cells are present on 80% of the common cancers. And if you

01:49:08.720 can develop unique reactivities, lymphocytes select reactivities against them and administer them,

01:49:15.280 they can cause those regressions. And in fact, now, because we know the exact T cell receptor

01:49:21.280 sequences that we've cloned and isolated, it's almost an engineering problem. Because since we

01:49:28.240 know the receptors, we've now isolated libraries of receptors against P53, KRAS, that we can now use to

01:49:36.240 genetically modify lymphocytes to turn a normal lymphocyte into a lymphocyte that can attack the cancer. And we

01:49:43.520 have our first example of that now that we've submitted for publication targeting P53 by genetically

01:49:49.920 altering a lymphocyte by giving it a receptor that could recognize some of these driver antigens.

01:49:56.800 So we know it can work. And to tell you the truth, I finally feel like I have the hang of this kind of

01:50:05.520 research. And that by sufficient work, creativity, this is going to be a problem that is solvable.

01:50:15.760 We know the antigens are there. We know the T cells are there. It should work. And it can work. And I

01:50:22.560 believe it will work as the years go on. And that's 100% of what I'm working on today. And that is how to

01:50:29.040 utilize these unique mutational reactivities to cause the solid common epithelial cancers that

01:50:37.280 result in 90% of all cancer deaths, how to get them to respond to immunotherapy.

01:50:41.760 I mean, of all the eureka moments in your career, of which you've had several,

01:50:48.560 this one seems to be the most promising, which of course, maybe they always seem that way when you're

01:50:55.200 glowing in them. But do you see it that way, that every one of these milestones that came before

01:51:00.960 this was vital, but this has the greatest potential? This recognition that virtually every

01:51:07.280 solid tumor out there has novel peptides that can be recognized by a patient's own immune system?

01:51:15.040 Right. Now, realize how current this is. We published a lot of these individual cases that can

01:51:21.360 respond. We published the first 40 or so colorectal cancers showing that mutations were all unique.

01:51:29.120 But we haven't published much of what I've told you. So for example, none of the breast cancer work

01:51:33.840 has been published. We now have looked at these 195 individual cancers and found,

01:51:40.720 regardless of histology, they're there. So it's very recent, this realization that mutations are the

01:51:47.440 antigens and now that T cells can recognize these mutations. It's really a new world.

01:51:55.200 But that happens every time you make an advance. You find the immune system can be stimulated.

01:52:00.720 OK, well, let's get to work on figuring out how. You know, cells can do it. Let's figure out how. And

01:52:06.880 science works that way by incremental advances. We know this can work. And I have every confidence

01:52:16.080 that scientists around the world will figure out ways to make it work.

01:52:20.320 That kind of reminds me of some of the important lessons that those of us who've been privileged

01:52:26.080 enough to work alongside you have learned along the way. You never sort of pounded the table to make

01:52:30.960 these lessons, but it was abundantly clear. And one of them was no secrecy. There was never any secrecy.

01:52:39.200 I remember working on my experiments and before data were published, people from other labs,

01:52:46.800 I don't mean other labs at NIH. I mean other labs in different parts of the country. You would encourage

01:52:52.720 me to reach out to them and share my results with them, even running the risk that they would

01:52:57.680 quote unquote scoop me. But none of that mattered to you. Your goal was, what is the fastest path to

01:53:04.640 the accumulation of collective knowledge in the field? Am I accurately representing that? I don't

01:53:11.200 think I'm overstating that. No, I've always been horrified by the secrecy that exists in medicine.

01:53:18.480 And it's an ongoing problem. The need for biotech companies, pharmacologic,

01:53:24.800 pharmaceutical companies to protect their intellectual property. Given current patent laws prevents them,

01:53:31.120 will often prevent them from sharing information, from sharing reagents, and this is holding back

01:53:38.320 progress. If we could somehow overcome this secrecy that results from either people's own personal

01:53:47.200 jealousies about wanting to be the one who does it or intellectual property that companies have to

01:53:54.880 protect to preserve themselves and raise funds to continue to do their work, we need kinds of

01:54:02.000 regulations that will bring lawyers and doctors together to figure out ways to prevent that kind

01:54:07.840 of secrecy from being a part of modern science. It's not like we're trying to create a better

01:54:14.400 air conditioner. We're trying to save the life of another human being. And I think when you take

01:54:21.120 care of cancer patients, it puts a lot of things in perspective. And the idea of having a policy or a

01:54:30.800 rule that you live by that inhibits your ability to help people who could potentially be helped is

01:54:36.400 abhorrent to me. I wrote, as you know, a perspective in New England Journal of Medicine trying to

01:54:41.920 change things, but they haven't changed. They're every bit as common today as they were back then.

01:54:48.160 And as you know, the first thing a fellow hears in my lab when they start the first day

01:54:52.960 is, look, anything you know, you share. Any experimental result you have, you can tell somebody.

01:54:58.640 Any experiment you plan to do tomorrow, you can tell somebody about. I mean, our goal is to help

01:55:04.160 people that are involved in the suffering of cancer. And there's no excuse for not

01:55:10.400 not doing everything you can to try to help. And that means sharing what you know.

01:55:14.640 On the other side of your office, right? If one side of your office is the lab,

01:55:19.680 the other side of your office is the clinic. The other lesson I think that you've infused into the

01:55:25.600 literally hundreds, you might even be into the thousands now of people who have come through

01:55:31.280 and trained with you. Basically, this idea that one never retreats from the bedside.

01:55:37.520 One of the things that struck me, actually, especially in medical school when I was there,

01:55:42.800 because I spent the entire time on the clinic, I lived in the clinical ward. You may recall,

01:55:48.080 I had rented an apartment in Bethesda, which I never went to except on Sundays to get new clothes,

01:55:52.800 but I slept. You're quite a legend at the NIH with respect to that, incidentally. I mean,

01:56:01.840 people thought I never left, but you never left. So it was really quite an experience to see you in

01:56:09.600 operation there. But the thing that was hard to believe and hard to process until you experienced it

01:56:17.040 was nine out of 10 people that walked in the door died. You know, eight or nine out of 10 of the

01:56:24.320 people who walked, because I would think most people don't maybe understand because it's implicit,

01:56:29.120 but it should be stated. The patients who are coming to NIH have progressed through every standard

01:56:35.200 therapy. People aren't coming here for whom there are standard options elsewhere. By definition,

01:56:42.000 these are patients who have the most advanced, the most aggressive, the most recalcitrant cancers

01:56:49.760 imaginable. These are people who would probably be expected to live no more than six months without a

01:56:56.160 miracle. And they come to the NCI for those Hail Marys. And if 20% of them are saved, that's remarkable,

01:57:06.480 but it means 80% of them don't. And I think what I remember most was the way in which you described

01:57:17.120 taking care of those 80% and fighting the urge to retreat from them because of the failure we saw in 0.96

01:57:24.800 ourselves. How did you develop that? I mean, I assume it came naturally to you, but how deliberate

01:57:32.240 has it been in how you teach those of us that came through? You know, I have enormous respect

01:57:39.440 for practicing oncologists who face this every day in their practice. And it's difficult if you point

01:57:48.160 out, especially when you give treatments that not only don't work, but actually cause some harm,

01:57:53.280 which has happened in the course of the development of these treatments as we try to figure out exactly

01:57:59.040 what we were doing and the right ways and the right ways to do it. But I always had the feeling

01:58:07.280 that I was working and working hard to try to improve the situation, to try to somehow repair

01:58:16.160 this Holocaust. And that kept me going. I don't know what it must be like to be taking care of cancer 0.99

01:58:25.040 patients knowing you have limited tools at your disposal that are not good enough. And yet that's

01:58:31.520 all you have. And that's what you do day in and day out. I mean, that must be even more trying.

01:58:40.240 And so I think one of the things that keeps me going, at least, is the fact that I'm doing everything I

01:58:48.240 possibly can within reason to improve the situation. Without that, I think it would be much, much more

01:58:57.360 difficult. Yeah. There are so many patients that I still remember from more than 20 years ago

01:59:05.520 who were those ones that didn't make it. And I can't imagine how haunting it is

01:59:12.080 for you sometimes because I can see their faces. I remember their names. I remember their voices and

01:59:17.120 I remember their stories. You know, the newlywed girl who came to clinic one day. And I mean,

01:59:23.520 she had literally been married for maybe three months, a beautiful 25 year old woman with metastatic

01:59:29.600 melanoma. And she was not one of the survivors. A young man whose name and face I remember every detail of,

01:59:37.840 single guy, metastatic melanoma. And what was most tragic in his case was I remember everybody kind

01:59:44.480 of abandoned him at the end of his life. And I've said this before. I feel like cancer takes families

01:59:50.800 that are close and brings them closer and takes families that are fractured and fractures them more.

01:59:56.640 And I got the sense that his was fractured to begin with. And he was maybe 26 years old.

02:00:01.680 So I certainly understand the motivation. There's no lack of motivation for how you do what you do.

02:00:08.160 I guess I'm amazed that, you know, you talked about how the immune system has the stimulatory

02:00:14.720 and the inhibitory components. Well, it's similar that taking care of patients like this, there's the

02:00:21.600 motivation that comes from it to do more. But at some level, there's the depression of the death toll.

02:00:27.680 I'm not sure everybody could do that. You seem to have found that balance.

02:00:35.600 Well, you know, when I lie awake at night, it's not the successes that I think about.

02:00:41.120 But it's the tragedies, patients that you're remembering even now that I'm sure are impacting on you.

02:00:49.280 And it gets even worse because there are patients that we've killed by doing the wrong thing to them,

02:00:56.960 not understanding some of the underlying biology.

02:01:00.880 That's that's that's the hardest thing to to deal with. But again, given the fact that

02:01:11.040 I'm doing everything that I can reasonably do to help them, it certainly eases the burden some.

02:01:18.880 And as you know, being a doctor, what an unbelievable privilege it is to have the opportunity to help

02:01:25.120 people like that, given the skills that you've developed. One of the first lines of the prayer

02:01:32.000 of Maimonides goes, you have been given the wisdom to alleviate the suffering of your brothers.

02:01:40.320 And that's true in medicine because, you know, we spend a lot of time just learning

02:01:46.560 how to help people. It's a unique, a unique opportunity in the world and in life in general.

02:01:53.920 So there are the satisfactions that you're trying hard, even if most often things don't don't work

02:02:02.400 out. But there clearly are sleepless nights involved in all of that process.

02:02:07.440 The good news is you have wonderful longevity in your family. So despite being 81, I have every

02:02:15.680 confidence that you're going to be doing this for many more years. I know you don't like golf enough

02:02:20.560 to hang up what you're doing for the golf course. You know, I found I pulled this off the wall today.

02:02:28.480 I wasn't I wasn't sure if you still recognize these guys here. This is us from I think I think this is

02:02:35.360 16 years ago. We both look quite a bit younger. And this is the only picture of me in my office

02:02:42.320 is this picture. And it speaks to what an influence you've been in my life. I think the list of people

02:02:49.680 who have had a greater impact on the course of my life than you is somewhere between zero and epsilon.

02:02:57.200 It's a decidedly small list. So I feel forever in your debt. And though I have not been able to

02:03:04.720 follow in your footsteps, your impact is greater than you could ever recognize.

02:03:13.040 Well, thank you for saying that. That means a lot to me knowing that someone of your incredible

02:03:20.000 intellect and perseverance feels that way. So thank you.

02:03:24.240 I know, again, what what what a sacrifice it was for you to take time today to speak. And I know

02:03:31.520 that every minute you spent talking with me was literally a moment you were not working on this

02:03:36.960 problem. So I'm beyond grateful. And I know that the people watching this or listening to this are

02:03:43.520 equally grateful. So thank you so much, Dr. Rosenberg, for everything. Well, you're very well.

02:03:48.080 Thank you for listening to this week's episode of The Drive. If you're interested in diving deeper

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The Peter Attia Drive - September 27, 2021

#177 - Steven Rosenberg, M.D., Ph.D.： The development of cancer immunotherapy and its promise for treating advanced cancers

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