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

Hey everyone. Welcome to the Drive Podcast. I'm your host Peter Attia. This podcast, my website and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in depth content. If you want to take your knowledge of this space to the next level, at the end of this episode I'll explain what those benefits are. Or if you want to learn more now, head over to peterattiamd.com subscribe Now without further delay, here's today's episode.

The guest this week is Dr. Steve Rosenberg. Steve is the Chief of the Surgery Branch of the National Cancer Institute, a position he has held continuously for for the past 47 years. Some of you may have heard of me talk about Steve Rosenberg in the past. He is unquestionably the most important mentor I've ever had. Steve has received numerous awards, in fact really too many to name, so it's probably easier to explain it this way. He has received essentially every major award in science except for the Nobel Prize. He is one of the pioneers in the field of immunotherapy, dating back to his early work in the 1970s and 80s with the discovery of Interleukin 2 and its effect on lymphocytes in mediating cancer regression in patients with metastatic cancer. In this episode we talk about his entire history from childhood basically until now, and it serves as effectively a roadmap for the field of immunotherapy, from the very non specific therapies such as Interleukin 2 into the discovery of tumor infiltrating lymphocytes up into checkpoint inhibitors which many people have heard of in the last decade, car T cells and adoptive cell therapy. We talk about all of these things in detail and perhaps most importantly, we talk about his optimism for what lies ahead, especially in the face of some of the more recent discoveries with respect to tumor antigenicity. We also talk about the human side of cancer, which I think when you listen to this just completely comes through him in every way, shape or form. He has really never lost sight of why he chose to become a physician basically at the age of 6 years old, and why he was so drawn to cancer. One other point I'll make if you find this episode particularly interesting, I would highly recommend going back and reading the book the Transformed Cell, which Steve wrote with John Barry about 30 years ago. It's one of the best books I've ever read on the process of scientific discovery and the journey to and the ebbs and flows of failures and successes. It's really an amazing book for anyone who wants to understand how biomedical research is conducted. So without further delay, please enjoy my conversation with Dr. Steve Rosenberg. Doctor Rosenberg, thank you so much for making time. I know how busy you are. I know as much as anybody how busy you are because I've sat next to you and watched how hard you work and how tirelessly you work. So it really means a lot that you would make any amount of time to sit and talk about what we're going to talk about today. I almost don't know where to begin, but I can't help but want to begin kind of chronologically with your life story, because you're probably one of the most focused people I've ever met, if not the most focused person I've ever met. And that focus seems to have started at a very young age. Let's talk a little bit about your childhood. You grew up in the Bronx, if I'm not mistaken, correct?

That's correct.

I was born in the Bronx, if I recall. We're coming up to your 81st birthday. So you were born, I think it's August 1st, August 1940. Yeah. So what are your earliest memories of childhood as they pertain both to your love of science and perhaps more importantly, your obsession with cancer?

So up until about the age of five or six, I wanted to be a cowboy. I have an older brother, and we would talk about going out west together and riding on horses and doing all kinds of exciting things. But the first things I remember, other than wanting to be a cowboy, occurred when I was about five or six years old. And I've given a lot of thought to how that came to pass. When I was about five or six, living at home right at the end of the Second World War, when all of the remarkable tragedies of the Holocaust sort of came home. As my parents got one postcard after another, I remember this, and they're suffering as they got word of relatives that died in the death camps during the war. And I remember being so horrified by that in terms of how evil people could be towards one another. And somewhere around that time, I developed an almost spiritual desire to become a doctor, to do research and make progress in helping people in alleviating suffering rather than causing suffering. And that persisted as I began to keep scrapbooks about anything I could find about medicine. Or research. And I think it was in response to the horrors of that particular time that inspired me to not only become a doctor, but to become a doctor who not only helped alleviate suffering now, but alleviate potential suffering in the future by doing research. And I stuck with that right through my education.

Now, you did very well in high school because, or at least we've never spoken about it, but I can only assume you did because you were accepted to the best medical school. And not only that, but you did the combined Bachelor's MD degree, which I assume would have been very difficult to go straight into medical school from high school, but you somehow managed to get into the six year program. So just talking about Hopkins for a moment, what was the impression that that place left on you in what would have been, I guess, the late 50s and early 60s?

So I went into this six year program, it was three years of college and three years of medical school, knowing that I would want to get further education, that I would take additional time. And I knew from the very beginning that I would go on to get a PhD in one of the sciences. It turned out to be biophysics. And Hopkins was a very nurturing environment with respect to that. As soon as I got to Hopkins, I started working in a biology laboratory in the afternoons and evenings doing some very simple projects in the biology lab. But I knew from the very beginning that I wasn't just going to try to practice today's science, practice today's medicine, but rather try to create the medicine of tomorrow. And that stuck with me for these last 60 or 70 years or so.

Who was the chief of surgery when you were there? Was Blalock still the chief of surgery?

Yes, and it was. The medical school was not necessarily a terribly nurturing environment. You were thrown in there and at rounds there seemed to be a spirit of calling people to task in front of others. It wasn't the way that I thought education should happen, but there were brilliant people around. And that's what I think is the most, probably one of the single most important components of a good education, and that is being surrounded by people who know a lot, know more than you, can inspire you. And that kind of person was at Hopkins.

Now I remember when I was in medical school, when I was spending time with you and we got talking one night and you explained that the reason you chose to do your PhD at Harvard in biophysics, and this is as close to, I remember as a direct quote as possible, is you never wanted to be intimidated by a differential equation, which presumably was a bit of A shortcut for. You wanted the biggest or the broadest education possible. But what led to that choice? To. I mean, at that point in time, for example, did you know you had an interest in immunology? Had that piqued your curiosity yet or were you still thinking just more broadly?

I was somehow interested in the mysteries of cancer through high school biology and in my college classes. I got a PhD because I wanted more formal learning. I never wanted to be intimidated by what I did not know. I wanted to be able to grasp any area of science and use it to answer questions. And maybe differential equations were in the source of that. I ended up doing a lot of math in graduate school, but it was more than that. I wanted to have the feeling that I had a good enough broad background in the sciences. Because when I got that PhD in biophysics, I was doing physical chemistry, quantum mechanics, thermodynamics. It was a lot of non biology in biophysics. I wanted to have a background in the sciences such that if I encountered a problem, I could get a good book, read some papers and understand it. And it was that base of knowledge that I tried to acquire.

So when you were doing your PhD, had you already applied to residency or did you take time out between medical school and the application to residency?

So I went immediately into the surgical residency at the Peter Ben Brigham Hospital right out of medical school, and then took off four years to get a PhD in biophysics. So it was a year of internship, took off four years and then went back to the residency and then came down to the NIH for several years to join the immunology branch here. This was during the Vietnam War, before going back to actually finish the residency in 1974.

Now, was Franny Moore sort of the most significant figure in your life at that point in time as a mentor?

Frannie Moore was the chief of surgery and an incredibly smart person. There are an awful lot of smart people in that educational system. But Franny stood out in that. Discussing a problem, discussing a patient. It wouldn't be at all surprising for him to come up with an idea or an outlook or a perspective on a problem that most people had not considered. So in that sense, he was an important figure. He was not so much loved as respected, which is a feature that I think can be very inspiring to young people.

Was it unusual for someone to leave their internship or leave after their internship and go into a PhD program at that time?

Well, it was, as a matter of fact. And the Brigham encouraged you to take off a year or sometimes two years in the middle of the residency program, generally after two or three years. But I knew at that point I was just itching to learn more. I was just not satisfied after medical school, college and medical school that I really knew enough to do creditable, meaningful, impactful research. And so, again, this was a real program. For two years, I did nothing but study, nothing but take classes and study and learn. And then the latter two years, I spent in the research laboratory doing basically physical chemistry and protein chemistry research of cell membranes.

And Franny was supportive of this.

He was, to an extent. To take that time off after internship required a few meetings, and ultimately I remember sending him a note saying, Look, I'm 23 years old. I've just finished the residency. I need to do what I'm excited about. And he gave in. And I have enormous respect for him for that. And he was quite patient because I came back for a year, and then I went down to the NIH as part of the Vietnam draft obligation. And he kept taking me back each time, which is very, very nice. But turns out I set some kind of record at the Brigham. It took me 11 years from the time that I started my internship to the time I actually finished the residency, which was some sort of record at the time.

So you would have been old for a chief resident at that time, I guess.

Yes, I was 33, 34 by the time I had my first job.

But of course, you made up for it because you sort of progressed so early at the outset, as you know. Well, the book that you wrote with John Barry In 1992, the transformed cell, is a book. I may have the record for most times reading it. I may also possess the record for most copies owned, which I know you get a kick out of that Every time I say something to that effect, you basically say, I'm one of the few people who's read it, which I know is not true, but I still remember the first time I read it. And it's a remarkable story. I suspect many people will go on to read it after this interview, because it is in many ways one of the best books about science, which I think was your motivation for writing it, and we'll come back to that. But in it, you talk about an important moment in your training, which occurred in 1968 with a patient who you met in the ER one day. Can you tell us a little bit about that story and why it altered the course of your career?

Well, there were actually two patients that I saw early on or was familiar with early on that influenced my Thinking about cancer. The first was a patient I saw when I was a junior resident at the West Roxbury VA Hospital. We rotated through there three or four months at a time during the residency. And it was a 68 year old fellow who came in complaining of right upper quadrant pain. It looked like a typical gallbladder attack. And I got pretty excited about it because it might be a patient that I might be able to perform one of the first operations I was allowed to do. And so I looked into his chart and a remarkable story was encountered. I looked into the chart and it turned out that 11 or 12 years earlier, that patient had been seen at the West Roxbury VA Hospital. He had had a gastric cancer, a stomach cancer. He had undergone a laparotomy. And I looked at the surgeon's note saying that he opened the belly, he saw a tumor that was encompassing about three quarters of the stomach. There were multiple liver metastases, deposits that were biopsied, shown to be the gastric cancer that had spread, multiple enlarged hardened nodes. And he took out part of the stomach, I guess as a palliative measure, left the rest of the disease in place. And the patient recovered and about a week later went home. Well, as I turn the page of the chart, patient comes back three months later. Nobody had expected to see him and he was doing fine. He was gaining weight. Six months later he was back working. And here he was 12 years later, having lived the past 10 or 11 years completely normally. And so I took part in removing his gallbladder, under supervision of course. And his belly was completely clean of cancer. There was no evidence of cancer of any kind. And we went back and looked at his Be sure it was the same patient. Re reviewed the pathology. Sure enough, it was a cancer that had spontaneously disappeared over time in the absence of any therapy. One of the rarest events in medicine, and that is to have the spontaneous regression of cancer without any treatments being given. Somehow his body had rejected the cancer. And I then did what turned out, of course, to be a very naive experiment. But I was wondering whether or not this patient who had somehow cured his own cancer, could be somehow taken advantage of to treat other patients. And it turned out we had another patient in the hospital with a gastric cancer, a veteran who happened to have the same blood type. And so I called up the head of the surgery department, Brownie Wheeler, and said, hey, I want to take a blood transfusion from this patient who spontaneously was cured and give it to this other patient. And he said, okay. That was the IRB as existed at that. At that time. And so we actually got blood from this one patient and infused it into the other veteran. But of course, it didn't do anything. And the other patient ended up dying of his gastric cancer, but at least planted the seed that, in fact, maybe there was something in the immune system that caused the rejection of that cancer, much as you would a foreign transplant. And the body's major defense mechanism, of course, against foreign invaders is the immune system. And it got me thinking about potential immune manipulations. But there was a second patient that also influenced me a great deal, and that was a patient that had been seen about a year before I came to the Brigham as an intern. And this was a patient who had received one of the early kidney transplants that were developed and innovated at the Brigham Hospital. He had received a kidney from a young individual who died in a motorcycle accident. And that kidney was transplanted into the recipient, and the recipient developed widespread renal cell cancer. And it turned out, after study, that the kidney that had been transplanted inadvertently had contained a renal cancer that then in this other patient, under the influence of immunosuppressive medications, had spread widely through his body. So in an attempt to control this, the immunosuppressive medications were stopped. Of course, the kidney rejected and had to be removed. But the patient's cancer then went away as well, because it too, was allogeneic. It, too came from the genome of the original donor. So what did that teach, Juan? Well, it showed that a large invasive vascularized cancer could be caused to reject completely by the immune system if you had a strong enough stimulus that could mediate that rejection. And so it was that spontaneous regression, maybe this demonstration that the immune system more directly, by removing immunosuppressive medications, could result in tumor collapse and regression. That tended to put me on the path towards cancer. But I was already pretty much there because of what I had seen as a doctor in cancer patients.

Now, in the late 1960s, what was understood about the human immune system as it pertained to even viruses, let alone cancer. I mean, had MHC Class 1 and Class 2 been identified yet? I don't think they were identified until the mid-70s. Right.

Class one in the 70s and the early 80s, class two. But when I started in 1974, the idea of immunotherapy was a dream. There were anecdotes way back to the late 80s of tumors going away when people got an infection, but really nothing stable. There was no ability to measure an immune reaction against any cancer. There was no such thing as a cancer antigen that had ever been found. There were no manipulations you could give that might work. So it was sort of a dark period when it came to knowledge about the immune system against cancer. It's a little hard to understand just how frequently immunologic information developed. In the 1957 issue of the Journal of Immunology, the word lymphocyte was not in the index. We did not understand what small lymphocytes did, what they were doing and circulating in the 1950s. And so that information only came to pass in the early 60s, when it was clear that you could transfer immunity by transferring lymphocytes in a way that you could not do by transferring blood or serum. And even in experimental animals, there was no manipulation that could cause an existing cancer to disappear. You could immunize a mouse against a tumor by letting it grow and then removing it, and cause that mouse to resist an implantation of the same tumor again. But once the tumor was growing, there was no maneuver that could keep it from growing, no immunologic maneuver that could keep it from growing. So the field was desperately in need of more information.

So before we get to how you arrived at the nci. Well, actually, let's talk about that. It's a very unusual first job. How did it come about, and what did you assume you would do at the completion of this otherwise very long residency?

So, as you're indicating, I finished my residency June 30, 1974, and the next day I was appointed chief of surgery at the National Cancer Institute, a position that I still hold. I'm still chief of the surgery BRANCH now, what, 47 years later, 46 years later, the NIH. When I came here, I knew it was a remarkable place. It had resources and a commitment, a mandate to make progress. It's a state of the art hospital that provides outstanding care to patients. But it exists, again, not only to practice the best of today's medicine, but to create medicine of tomorrow. And that always intrigued me from my first knowledge of the NIH when I came here in the midst of the residency during the Vietnam War.

Now, you did have an offer to stay at Harvard, correct? Was Dana Farber still. Was it in existence at the time?

Dana Farber was just being built. The hospital was just being built. Franny Moore, who was chief of surgery, offered me a position as the head of surgery in that new Dana Farber institution. Emil Frey was the director of IT and head of medical oncology, and he too offered me the position And I had tentatively accepted it, although we're in the midst of some negotiations about whether there would be individual and independent operating rooms in the hospital and so on. But in the course of that, I heard from one of the division directors here at the NIH, who I had gotten to know when I was a fellow who came to the Brigham to interview me. He was wondering whether I would be interested in the position. And so he interviewed me. And I was expecting to stay at the Brigham at Harvard. But one day I got a phone call from him saying that the chief of surgery offered Ketchum. I decided to retire, and the position was open July 1st. Was I interested? And I knew I was, but I had to call my wife. Alice told her about it. She said, just pack. Let's go. And off we went.

Was Franny disappointed?

Oh, it was a really shocking encounter that I had with him and that I went in to tell him I decided to go to the nih. I thought it was a place where I could best utilize my interests and knowledge. And he said no. And I said, look, I've decided to do it. He said, you have to stay here. It's too great an opportunity to turn down. And I said no. And he wasn't an easy guy to say no to, but I knew I wanted to come back to the NIH. And finally, after almost an hour, I finally said, Dr. Moore, I'm not. I'm going down to Bethesda, Maryland. And I offered my hand to shake his hand because I was going to leave. And he refused to shake my hand, which was a little shocking. But he got over it. Finally I left, and we became good friends. And he said all kinds of nice things about me when he needed to. So worked out. Well, you see, at that point, I knew I wanted to study cancer. I had already made that absolute commitment. And the National Cancer Institute seemed like the right way to do it. And in some sense, it was a logical decision for me, given my childhood experience that got me interested in medicine and science. Cancer is such a devastating disease. It attacks innocent people through no fault of their own, makes them and their families watch impotently as they progress and then die. Cancer is a holocaust and just seemed like the kind of thing I wanted to study.

So it was around this time, I guess, a little bit before this time, that Richard Nixon and that administration had declared a war on cancer. I believe it was just a year prior to that. How did that resonate with you? Did you view that with great optimism, or did you think that it was naive that in a matter of years, cancer would be eradicated in the same way that man had gone to the moon.

Well, I had great hopes for making progress, Perhaps naively, even at that point, not fully understanding all of the complexities. The national cancer act mainly influenced funding outside of the nih. The nih was already, I thought, well funded, Had a building that had been built in 1953, one of the largest buildings in this area dedicated to doing research. It had hospital beds. And so that national cancer act didn't have much impact on the intramural nih that I could see. But again, remember, I'm a worker bee. I became chief of the surgery branch and have never advanced in the hierarchy. I was where I wanted to be, Turned down a fair number of positions. And so when it came to the influence of the national cancer act on the country as a whole, I really wasn't involved with that very much at all. I focus on the work that I wanted to do intramurally at the nih.

So how did you lay out a research agenda when you arrived in 1974? You're now finally able to, not only with the resources of money, but perhaps more importantly, with the resources of time, lay out an agenda for hypotheses that you want to test to build effectively a program to systematically narrow down the set of questions. So what was the process by which you went about doing that?

So when I came to the nih, knowing I wanted to study cancer, I started reading everything I possibly could about therapeutic approaches, which at that point were simply surgery, radiation therapy, and chemotherapy, most used alone. And it was clear to me at that point that although incremental advances had been made over the years, surgery 3000 years old, radiation therapy began immediately after roentgen discovered X rays in 1895, and chemotherapy arose in biological and chemical warfare laboratories here at fort detrick, in detrick, Maryland, to attempt to develop these agents. And it was in laboratory accidents in 1942, when nitrogen mustard was inadvertently exposed to laboratory technicians and found to develop a lymphopenia throughout their body, with their lymph nodes shrinking down, that led a yale physician to attempt to use nitrogen mustard, now known as melphalan, as a chemotherapy agent. And that was the Birth of Chemotherapy, 1942. And that started chemicals to treat. Search for chemicals to treat cancer. But the advances that were being made were slowly and tiny, incremental. I wanted something that big that would make a big difference. And as I began to read about the immune system, how little was known about it, but with the examples That I had the intuition that I had developed, which is so important in science, that this might be something valuable, that I decided to study immunology, looked at everything I could read about, and it seemed to me that the immune cells that were then being recognized as the mediators of organ rejection were the agents that one needed to stimulate. And why not use an immune cell as a drug that has taken advantage of a patient's own immune reactions to try to treat the disease? Immunotherapy and I started with unbelievably naive experiments. There was no way at that point to keep lymphocytes alive outside the body. We're talking about 1974. You could take them out and they would die in a day or two, and you had no way to keep them alive. You could mix them with other cells and they would stimulate for a few days, but then they would die after about a week. And yet I was desperate to try to use lymphocytes with immune reactivity to treat patients. And so I began implanting human tumors into the mesentery of mini pigs. Good friend of mine, David Sacks here had developed a mini pig colony that was partially inbred at MHC loci. And so I would embed tumor in the mesentery of these mini pigs, wait about two weeks, operate and remove the inflamed lymph nodes that were draining that tumor, and gave those lymphocytes to six patients, that is, would take out their tumor, generate lymphocytes reactive against that tissue, and then harvest lymphocytes from that pig and administer them intravenously to patients. And of course, nothing happened, but it's just a sign of how desperate I was at that point to have some impact, to be doing something I have over the door of my lab. You probably remember it when you were in the lab, it said, it's a modification of a Louis Pasteur saying that said, chance favors the prepared mind. And what I added to it was, chance favors the prepared mind only if the mind is at work. And so I was trying things, and it was only with the discovery of T cell growth factor in 1976 by Morgan, Rossetti and Gallo, that opened the door to be able to manipulate lymphocytes outside the body by putting them in a growth factor called interleukin 2. That was something I began to study quite intensively to see if one couldn't then grow lymphocytes that had antitumor activity and would retain it as they grew. None of that was known, but those were the first Experiments I was doing along those lines.

Now, before we go further, I think it's worth making sure people understand Some of the semantics, because obviously, you and I can take so much of this for granted. But let's start with some basics about cancer. How does one define cancer? What separates a cancer cell from a non cancer cell?

Well, if you look at the broadest properties, There are two properties that separate cancer from other cells in the body. The first is uncontrolled growth. Virtually all of the tissues we have, either fingernails or eyebrows, or, you name it, they'll grow to a given amount, and then they'll stop. Well, cancers don't have that signal to stop. They'll keep growing. And the second is it's the only cell that can arise in one part of the body and spread and live and divide and grow in another part of the body. And that's not true of virtually any other kind of cell. So cells with uncontrolled growth that can spread and grow elsewhere Are the biologic properties. Now we can dig down layer by layer by layer and get to the point of, well, why does a normal cell ultimately become a cancer cell? And we now understand that that's due to the accumulation of mutations in DNA of these cells divide, which explains why it's the common organs of the body, all of which have ducts. The lining of those ducts are constantly turning over. And as that DNA is turning over, Mistakes are made, called mutations. And it's that accumulation of mutations that results in the cancer itself. So we can take it all the way from the biology of uncontrolled growth, but down to the very molecules that are involved, we can describe it. Doesn't mean we really understand it all, but we can describe it.

And let's also explain to people the difference between the epithelial tumors, the hematologic tumors, and even let's frame it as it was in 1974 in terms of what was a person's odds of surviving. So maybe tell folks what the common epithelial tumors are and explain a little bit about the. We're not going to go into staging in great detail, but what's the difference between local tumor versus metastatic tumor, and what's the impact that has on a person's survival at the time you arrived at nci.

So the hematologic cancers, of course, are the blood cancers, and they start from progenitors in the hematopoietic system, because after all, the hematopoietic system starts from an individual stem cell that then divides into multiple different Characteristics, much as we all grow from a single cell, fertilized egg from one cell, that makes us what we are. So even back then and a little more so now, if you developed a cancer of the bloodstream, which were about 10% of all cancer deaths are due to those. 90% of cancer deaths are due to the epithelial cancers. So these start in the solid organs of the body and that go all the way from the rectum, up through the GI tract, through the stomach, through the esophagus, the pancreas, the gu organs, the testis, the ovary, the prostate. All of these solid organs have ducts. And as I've mentioned, it's the epithelial lining of the ducts that are turning over that become the cancer in blood cancers. It's the more primordial cells that develop into neutrophils and lymphocytes and other types of cells. So let's talk about the solid tumors, which are 90% of all cancer deaths. Last year in the United States, There were about 600,000 deaths due to cancer. 550,000 were due to the solid epithelial cancers. If you operate on a patient who develops a cancer to remove that cancer, then well over half the time that patient will be cured that has gone and lived their normal lifespan. But the half, a little less than half of patients that cannot be cured result in this enormous tragedy of 600,000 innocent people dying of cancer every year. Once the cancer spreads, however, and this, in my view, is a dirty little secret of oncology, and that is that if a cancer spreads from its local site and cannot be surgically removed, then the death rate in that patient is 100%. That is, we have virtually no treatments that can cure systemic treatments that can cure a patient with a metastatic solid cancer that is one that has spread to a different site that can't be surgically resected. Now, there are a couple of exceptions to that. There are two solid tumor exceptions that have existed for several decades. One is choriocarcinoma. These are cancers that start in the placenta of pregnant women that then spread. And you can have 90% of the lung replaced by that tumor, receive methotrexate, a chemotherapy drug, and it will all disappear. Still don't understand exactly how germ cell tumors in the male, tumors of the testis, like Lance Armstrong, who had brain mets and lung mets, no matter how much they've spread, if give patients platinum derived chemotherapy regimens, you can cause complete, durable regression of that metastatic disease. Up until 1980, 5. Those were the only cancers that could be cured. We can now add to that list solid cancers. We can now add to that list melanoma and renal cancer. Because interleukin 2 administered to patients back in the mid-80s caused complete regression to widely metastatic cancer in patients that are still alive today. But that said choriocarcinoma, germ cell tumors, melanoma, renal cancer. Other than those four, everyone who develops a spread cancer will die of it, despite all the best treatments that we have. Well, you read in the paper that this celebrity has cancer and they're going to fight it and they're going to beat it. But nobody beats it. We're in such desperate need of better treatments for patients with metastatic cancers because we can beat them back a little bit. We can improve survival by months, and for some cancers, maybe a few years, like breast cancer and colon cancer, but everybody ultimately will succumb to the disease.

And that's what I was actually going to ask you about, which is if you think about the past 50 years in cancer and what you just said, I really, I still starkly remember having those discussions as a medical student with you. And the main point was we've basically just extended median survival of metastatic cancer, but we haven't increased overall survival. And what would be the extent to which even median survival has changed? If we are just talking about stage four of the common cancers, breast, colorectal, lung, pancreatic. How much has the needle been moved with respect to median survival, notwithstanding the fact that overall survival hasn't changed?

Well, if you look at current papers and advertisements, most regimens that ultimately get approved by the food and drug Administration prolong survival by months. Probably the best example in modern oncology is the treatment of metastatic colorectal cancer. When I started, median survival would have been maybe eight to ten months. Now it's two and a half years. So there's an example where life has been extended by years. Breast cancer patients can go from one regimen to another, each one causing some temporary regression of the cancer or limitation of its growth. But the cancer will ultimately grow and the patient will have to move on to something else. And that's why cancer care is so remarkably expensive, because people just move from one treatment that can prolong life by a few weeks, like erlotinib and pancreatic cancer. Six week improvement in survival for $40,000.

Right.

For enormous toxicity and huge, huge life altering expense. The most frequently prescribed drug in oncology today is Avastin bevacizumab, which can Impact on blood vessels and tumors. And the trials of that regimen in combination with others, Will prolong survival in patients with colorectal cancer by about four and a half months. But those are the tiny increments which can provide substantial. Some can provide substantial benefit to patients, but none of curative. And people are always living under the cloud of that cancer that is going to regrow. So we need something more dramatic Than the application of surgery, radiation, and chemotherapy, Barring some enormous advances in those fields.

And I think one other point worth making for folks with respect to chemotherapy. I was actually just on the phone yesterday with one of my patients whose wife is currently recovering from surgery from a cancer, and he asked a question about the efficacy of chemotherapy and how good is chemotherapy at killing cancer cells? Which I thought was an interesting question. And it led to a discussion where I said the challenge with chemotherapy Is not finding chemotherapeutic agents that can kill cancer cells. I made a point that he probably had 20 chemicals in his home and in his garage that could kill every cancer cell remaining in his wife. The issue is how can you do that selectively? How could you do that and not at the same time kill the normal cells? And I think therein lies the arbitrage that needs to be exploited with chemotherapy and ultimately what we're going to talk about, which is immunotherapy. But I think that's an important point that many people don't understand, which is how difficult it is to thread the needle of chemotherapy. It's not the killing of cancer that's hard. It's the killing of cancer and not killing the non cancer.

The point you make is incredibly important because it's the selective killing of cancer without killing normal cells, which is not the case for virtually any chemotherapy or radiation therapy. Even in surgery, you have to remove some normal tissue. And so it's that selectivity against the cancer that's so important. And in fact, that's almost the perfect explanation for another reason that I think immunotherapy has potential importance because of its immense selectivity and sensitivity of recognition. Can recognize single amino acid changes in a protein and develop an immune response against it. Trivial differences that can distinguish normal from tumor, or if you get a viral infection, Destroy the virus in the respiratory system without destroying the respiratory epithelium. It's the exquisite sensitivity and specificity of the immune reaction that I think makes it such a seductively interesting approach to trying to develop new cancer treatments.

Let's take a moment and have people get a little bit Deeper on how the immune system works. I remember, for me personally, in medical school, it was one of the most interesting sets of courses we took were the courses in immunology. In particular, how T cells worked was fascinating. It seemed to lend itself to a story almost with generals and soldiers and all of these things. So explain to people. Let's maybe start with a virus as the example, because obviously, in the era of coronavirus, that's on everybody's mind, and we can talk about how the body defeats a virus, but then pivot to then how, in the case of cancer, that exact same immune system can accomplish what you just said.

So let's take viral infection as an example. Whether it's the common cold or coronavirus, the virus comes into the body and infects the respiratory epithelium in the pharynx and the bronchi in the lung. And as that virus then infects those respiratory epithelium, the virus replicates, and the infected cells then express the viral proteins. The immune system has evolved to detect proteins or other molecules that are not part of the normal self of the body. As the immune system evolves, cells that can recognize foreign invaders get spared, Whereas cells that can attack normal tissue get eliminated in the thymus. And so, except for autoimmune diseases, we don't have cells that can recognize normal tissues. They've been eliminated in the evolution of our immune systems. So you have lymphocytes, B cells that make antibodies, T cells that act directly by interacting with other tissues. And so the immune system, via antibodies or T cells, recognizes viral protein that's now being expressed by the respiratory cell. The lymphocytes are constantly patrolling the body. Every 14 or 15 seconds, your heart's pumping out these lymphocytes that are circulating through the vascular system, sometimes extravasating into tissues, coming back into the lymphoid system and returning to the heart via the thoracic duct. Well, when the lymphocyte encounters a foreign antigen to which it can have reactivity that's not self.

And define an antigen for folks. Tell people what an antigen is. How long is it? What's it made of?

So an antigen is a molecule in the body that is not normally being expressed in the body by tissues. They're generally proteins, but they can be carbohydrates. And what makes that molecule an antigen is its ability to be recognized by a T lymphocyte or a B lymphocyte, that is a T lymphocyte that can directly recognize an infected Cell or a B lymphocyte that can make antibodies against it, plasma cells. And so if a molecule is recognized as foreign, the immune system can recognize that antigen. Well, lymphocytes are patrolling the body. They encounter this viral antigen in the respiratory epithelium. They stop at that location, and you can visualize this in mouth, ears with something called two photon microscopy. They stop at that location and you can see them extravasate into the tissue. When they're there, they then begin to divide. As they divide, the dividing cells can further recognize the viral protein and starts making molecules that can destroy the infected cells, but also call other cells into that arena. Macrophages, neutrophils, and so on. And that's what an immune reaction is. As the antigen is eliminated by these mechanisms, lymphocytes, other cells, there's no reason for those cells to stay around anymore. They're not stimulated, they enter the circulation. But now you have patrolling the body for the rest of your life. Long live lymphocytes that can recognize those foreign molecules. And that's why when you get immunized against smallpox, you have that immunization for the rest of your life, and hopefully for coronavirus, although we don't know that. We don't know the, the extent to which those cells survive.

Now, at the outset, you said there are two things about cancer that make it different from self. It has these two properties that individually wouldn't be the end of the world, but when you combine them, they're devastating. It's this failure to respond to cell cycle signaling, which results in unregulated growth. And it's this capacity to leave the site of origin and grow in an unregulated manner elsewhere. And you also mentioned that this is the result of, although you didn't use the word somatic, mutations. And we can clarify for people. These aren't typically mutations that people are born with, although in diseases like lynch syndrome, that might be the case that it leads to that. But these are acquired mutations. So the natural question would be, why is it that a cell that has these acquired mutations that clearly produce a phenotype that is different from self, why wouldn't that be foreign enough for the immune system to act? In other words, why does cancer even exist in the first place? Why doesn't it get squashed out in its infancy?

These mutations, these changes in DNA that are random events as the cell is dividing, can produce proteins that can be recognized or other molecules recognized by the immune system. And they do it in complex ways by breaking down Small molecule peptides and putting it on the cell surface. But the immune system can recognize these mutations. And it's only been in the last, I'd say three or four years that we now recognize these mutations as commonly recognized by the immune system. And about 80% of patients with the common epithelial cancers, it turns out, as a result of the research done in recent years, do exist that can recognize the products of the mutations. But the immune system against them is too small. It's not vigorous enough. What does that mean? Create enough cells, create receptors that have a high enough avidity for recognition to the tumor. The immune reaction is not very strong. And the growth of the tumor can overcome the small impact that an immune reaction might have in killing some tumor cells. Plus, for a tumor cell to survive and grow, it develops certain properties that can suppress the local immune reaction. It can make molecules like transforming growth factor beta, TGF beta. It can make cytokines like interleukin 10. It can cause the development of cells, lymphocytes, that inhibit immune reactions. I mean, virtually every physiologic system in the body has stimulatory elements and inhibitory elements. You have hormones that can increase gastric secretion, some that can decrease it. You have a sympathetic nervous system, a parasympathetic nervous system. Well, the immune system is the same. It has effector cells that can be very aggressive in recognizing antigens, and it has regulatory T cells that deliberately suppress immune reactions. And that's one of the things that keeps us from developing autoimmune disease. But there are many of these regulatory elements recently described. Myeloid derived suppressor cells can suppress immune reactions. And so it's the balance of the aggressive immune reaction against the inhibitory molecules that can prevent that immune reaction. That is the holy grail of trying to find effective treatments. And effective treatments come in both directions. Interleukin 2 stimulates immune reactions, and we now have checkpoint modulators like ipilimumab or PD1 inhibitors that can inhibit these inhibitory factors and thereby stimulate the immune reaction by taking away the brakes on the immune system. So the more we understand, the more we can take advantage of the biology.

So let's go back to the first of those, because that seems to have been the first big break you got at NCI after Gallo's discovery was Interleukin 2. So now you had both a cytokine that could allow you to grow lymphocytes in vitro, but also something that could be given to patients in vivo to stimulate the immune system. So how did that sort of propel your work?

Well, with the advent of Interleukin 2, what had been shown was that there were some bone marrow cells could make a substance which would keep lymphocytes alive outside the body. But the minute I heard about that, there were a series of questions that arose. Well, if it kept lymphocytes alive, would it keep lymphocytes alive and dividing in a format that enabled them to have all of their immune recognition, that is, as they grew, they just lose that property. And so we try to demonstrate that by developing cells that could recognize what we call alloantigens, that is, very strong antigens that are present in one person that inhibit the ability to transplant organs, for example. And so our initial studies were to see whether or not we could develop lymphocytes, grow them in culture, and cause experimental skin grafts in mice to disappear faster. We're not talking about tumor. That's normal tissue. And we showed that, in fact, we could grow lymphocytes that retain their function in the laboratory and then retain their function in vivo. Well, with that knowledge, we didn't want to cause skin grafts to disappear more quickly. With that knowledge, we had to try to develop cells that could react against the cancer. And very early on, when we grew cells in interleukin 2, we found that, in fact, they could destroy tissue. Cultured cancer cells have some impact on normal cultured cells as well, just by virtue of exposure to interleukin 2. And we call them lac cells, lymphocyte activated killer cells. And we studied them for three or four years. Turned out to be a false alarm, because they could impact on tiny little tumors in mice before they became vascularized. But by the time they were vascularized, they would not work in mice at all. But Interleukin 2 seemed like a molecule that might be able to stimulate those rare cells in the body that could recognize the cancer as foreign or develop cells in the laboratory that could do that recognition. And that then led us to many years and of experiments in the laboratory, but also clinical trials trying to see whether or not either interleukin 2 administration alone, or cells that you could devise in vitro that could recognize a tumor and administer those. And that was a very frustrating time. It wasn't until 1984 that we finally figured out a way to use interleukin 2 to mediate regression. We treated over 70 patients with either interleukin 2 or cells that we grew in interleukin 2 and administered to patients without Seeing a response until we modified the schedule of interleukin 2 administration, knowing it's pharmacokinetics, that is, only after half life inside the body of about seven minutes. So we had to alter the schedule. We had to give higher and higher doses, which mediated toxicity, until finally, a patient that we treated in 1984 who had widespread melanoma was administered interleukin 2 and was the first patient, finally, after over 70 other patients, to show us a tumor regression, the first time that a deliberate immunologic maneuver could reproducibly cause cancer regression. It was one of the few eureka moments that I've had in doing research. But the realization for finally that after all of those patient deaths due to everybody had advanced cancer, all would go on to die of their cancer, survived. And that patient, now alive over 35 years later, free of disease.

It reminds me a lot of Thomas Darzel's work in the 1960s with liver transplantation, where the number of patients who died, it was hard to keep track of before finally achieving the technical success that was necessary. Both the perioperative care and the postoperative care, and the technical skill necessary, plus the immunosuppressive regimen. All of those four things had to be firing on all cylinders for patients to finally undergo liver transplantation. And this patient in 1984, if I recall, was the 67th patient treated, meaning 67 consecutive patients died of metastatic cancer and were unresponsive to Interleukin 2. The first question is really just a logistics question. How many different histologies were in that group? How many different types of cancers were you treating at that time?

We were treating all cancers, metastatic cancers, with the idea that although they each arose from different organs, had somewhat different properties and methods of spread, they would be commonalities that could be attacked. And so we were treating all kinds of histologies. It was the first patient that we treated with this revised regimen happened to have a melanoma. The third and fourth patients had renal cancer. And as we continued to use interleukin 2, we found that those two histologies, patients with those two histologic types of cancer could respond. And ultimately response rates in those two diseases turned out to be about 15 to 20% of patients, with about a third of those patients having complete, durable, durable regressions. But it was a little different than the liver transplant situation, because in that situation, there were technical problems that had to be overcome. And it was a genius of Tom Starzl to stick with it. And to figure out those technical problems. When it came to immunotherapy for cancer, it was a little different. We didn't know that it would ever work. We didn't know that there was ever going to be an immune system that could cause a cancer to disappear. In contrast to if. Well, you could work the technical problems out or sew the vessels together, you could get this thing to work. And so that first patient had an enormous impact on me and on the field because it showed that it was possible. And until you know it's possible, you never know that it's ever going to occur. And so that changed everything, because it showed that simply administering this one molecule, A t cell growth factor, could cause a cancer regression in a patient. And that then led us to studies to understand how that was occurring. And that then led to a lot of different directions. Cell transfer, gene modification, and so on.

How did you keep going in the face of all of those failures up until this patient's miraculous remission in 1984? Because, again, if you were working as a surgical oncologist at the time, you, would not have been exposed to that death. The surgical oncologist's work would have been done after the primary resection. Typically, the medical oncologist would be the one that would be at that patient's bedside as they progress through treatment. But you were seeing something that you would not have seen had you chose a different arc to your surgical career. And I just. I wonder how you coped with that. What were those drives home, you know, what was it like to be alone in your thoughts?

Well, you know, as I look back on it, it seems remarkable that there were so many patients, One after another, Everyone died eventually of their cancer, but because we did not have any impact in the manipulations that we were applying. And you're a doctor, and you know that it's not the patients that do well that you remember, it's the patients that you fail to help that you remember. And there was just a remarkable number of tragedies, Young people dying of cancer, people of all ages. But I had this intuition Based on everything I knew about biology and everything I had studied in biophysics. I had an intuition and also influenced by these inklings of the first two patients I mentioned that this would work. I recently saw a quote by abraham Lincoln that said, success consists of moving from failure to failure without loss of enthusiasm. And that actually happened to me. I actually just saw that quote a few months ago. But I always felt it was going to work, and it did, eventually. And a Small number of patients, still a long way to go. But at least now we have effective immunotherapies for a variety of diseases that can be effective. And when that first patient responded, it all exploded in my brain. This does work. This can work. And we'll figure out now ways to make it better.

And I imagine Alice was a big part of that support for you. Again, I have the privilege of knowing her and knowing how important she is. Do you think you could have got through this alone without the support of your family? I mean, you had to do this very difficult thing, which was basically have this remarkable obligation to your family, which every father does. And at the same time, you felt like you were carrying the weight of the world on your shoulders, trying to take care of these patients who were otherwise really left with no hope. Do you see that as sort of a synergy between those two?

There were probably, and I'm not exaggerating, 40 days in the first 40 years of my work here that I was in town, not traveling, that I was not in this hospital. I would come in every day, of course. I would come in every Saturday. Sundays I would come in to go over research with some of the fellows. You probably remember that, or see some patients. And that kind of life requires support of some kind. And there are not a lot of wives who I think would tolerate that kind of commitment outside the home. And Alice was such a person. Never hassled me about it. Always understood that. I remember once she said, look, I know what you're doing is important, and so what I'm going to do as much as I can, is relieve you of the burdens that we commonly face as part of daily living she handles. I haven't written a check in 20 years. Alice pays our bills and really takes care of so much that enabled me to work at that level. But it was a family thing. I have three daughters who are growing up as all of this was happening. And I remember when my oldest daughter applied, first order, applied to college, Beth, she opened her college essay with it, sentenced somewhat along the lines of at our dinner table, at home, were much more likely to be talking about cancer and AIDS than the Washington Redskins, and made me understand how much the kids had been affected by all of this talk of death and suffering from these diseases. So it takes a family, and I doubt I could have done it without that kind of support.

So once you identified this patient, patient number 67, did you have an inkling what it was about melanoma and renal cell cancer that made them particularly immunogenic Relative to this whole host of other epithelial cancers that were less reactive.

The answer is no. But the answer would be yes 35 years later, because I think now we do understand what's different about melanoma. But we didn't at the time. We were seeing responses to interleukin 2 in patients with melanoma and kidney cancer, but no other diseases would respond to Interleukin 2. And we learned that the hard way, treating over 600 patients with Interleukin 2 here at the Clinical Center. It turns out those two diseases were uniquely responsive. And we now know, at least for melanoma, why that's the case. And that is the immune system system is recognizing the products of mutations and melanoma. If one looks at the number of the frequency of mutations among different cancer types, Melanoma has more mutations than any other cancer type, with the exception of lung cancer. They're about equivalent, about 400 mutations per tumor as a median. And that's very likely because melanoma induced by a carcinogenic ultraviolet light, Lung cancer by the carcinogens, largely in cigarette smoke or the environment, that leads to an increased number of mutations. And that at least is part of the answer. And that is the more mutations you have in the cancer, the more likelihood that you'll develop a particular protein, foreign protein, that can be recognized by the immune system.

Did you ever see patients with lynch syndrome response? They would typically have many mutations as well, wouldn't they?

You're exactly right. So there are some situations, like the microsatellite, unstable cancers, colon cancer, Other kinds of cancer types, lynch syndrome, but we didn't understand it was mutations that were involved at that point. And I don't remember ever treating a patient with lynch syndrome. You're right. They would have a very large number of mutations.

So for comparison, if we talk about a standard. You can't even use the word standard. There's no such thing as a standard cancer. Right now we know so much about cancer that every cancer cancer is different. But what would be the median number of mutations in a metastatic breast cancer, colon cancer, or pancreatic cancer?

You would probably encompass 80% of these common cancers. If you considered mutation frequency between 60 to 70 and 150, that would be the major. The median would probably be somewhere about 110, but it would vary from cancer type to a cancer type. Some pediatric cancers have very few mutations. Some cancers have more, but about, I'd say the median very likely to be about 110.

How many of those Mutations would be driver mutations. So they are oncogenes, Tumor suppressor genes. They are playing a functional role in the cancer Versus what we might call passenger mutations that can still produce antigens. They would still generate a peptide that could be recognized by mhc, but they're not playing a functional role in those two properties of cancer that we spoke about.

So about six years ago, we described an assay that would enable us to actually identify the exact molecular nature of these antigens that are recognized by T cells. And that came from, again, the understanding that it was the products of these unique cancer mutations that were being recognized by the immune system. Well, it turns out that some of these antigens that are recognized by T cells Are recognizing the proteins that derive from driver mutations, that is, that cause the cancer in the first place. Like p53, present in half of all cancers, but only about 2% of patients develop immune reactions against it. KRAS, about 90% of pancreatic cancers Will have that as a driver mutation. But what's stunning to me about oncology and the biology of cancer, and that is how few of these shared cancer mutations exist. There's p53, there's KRAs to some extent, pIK3CA, and breast cancer, maybe BRAF mutations in melanoma. Other than that, the incidence of driver mutations As a cause of cancer Is low. Single digits. You'd think there would be many mutations that would change the cell so dramatically. But it turns out it's not only those few driver mutations, but the accumulation of mutations, each with its own property, that in and of itself Appears unlikely to cause cancer. But in concert with the action of other genes, Other mutations does cause a cancer. And we've more recently shown In a breast cancer patient that we published a few years ago, that we could mediate complete, durable regression now, over six years later, by targeting four what appeared to be random somatic mutations, none of which had a driver function, but in concert, cause the cancer, and by attacking them, you could cause cancers to disappear.

I mean, I still. I'm struggling to understand why it is that a P53 mutation or a kras mutation Is not immunogenic. Is that simply due to the evolution of cancer, that because of the ubiquity of these mutations in cancer, Cancer has come up with enough evolutionary tricks to evade detection of those mutations? I mean, that's a teleologic question, But, I mean, do we have any biologic insight into this?

So you have to dig a little deeper into the biology. For a mutation gives rise to a molecule, a protein, Right. It's DNA, RNA transcribed, translated into a protein for that protein, even though it has now a mutation, a string of amino acids that are not seen as normal by the body. That mutation, that abnormal amino acid called a non synonymous mutation, is only recognized by the immune system if the molecule in which it occurs is broken down inside the cell into small peptides, I.e. small sequences of amino acids. Or the tumor cell or the antigen presenting cell takes an antigen, a protein, from the outside of the cell into the cell and breaks it into small peptides, strings of amino acids. Well, that has to happen. And then one of those strings of amino acids has to fit onto the surface of the patient's own HLA molecule. That is the kind of molecules that we call transplantation molecules. And so for a mutation to be recognized by the immune system, it has to be broken into these 9 to 11amino acid peptides and fit on that patient's own transplantation molecule. And that transplantation molecule is highly polymorphic. There are hundreds of them. And so if you had a mutation and your cells made small peptides, but it didn't fit on your HLA molecule, it wouldn't be recognized by the immune system. And so, as we've learned more in the last five to six years about what cancer antigens are, it's these mutations that are broken down and put on the surface of a patient's presenting cells or tumor cells, and that turns out to be between 1 1/2 and 2% of all mutations. And when you look at melanoma, it's 1.3%. When you look at the gastrointestinal cancer, it's 1.6% breast cancer, 2.1% of mutations are immunogenic because they happen to fit into that individual patient's HLA molecule. And the most stunning finding of recent years, in my view, in this field, is that virtually every patient recognizes a unique antigen. And so we're in the process of writing a paper now on 195 consecutive patients that we've identified the exact antigenic nature of what the T cell can recognize and it can recognize in about 80% of all histologies. And that turned out to be 363 individual antigens that were recognized in these 195 patients. And no two patients shared the exact same antigen, with the exception of two patients that had a KRAS mutation that was recognized on a very rare class 1 molecule, CWO 802 HLA molecule.

So just to make sure I understand that you're saying that in this series of nearly 200 patients, the first interesting finding is each of them produces at least one neoantigen that is immunogenic.

80% of patients will.

Yes, okay, 80%. And secondly, outside of the kras overlap, they were novel across the board.

That's right. Of those 393 antigens, 392 of them were unique, not shared by any patients with the exception of KRAS. That's not to say that P53 or other driver genes can't recognize it, but they don't naturally recognize it. You might be able to raise those very rare cells, but that's correct. It's good news and it's bad news.

Explain why that is to people. Because I was just about to say that's really good and creates a huge problem for scale.

You got it exactly right. It's good news because we finally understand after all of these decades what a cancer antigen is. Back in 1985, I knew one existed. I didn't know what it was, whether it would be shared. And we spent an enormous amount of time Trying to identify shared antigens, Especially in melanoma, these melanocyte antigens shared by normal pigment producing cells. But now that we understand what an antigen is, and we understand that most cancers contain multiple mutations which give rise to the antigens. Well, since almost all cancers have mutations, if we can figure out ways to target these mutations that are foreign, we potentially have a treatment applicable to all cancer histologies. Since almost all cancers have mutations, recognize them. And now you don't have to worry Whether it's a breast cancer or a colon cancer or a brain tumor, the T cells are there. So the possibilities of developing broadly applicable treatments exist. The bad news is, as you point out, it's going to have to be, as you target these mutations, Highly individualized treatments. Unless you can fully unleash the immune system against even the most minor of antigens, which we can't do. Now, checkpoint modulators have virtually no impact on the overwhelming majority of the solid epithelial cancers. It means that if you're going to stimulate immune reactions via a vaccine or a T cell as a drug, it has to be individualized to target that cancer, because that antigen is present only in that patient, but not in any other patient. And that's going to make it very complex to develop. But when we developed this other form of T cells, car T cells, a whole other story, people said that it could never be applied. But in fact, if you have something that works and can cure people, the genius of modern industry Will figure out ways to make it available.

Well, I wanted to go back to 1985 to pick up the story with both Ronald Reagan and tittle unrelated but temporally related. But before we do, because you brought up car T cells, let's tell the story about the diffuse B cell lymphomas that ultimately led to kite because it's a great way to. I think most people listening to this will have heard of a car T. This is an illustrative case to explain how they came about, how they differ, of course, from a regular T cell receptor, and as you said, how industry basically came in to solve a problem that at the outset looked pretty daunting. So pick it up wherever it makes sense with respect to.

So again, you have to understand the biology. You have to go back to the biology that normal T cells have receptors that can recognize antigens on the surface of a cancer cell, right? These tiny peptides that are put on the surface, those alpha beta chains, are expressed by a lymphocyte. And that's how the immune system recognizes antigens. Well, there's a way to create an alternate way for a lymphocyte to recognize an antigen. It was created by some scientists at the Weizmann Institute about 10 or 12 years ago. Zeligashar and Gideon Gross, they took advantage of antibody recognition. Now, antibody recognition is very different than that of T cell recognition. Antibodies recognize the three dimensional structure of a molecule on the surface of a cancer cell or of any cell. Not a processed peptide brought to the surface, but an actual molecule on the surface. And that antibody, like a lock and a key, will latch onto that antigen and recognize it. Well, T cells can't do that. But by creating a chimeric T cell, you put antibody recognition domains into a lymphocyte that converts the lymphocyte from its normal recognition, from its own receptor into the recognition of this antibody that you've put into the lymphocyte. And that expands the number of molecules that can be recognized by T cells. And so it's this chimeric antigen receptor, which is part receptor, normal receptor, but with antibodies attached to it, that enables the lymphocyte to recognize, now, molecules that it never was able to recognize in the course of evolution based on antibody recognition. And it turns out that there are very few molecules on the cell surface, very few. Like I could name the few I know of and the fingers of one hand that are unique to a cancer that are not on normal cells. And we learn the hard way that the immune System will destroy a normal cell just as quickly as it will a cancer cell. And we've mediated cancer deaths by targeting antigens that are present even in very low levels on normal cells. Well, it turns out there's a molecule on B lymphocytes called CD19. We don't exactly know what its function is, but when B cells turn into lymphomas and leukemias, they continue to express CD 19 with this understanding. And as soon as I heard about these chimeric T cells, I invited Zelageshar to come to a sabbatical in my lab. He came the next day, the next year, and spent three years working in the surgery branch. We worked out ways to use CAR T cells to attack cancers. But we could never get them to disappear because the molecules that we were giving could not be used in large enough in numbers because of their ability to recognize normal. Well, CD19 expressed by Leukemias and lymphomas, they develop from normal B cells express CD19. And we developed a technique to introduce these anti CD19 car molecules, chimeric antigen receptors, into T cells to create a CAR T cell that when we administered to patients, would kill every cell in the body that expressed CD 19. So all the normal B cells were eliminated, but so too were lymphomas and leukemias. And that became the first actual cell and gene therapy Ever approved by the fda. So how did that happen? Well, we studied the ability of these anti CD19 car T cells to kill cells and experimental animals. And they did. They wiped out normal B cells. But you can live without normal B cells because you can give antibodies by giving antibody infusions. We used these CAR T cells to treat the first patient Ever to receive a CAR T cell. This was in 2009. This was a patient that had a lymphoma that had spread throughout his chest, had been through four different chemotherapy regimens, had enormous kilogram tumor burdens in his body. We treated with CAR T cells that could recognize a CD19 molecule on the surface of normal B cells and tumor. And all this tumor disappeared. And he's well, we treated him in 2009. He's 12 years later and completely disease free. We published a series of those over the course of the next two years. And we had seven or eight patients who had a complete disappearance of all of their lymphoma. Diffuse large B cell lymphoma is the most aggressive form of and lethal form of lymphomas that people develop. And they develop complete regressions that were ongoing for at least seemed like Several years. Well, once we did this, and incidentally, all the patient's normal B cells disappeared. But again, you can live without B cells. And so in 2011, two years later, after we had published several of these papers, and a year after we published that work, Carl Jun at the University of Pennsylvania used these CD19 car T cells to treat leukemia patients. Two years after our description of multiple lymphoma patients undergoing a complete regression, I was contacted by a former fellow named Ari Beldiran who had worked in my lab 25 years earlier. He just finished his urology training, became a professor of urology at ucla and he we had become friends and he came to see me in 2011 saying, hey, you're treating patients with these T cells, these chimeric T cells, these CAR T cells, and successfully treating lymphoma patients. I want to commercialize this, I want to start a company to do this. And we had had several companies come through, like Johnson and Johnson, brought in 12 people, examined everything we had done, said, hey, if we have a lymphoma, we'll come back and get treated by you. But we don't see how we can make any money doing this at Johnson and Johnson. Well, Ari Beldegon had a different vision. He said, we can figure out a way to make this available. And in 2012, we formed what's called a crate, a cooperative research and development agreement that enabled us in the lab to work with this company. This biotech company started Kite Pharma. They were able to give us funds to help support the research, research. And so we started that in 2012. We signed the CRADA. We worked together, we treated over 50 patients, showed that this could happen, and over half of patients will undergo durable regressions. He then did a multi institutional study, and Novartis was doing this in leukemia patients. Almost simultaneously, his multi institutional study reproduced the results exactly about a 70% objective response rate with 50% durable complete regressions. And in 2017, five years after Kite started working with us on this, Kite was sold to Gilead for $11.9 billion. That all happened in the course of those five years. And that treatment is now available, thanks to Kite and Novartis, available for use in patients in the United States and Europe and parts of Asia that can effectively treat these B cell lymphomas and leukemias. So really a pretty incredible story that evolved so rapidly.

Yeah, it is. I mean, do you think that CAR T cells can have efficacy against non hematologic cancers?

Right now the answer is no. We have no way to use Them against solid cancers. Again, because the solid cancers, to be treated with a car T cell, you have to have a molecule on the cell surface that's unique to cancer. We originally didn't fully realize quite how sensitive they could be. And when we targeted molecules that were on normal cells, patients died. Devastating events in the development of the treatment. But monoclonal antibodies were first described about 45 years ago. And no one has found unique monoclonal antibodies against molecules uniquely on cancer cells and not normal cells. And that's what you need to make a chimeric T cell receptor. You need an antibody that you can put into a lymphocyte that has specificity. And antibodies just have not evolved to recognize individual cell surface molecules on cancer which are shared by normal cells, Whereas conventional T cells do, because internal proteins then get digested and brought onto the surface. So right now there's very little prospect for car T cells being useful for the treatment of solid tumors. But that's not to say that some brilliant ideas will come forth in the years to come that will make them available. Right now, they're not useful.

Now, what about for organs that are not essential? So where you could waive the need to recognize or differentiate between cancer and non cancer. So for example, breast or even pancreas, I mean, if a person had metastatic pancreatic cancer and you were willing to completely lose both normal and non normal pancreatic cells and render that person a type 1 diabetic, it would still be worth it. So are there any antigens that are present on exclusively pancreas or exclusively breast or colon? Obviously this wouldn't work for liver and lung, but is that a slightly easier problem to solve or is it just as hard?

Well, it's just as hard because for the past 45 years, some of the best immunologists in the world have tried to develop these monoclonal antibodies that can uniquely recognize cancer. And they have not found any either because they haven't done it right, or there just aren't these molecules on the cell surface. And even very recently, last several months, you probably heard about this T immunity, these two deaths for patients that were targeting what was thought to be a prostate specific molecule, bsma, but it was present on normal cells and that can result in death of patients. And so, yes, if you could find the molecule unique to prostate cancer, breast cancer, that is expendable organs, you could develop more effective cell based therapies against them. But right now, none of those molecules have been identified.

So let's now go back in time. To post the IL2 insight, you have this other amazing realization, which is there are certain types of lymphocytes that manage to track to tumors these T cells that infiltrate the tumor, and they're called til. How did you come to understand these and understand the efficiency with which they could identify tumors?

So things seemed to move very slowly, although we had an explosion of ideas. But looking back on it, when it comes to scientific advance, it actually moved along pretty quickly. Because Illinois 2 as a T cell growth factor, was mediating reproducible regressions, it seemed reasonable that it's being mediated by the ability of inter interleukin 2 to stimulate lymphocytes in vivo. And so in melanoma patients, we looked for T cells that could recognize the tumor deposit itself. We didn't know what it was recognizing. And what better place intuitively to look for a cell doing battle against the cancer than within the cancer stroma itself. And so we grew those cells one out of peripheral blood, but we also grew cells invading into tumor, called tumor infiltrating lymphocytes, or TIL cells. We grew them in vitro and in animal, and then very quickly in human experiments, grew those lymphocytes to large numbers in vitro and administered them to patients with metastatic melanoma. And now, Instead of the 15% response rate that we got from giving interleukin 2 alone, by giving lymphocytes that we grew in interleukin to these TIL cells, we got response rates 30, 35% in melanoma patients. And so it represented a substantial improvement. But they were pretty short durations. They were real, but they did not appear to be durable. But it was the first demonstration that lymphocyte transfer as a sole modality could cause tumor regression in patients with melanoma. And to some lesser extent, kidney cancer was mediated by lymphocytes. So that intuition then became a reality of a biologic finding. And that is, lymphocytes were the cause of these regressions or could be the cause of regressions. And then things moved along fairly well, slowly and quickly, depending on your point of view. It immediately became apparent that if we had these lymphocytes naturally, maybe we could genetically modify them to be more potent, that is, they were making factors that drew other cells in. Well, let's introduce that gene into them. But no one had ever introduced a gene into human cells. And so I teamed up with two scientists at the nih, French Anderson and Mike Blaze, who were trying to develop gene therapies to replace adenosine deaminase deficiencies, a lethal deficiency in young children to see if they couldn't introduce those genes. But of course, no genes had ever been introduced into people. We decided to see if we could break the ice about putting foreign genes into humans by putting a marker gene into the lymphocytes we are administering to patients. We picked a gene, a bacterial gene called neomycin phosphotransferase, inserted that gene into a patient's normal lymphocytes, and our plan was to administer them so we could track where these lymphocytes were going inside the body because they would have this unique bacterial gene. They were being expressed. We proposed that to investigational review boards. At that point, the government had established what's called the Recombinant DNA Advisory Committee, the rac adequately named who had a review. Any clinical proposals we went through. We tabulated 117 different review groups, having to go back and forth as they made changes until the RAC finally voted. It was a painful time, 13 to 4, to allow us to do it. But the director of the nih, James Weingarten, insisted that before we would start tampering with the human genome, we needed unanimous consent, back and forth, making changes. Finally there was a vote of the RAC, 13 to nothing to zero with one abstention, which was unanimous. And so we got permission to proceed with the clinical trial. Biotechnology activists and filed lawsuits against the NIH saying we shouldn't be tampering with the human genome. It was immoral, it was ungodly. But we finally got permission to do it and inserted these lymphocytes that were genetically modified with this bacterial gene. That did enable us to track the cells inside the body. When we did biopsies at a paper we published in New England Journal of Medicine. And that then led to the gene modifications of lymphocytes that we attempted to use to improve them. We put in the gene for interleukin 2 that didn't improve them because we couldn't regulate it. But it just started our endeavors to genetically modify cells that finally came to their fruition in the CAR T cells by inserting the genes that would insert these new receptors that could recognize molecules on lymphomas and leukemias. So that started us on the track of trying to improve the cells. And then there were a variety of advances. We learned that you had to first wipe out all of these inhibitory T cells regulatory cells before you gave the administered cells. And that then jumped the response rates up to 55% in melanoma patients with about 25% being durable complete remissions. We then started developing ways to use T cells to do cancer treatment. 2013 finally realizing that it was unique mutations, we developed techniques that enabled us to develop T cells specifically targeting mutations and published the first paper that in 2000. It was a patient with a bile duct cancer cholangiocarcinoma that was widespread in the lungs and liver. We gave her bulk til cells did not work. We gave cells that were uniquely directed against her mutations and she's undergone a dramatic regression, is now disease free.

But those were til that were not genetically modified.

Those were the natural. So our work went in two directions. Genetically modifying till or figuring out ways to use natural til. These were natural TIL that were selected for mutation reactivity and given to a patient whose natural immune system was temporarily eliminated. She's living disease free now. Eight years later, all of her liver and lung disease is gone. We subsequently now have published on these T cells that recognize unique mutations in their ability to cause regression and cervical cancer induced by human papilloma virus by colon cancer. That patient recognized Kras breast cancer, recognized four random somatic mutations. We're now struggling to figure out ways to more efficiently target the products of unique mutations that cause the cancer. Sort of ironic that the Achilles heel of the cancer is going to be the very abnormalities that caused it in the first place. And so that brings us up to 2021. Can we now take advantage of all this new biologic information about the role of mutations and T cells that target them, about the ability to genetically modify cells in large numbers using retroviruses? Can we take advantage of that technology, that biologic information, to develop more effective immunotherapies in the years to come? And that's what we're working on today. That's what we're working on in the lab as we speak.

Well, I want to go back a little bit and talk about a few other things, both for posterity, I suppose, and also because I think there were some other things we've glossed over quickly. But in 1985, you had this opportunity to operate on the then president of the United States who had developed colon cancer. Why is it that you were a part of the team that would take care of the president? Why is it that the chair of the National Cancer Institute would be involved in the president's care? Was that, is that something that's sort of mandated at the federal level?

No, it's part of the aberrancy involved in treating high government officials. It turns out that there is a set of modules in Walter Reed or Bethesda Naval Hospital that are set aside for the treatment of the president. It's an isolated set of rooms. I learned this as it happened. I didn't know it ahead of time. Where the kinds of equipment and availability of technologies was available so the president could actually run the country from his hospital bed. But it turned out that it was the physicians in this particular case at Bethesda Naval Hospital, and they have marvelous doctors there that would be treating the president. And it turned out that the chief of surgery at Bethesda Naval Hospital had just rotated off an aircraft carrier to be the chief of surgery at Bethesda Naval. It would change very commonly, as officers in the Navy had different assignments. And he happened to be an expert in vascular surgery, not oncology. And he was the one responsible for calling the shots about the patient's cancer. And it turned out he was a excellent doctor and excellent vascular surgeon, but not an oncologist. Never really was operating on cancer patients in any volumes. And so they needed an expert in oncology to take part. And just out of the blue, one Friday evening, I got a call saying, would you come over to Bethesda Naval Hospital? We have a patient we need your help with. And it turned out to be President Reagan. And it was simply because I was nearby. I had previously gotten a security clearance because I had tentatively been assigned to be part of a medical team that would take care of high government officials in the case of calamitous nuclear emergencies. So it was because the vascular surgeon was in charge, and I was across the street that I got called and took part in that surgery.

And if I recall, at the press conference following the surgery, you explained point blank that the president had colorectal cancer. And if I recall, Nancy Reagan wasn't too pleased about that. Right?

No. And I'm not telling stories out of school here about a patient because it was public information. And he later wrote a memoir that describes some of this. But Nancy Reagan, when we had to have a press conference and they were a little concerned about having a vascular surgeon hand the questions, and I had been as an operating surgeon, as part of the operating team, she before I went on to hold a press conference, I remember standing backstage and she said, you cannot use the word cancer in describing this, because if foreign officials think the patient has cancer, the president has cancer, they won't pay any attention to him anymore, thinking he would not be around. And I said, I'm sorry, I can't do that. You know, If I have to, I go out. I have to just tell the truth. And it was Don Regan, who was the chief of staff, who finally talked her off that ledge and said, look, we've just got to let him do what he wants to do. So we went out and the surgeon who led the discussion just basically read off the the path report is an adenocarcinoma, just a portion of the colon and so on. And nobody understood what he said. And so they asked me to explain it. So I said the president has cancer. Which got me into all kinds of trouble. I later learned that when Vince DeVita, who was the director of the NCI, resigned to become chief at Memorial Sloan Kettering, I was on a short list to become the director of the nci. Not a position I would have thought of accepting. And I was told at that point, when I actually wrote this book in 1992, that my name got taken off the list as someone who would become the director of the nci. He was very upset that I used the word has cancer and not had cancer. That is past tense. But we got over it. And the president did very well and recovered and never recovered from his is early colon cancer.

You mentioned it in passing earlier that although you've been in the post you're in now for 47 years, along the way you've had a few job offers that have tempted you. I'm sure you've had many job offers. What are some of the other ones that tempted you? At least where you thought you could even do better work or continue your work because obviously you're so mission focused. It's. It would be a special opportunity that I would imagine would get you to leave nci. But what were some of those other opportunities that you even contemplated?

There were only three that I looked at once. One was here at Georgetown because of a relationship I had with the surgeon in terms of collaborating things. And it was sort of a favor to him to look at the job. I was also invited to look at the job as chief of surgery at Hopkins, and ultimately I was told got boiled down to John Cameron and me on the short list. But I went back a second time, but refused to go back a third time because I knew I would not go to Johns Hopkins and leave the nih. I was also asked to look at the job at the Brigham where Murray Brennan, a friend of mine, and I were again being pursued to accept that position. But again I backed out. I knew that I didn't want to take an administrative job. I wanted to be in the Lab. I wanted to be mentoring fellows. I wanted to be trying to make progress. I didn't want to guide other people making it, I wanted to be there. I wanted to be doing it. I wanted to be guiding it because I thought I could do it well. So I actually refused any of those offers, never looked at another job and actually turn down opportunities to advance in the hierarchy here at the nci. Because I wanted to remain at the level that I'm at the control of resources that enabled me to pursue the kinds of research that I thought needed to be done in an environment of enormous resources.

So let's talk a little bit about checkpoint inhibitors. They've come up now a couple times in this discussion. You've mentioned anti CTLA 4 and anti PD1. Certainly my time at the NCI, my second stint got me very familiar with NTCTLA 4 and it was an exciting time. And of course, James Allison would go on to receive the Nobel Prize a couple of years ago for his work in the discovery of this. Maybe go back and explain how that system works, how the remote removal of brakes works. And of course, as part of the undercurrent of this, it only works if there's a tumor antigen to be recognized. In other words, taking the brakes off when there's no stimuli doesn't do anything. But how does that system work and how is it a two edged sword?

So again, there are stimulants and there are inhibitors of virtually every physiologic system that we have. And one of the inhibitors are molecules on the cell surface, on the surface of a lymphocyte that when engaged by a receptor, will inhibit a lymphocyte from developing an immune reaction. And surprisingly, there are two molecules that have been found on the cell surface now, many more that when targeted by an antibody, will not kill the cell, but actually turn off the brakes that are keeping that cell's activity from exhibiting itself. So it's releasing the brakes. And it turns out to have a very important function in the body because there are some cells that can react against normal tissues that do not react because they're being inhibited by these brakes. And when you release those brakes now, the T cell can be very active. And it turns out that cancer has manipulated those. And by taking the brakes off, you can attack certain cancers. And explains why melanoma is one of the more common cancers to be attacked because it has so many antigens, so many mutations. And it was a startling discovery that simply attacking a molecule, a single molecule on the cell surface could take the brakes off a lymphocyte and let it attack cancer. And when it comes to melanoma, kidney cancer, cancers that have large numbers of mutations because they have mismatched repair gene mutations, lynch syndrome, emsi, the microsatellite unstable tumors, they can very strongly react against cancer. But the common epithelial cancers that result in 90% of deaths in patients have very little reactivity against the checkpoint modulator. So although they can be life saving and very likely, although it's been too soon curable for some cancer patients, the overwhelming majority of cancer patients just do not respond to taking off the brakes. Because when you take off the brakes, there's not a strong enough reaction to take advantage of. But hopefully combinations of treatments using checkpoint modulators will be more effective in the future. But it was a major step forward. And the beauty of it easy to apply because all it required was the injection of an antibody.

So when you think about these amazing conceptual advances in the field, the ability of car T cells to recognize CD19 on B cells and eradicate any lymphoma originating from that lineage, the CheckPoint modulators, Anti CTLA 4, Anti PD1 and the durable effect that they can have on patients in whom you have enough mutagenic burden that relieving the checkpoint is enough to initiate it. Obviously, what you've alluded to earlier with IL2, high dose IL2. I don't want to at all sound disparaging, but just for the lack of. Let's just call that the low hanging fruit of immunotherapy, which is of course completely ridiculous, given that that's 50 years of work and countless lives. But if for the sake of being cheeky, the low hanging fruit of immunotherapy are those pillars, do you believe that the final frontier to go from where we are in 2021 until the point where all of those. Let's just call the 550,000 patients with solid organ metastatic cancer who have neoantigens, or 80% of them have neoantigens that are unique to them but not occurring in high enough frequencies that they will respond to a checkpoint inhibitor in isolation and or in combination with cytokines. Do you believe that there is a path for these people to be cured using adoptive cell therapy, either genetically or naturally occurring in some sort of a customized format. Do you think that that is the path forward from here?

My intuition is very strong that the answer to that is yes for a variety of reasons. One, we know it can work for multiple tumor types and as I've mentioned, we've described it and published treatment of liver tumors, bile duct cancers, breast cancer, colon cancer, cervical cancer. We have responses in ovarian cancer that we've published. And so it's no longer a question of can it work in these other cancers. The answer is yes, it can work. And there's a world of difference. Like before IL2, we never knew that immunotherapy would work, but once it did, we knew the immune system could do it. Now we know that antigens recognized by T cells are present on 80% of the common cancers. And if you can develop unique reactivities, lymphocytes select reactivities against them and administer them, they can cause those regressions. And in fact, now, because we know the exact T cell receptor sequences that we've cloned and isolated, it's almost an engineering problem, because since we know the receptors, we've now isolated libraries of receptors against p53Kras that we can now use to genetically modify lymphocytes to turn a normal lymphocyte into a lymphocyte that can attack the cancer. And we have our first example of that now that we've submitted for publication targeting p53 by genetically altering a lymphocyte, by giving it a receptor that could recognize some of these driver antigens. So we know it can work. And tell you the truth, I finally feel like I have the hang of this kind of research and that by sufficient work, creativity, this is going to be a problem that is solvable. We know the antigens are there, we know that T cells are there. It should work, and it can work. And I 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 utilize these unique mutational reactivities to cause these solid common epithelial cancers that result in 90% of all cancer deaths. How to get them to respond to immunotherapy.

I mean, of all the eureka moments in your career, of which you've had several, this one seems to be the most promising. Which, of course, maybe they always seem that way when you're glowing in them. But do you see it that way? That every one of these milestones that came before this was vital, but this has the greatest potential, this recognition that virtually every solid tumor out there has novel peptides that can be recognized by a patient's own immune system.

Right. Now, realize how current this is. We published a lot of these individual cases that can respond. We published the first 40 or so colorectal cancers showing that mutations were all unique. But we haven't published much of what I've told you. So, for example, none of the breast cancer work has been published. We now have looked at these 195 individual cancers and found, regardless of histology, they're there. So it's very recent, this realization that mutations are the antigens. And now that T cells can recognize these mutations, it's really a new world. But that happens every time you make an advance. You find the immune system can be stimulated. Okay, well, let's get to work on figuring out how, you know, cells can do it. Let's figure out how. And science works that way. By incremental advances, we know this can work. And I have every confidence that scientists around the world will figure out ways to make it work.

That kind of reminds me of some of the important lessons that those of us who've been privileged enough to work alongside you have learned along the way. You never sort of pounded the table to make these lessons, but it was abundantly clear. And one of them was no secrecy. There was never any secrecy. I remember working on my experiments and before data were published, people from other labs, I don't mean other labs at nih, I mean other labs in different parts of the country. You would encourage me to reach out to them and share my results with them, Even running the risk that they would quote, unquote, scoop me. But none of that mattered to you. Your goal was what is the fastest path to the accumulation of collective knowledge in the field? Am I accurately representing that? I don't think I'm overstating that, no.

I've always been horrified by the secrecy that exists in medicine. And it's an ongoing problem. The need for biotech companies, pharmacologic, pharmaceutical companies, to protect their intellectual property, given current patent laws, prevents them, will often prevent them from sharing information, from sharing reagents, and this is holding back progress. If we could somehow overcome this secrecy that results from either people's own personal jealousies about wanting to be the one who does it, or intellectual property that companies have to protect to preserve themselves and raise funds to continue to do their work, we need kinds of regulations that will bring lawyers and doctors together to figure out ways to prevent that kind of secrecy from being a part of modern science. It's not like we're trying to create a better air conditioner. We're trying to save the life of another. Another human being. And I think when you take care of cancer patients, it Puts a lot of things in perspective. And the idea of having a policy or a rule that you live by that inhibits your ability to help people who could potentially be helped is abhorrent to me. I wrote, as you know, a perspective in New England Journal of Medicine, trying to change things, but they haven't changed. They're every bit as common today as they were back then. And as you know, the first thing a fellow hears in my lab when they start the first day is, look, anything you know, you share, any experimental result you have, you can tell somebody. Any experiment you plan to do tomorrow, you can tell somebody about. I mean, our goal is to help people that are involved in the. In the suffering of cancer. And there's no excuse for not doing everything you can to try to help. And that means sharing what you know.

On the other side of your office. Right. If one side of your office is the lab, the other side of your office is the clinic. The other lesson, I think that you've infused into the literally hundreds, you might even be into the thousands now of people who have come through and trained with you. Basically, this idea that one never retreats from the bedside. One of the things that struck me, actually, especially in medical school when I was there, because I spent the entire time on the clinical. I lived in the clinical ward, you may recall. I had rented an apartment in Bethesda, which I never went to, except on Sundays to get new clothes, but I slept in. I remember that.

Yes, you're quite a legend at the NIH with respect to that, incidentally. I mean, people thought I never left. But you never left. So it was really quite an experience to see you in operation there.

But the thing that was hard to believe and hard to process until you experienced it was 9 out of 10 people that walked in the door died. 8 or 9 out of 10 of the people who walked, because I think most people don't maybe understand because it's. It's implicit. But it should be stated. The patients who are coming to NIH have progressed through every standard therapy. People aren't coming here for whom there are standard options elsewhere. By definition, these are patients who have the most advanced, the most aggressive, the most recalcitrant cancers imaginable. These are people who would probably be expected to live no more than six months without a miracle. And they come to the NCI for those Hail Marys. And if 20% of them are saved, that's remarkable, but it means 80% of them don't. And I think what I remember most was the way in which you described taking care of those 80% and fighting the urgent to retreat from them because of the failure we saw in ourselves. How did you develop that? I mean, I assume it came naturally to you, but how deliberate has it been in how you teach those of us that came through?

You know, I have enormous respect for practicing oncologists who face this every day in their practice. And it's difficult, as you point out, especially when you give treatments that not only don't work, but actually cause some harm, which has happened in the course of the development of these treatments as we try to figure out exactly what we were doing and the right ways to do it. But I always had the feeling that I was working and working hard to try to improve the situation, to try to somehow repair this holocaust. And that kept me going. I don't know what it must be like to be taking care of cancer patients, knowing you have limited tools at your disposal that are not good enough, and yet that's all you have, and that's what you do day in and day out. I mean, that must be even more trying. And so I think one of the things that keeps me going at least, is the fact that I'm doing everything I possibly can, within reason, to improve the situation. Without that, I think it would be much, much more difficult. Yeah.

There are so many patients that I still remember from more than 20 years ago who were those ones that didn't make it. And I can't imagine how haunting it is for you sometimes, because I can see their faces. I remember their names, I remember their voices and I remember their stories. The newlywed girl who came to clinic one day and I mean, she had literally been married for maybe three months. A beautiful 25 year old woman with metastatic melanoma. And she was not one of the survivors. A young man whose name and face I remember every detail of. Single guy, metastatic melanoma. And what was most tragic in his case was I remember everybody kind of abandoned him at the end of his life. And I've said this before, I feel like cancer takes families that are close and brings them closer and takes families that are fractured and fractures them more. And I got the sense that his was fractured to begin with and he was maybe 26 years old. So I certainly understand the motivation. There's no lack of motivation for how you do what you do. I guess I'm amazed that you talked about how the immune system has the stimulatory and the inhibitory components. Well, it's similar that taking care of Patients like this, there's the motivation that comes from it to do more. But at some level, there's the depression of the death toll. I'm not sure everybody could do that. You seem to have found that balance.

Well, when I lie awake at night, it's not the successes that I think about, it's the tragedies. Patients that you're remembering even now that I'm sure are impacting on you. And it gets even worse because there are patients that we've killed by doing the wrong thing to them. Not understanding some of the underlying biology, that's the hardest thing to deal with. But again, given the fact that I'm doing everything that I can reasonably do to help them, it certainly eases the burden some. And as you know, being a doctor, what an unbelievable privilege it is to have the opportunity to help people like that, given the skills that you've developed. One of the first lines of the prayer of Maimonides goes, you have been given the wisdom to alleviate the suffering of your brothers. And that's true in medicine because we spend a lot of time just learning how to help people. It's a unique opportunity in the world and in life in general. So there are the satisfactions that you're trying hard, even if most often things don't work out. But there clearly are sleepless nights involved in all of that process.

The good news is you have wonderful longevity in your family. So despite being 81, I have every confidence that you're going to be doing this for many more years. I know you don't like golf enough to hang up what you're doing for the golf course. You know, I found the. I pulled this off the wall today. I wasn't sure if you still recognize these guys here. This is us from. I think this is 16 years ago. We both look quite a bit younger. And this is the only picture of me in my office is this picture. And it speaks to what an influence you've been in my life. I think the list of people who have had a greater impact on the course of my life than you is somewhere between zero and epsilon. It's a decidedly small list. So I feel forever in your debt. And though I have not been able to follow in your footsteps, your impact is greater than you could ever recognize.

Well, thank you for saying that. That means a lot to me, knowing that someone of your incredible intellect and perseverance feels that way. So thank you.

I know, again, what a sacrifice it was for you to take time today to speak. And I know that every minute you spent talking with me was literally a moment you were not working on this problem. So I'm beyond grateful and I know that the people watching this or listening to this are equally grateful. So thank you so much, Dr. Rosenberg, for everything.

Well, you're very well.

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