177 - The development of cancer immunotherapy and its promise for treating advanced cancers

hey everyone welcome to the drive podcast i'm your host peter etia dr 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 i've 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 1944 1940. so um what are your 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 uh going out west together and riding on horses and doing all kinds of exciting things but the first things i remember uh 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 the when i was about five or six living at home right at the end of the second world war when all of the uh 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 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 a 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 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 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 right through my education now you did very well in high school because or at least you we've never spoken about it but i can only assume you did because you were accepted to you know the best medical school and not only that but you you 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 you somehow managed to um get into the six-year program and uh what 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 in one of the sciences it turned out to be biophysics and hopkins was a very nurturing environment with respect to respect to that i as soon as i got to hopkins i started working in a biology laboratory in the afternoons and evenings doing some very uh simple projects in the biology lab but i i knew from the very beginning that i wasn't just gonna 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 blaylock still the chief of surgery was alfred blaylock yes and a 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 uh of calling people to task uh in front of others it wasn't the way that i thought education should 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 it 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 a this is as close to why i remember as a direct quote as possible is you never wanted to be intimidated by a differential equation um which which presumably was was was a bit of a shortcut for you you wanted the the biggest or the broadest uh education possible but um what what what led to that choice to i mean at that point in time for example did you did you know you had an interest in in immunology had that peaked your curiosity yet or were you still thinking just more broadly i knew i was somehow interested in the mysteries of cancer through high school biology and my college my college classes i got a phd because i wanted more formal learning i 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 to answer questions and maybe differential equations were in the 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 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 that i tried to 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 peterborough brigham hospital right out of medical school and then took off four years to get a phd in 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 uh join the immunology branch here this was during the vietnam war before going back to actually finish the residency in 1974. now was frannie 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 [Music] an incredibly smart person there are an awful lot of smart people in that in that educational system but frannie 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 had not considered so in that sense uh he was a an important figure he was not so much loved as respected which is a feature that i think can be very inspiring to young young people and 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 after medical school the 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 frannie was supportive of this uh he was to an extent uh to take that time off after internship required a few meetings and i ultimately i remember sending him a note saying look i'm 23 years old i've just finished the residency i i need to do what i'm excited about and he 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 to uh was part of the vietnam draft obligation and they kept taking me back each time which was 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 record at the time so you would have been old for a chief resident at that time i guess yes i was what that was 33 34 by the time i had my first job but of course you made up for it because you you sort of progressed so early at the outset um as as as you know well uh the book that you wrote with john berry in 1992 the transformed cell is a book i 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 you basically say i'm one of the few people who's read it which i know is not true um but you know i still remember the first time i read it um and it's a 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 um which i think was your motivation for writing it but and we'll come back to that but in it you talk about um an important moment in your training which occurred in 1968 um with a patient who you met in the er one day can you 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 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 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 12 years earlier that patient had been seen at the west roxbury va hospital he had had a gastric cancer of 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 it 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 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 a 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 uh 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 allergenic it too came from the genome of the of the original of the original donor so what did that teach one 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 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 in tumor 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 i i don't had mhc class 1 and class 2 been identified yet i don't think they were identified until the mid 70s right class 1 in the 70s and the early 80s class 2. but when i started in 1974 the idea of immunotherapy was a dream there were anecdotes way back into 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 uh that might work so it was uh a a sort of a dark period when it came to knowledge about the immune system against cancer it's it's a little hard to understand just how frequent 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 how they was 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 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 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 30th 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 the 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 uh during the vietnam war now you did have an offer to stay at harvard correct was was dana farber still was it in existence at the time dana farber was just being built the hospital that was just being built frannie moore who was chief of surgery offered me a position as the head of surgery and that new dana-farber institution amel frye 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 at the brigham at harvard but one day i got a phone call from him saying that the chief of surgery offered ketchum was i decided to retire and the position was open july 1. was i interested and i knew i was but i had to call my wife alice told her about it she said just pack and let's go and off we went was frannie disappointed oh it was a it was a really shocking encounter that i had with him in 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 uh but i knew i wanted to come back to the uh to the nih and finally after almost an hour uh i finally said dr moore i'm not i'm going down to bethesda maryland and i offered my my hand to shake his hand as 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 absolute commitment and the national cancer institute seemed like the right way to to do it and in some sense it was a logical decision from 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 of their own it makes them and their families watch impotently as they progress and then die of 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 um or did you think that it was naive that you know 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 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 uh 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 focused 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 uh effectively a program to systematically you know narrow down the the set of questions so how 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 renkin discovered x-rays in 1895 and chemotherapy uh arose in biological and chemical warfare laboratories here at fort dietrich in dietrich 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 or the agents that one needed to stimulate and why not use an immune cell as a drug that is take advantage of a patient's own immune reactions to try to treat the disease immunotherapy and i started with some unbelievably naive experiments uh there was no way at that point to keep lymphocytes alive outside the body we're talking about 1974. you could take them out 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 pigs good friend of mine david sachs here had developed a mini pet colony that was partially inbred at mhc loci and so i would embed a 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 chance it's it's a 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 uh with the discusses the discovery of t-cell growth factor in 1976 by morgan mercedes 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 and that was something i began to study quite quite intensively to see if one couldn't then grow lymphocytes that had anti-tumor 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 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 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 or your 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 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 what is 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 away 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 then 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 what the common epithelial tumors are and explain a little bit about the not 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 hemologic cancers of course are the blood cancers and they start from progenitors in the hematopoietic system because after all the metabolic system starts from an individual stem cell that then divides into multiple different different uh characteristics much as we all grow from a single fertilized egg from one cell that makes us what we 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 cancer so these start in the solid organs of the body and that 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 other types of cells so let's talk about the solid tumors which are 90 of all cancer deaths of last year in the united states or 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 is go on and live their normal lifespan but the half little 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 the 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 a hundred percent 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 uh 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 choreocarcinoma these are cancers that start in the placenta of pregnant women that then spread and you can have 90 percent 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 uh tumors of the testis like lance armstrong who had brain mats and lung mets no matter how much they've spread if you give patients platinum-derived chemotherapy regimens you can cause complete durable regression of that metastatic disease up until 1985 those are the only cancers that could be cured we can now add to that list solid cancers we can now edit that list melanoma and renal cancer because interleukin-2 administered the patients back in the mid-80s caused complete regressions of widely metastatic cancer in patients that are still alive today but that's it coriocarcinoma germ cell tumors melanoma renal cancer other than those for everyone who develops a spread cancer will die of it despite all the best treatments that we have we 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 just 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 well and that's what i was actually going to ask you about which is if you if you think about the past 50 years in cancer um and what you just said i 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 if we are just talking about stage four of the common cancers breast colorectal lung pancreatic how much has the needle been moved um with respect to media and 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 prolonged 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 uh 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 our lot live and pancreatic cancer six week improvement in survival for forty thousand dollars 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 concer 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 is going to regrow so we 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 um uh wife is is currently recovering from surgery uh from a cancer and and he asked 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 um it led to a discussion where i said you know the challenge with chemotherapy is not finding chemotherapeutic agents that can kill cancer cells uh you know 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 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 no the 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 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 well let's take a moment and have people get a little bit deeper on how the immune system works i i remember for me personally in medical school it was one of the most interesting uh sets of courses we took where the courses in immunology in particular how t cells worked was fascinating it it it seemed to lend itself to a story almost and 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 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 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 a common cold or coronavirus the virus comes into the body and infects the respiratory epithelium in the pharynx and the bronchi and 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 uh with other 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 uh 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 cells and define an antigen for folks to 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 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 that antigen well lymphocytes are patrolling the body they encounter this viral antigen and 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-lived lymphocytes that can recognize those foreign molecules and that's why when you get immunized against smallpox you're you have that immunization for the rest of your rest of your life and hopefully for coronavirus although we don't know that we don't know 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 go and grow in an unregulated manner elsewhere and you also mention that this is the result of although you didn't use the word somatic mutations and we'll which 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 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 so these mutations these changes in dna that are random events as the cell is 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 percent 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 uh 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 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 they 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 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 effective treatments and effective treatments come in both directions interleukin-2 stimulates immune reactions and we now have checkpoint modulators like hippolyme or pd-1 inhibitors that can unleash can inhibit these inhibitory factors and thereby stimulate the immune reaction by taking away the breaks 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 gallows 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 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 could would it keep lymphocytes alive and dividing in a format that enabled them to have all of their immune recognition uh that is as they grew would they just lose that property and so we try to demonstrate that uh by developing cells that could recognize what we call allo antigens 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 lymphoclein-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 become 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 cancerous 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 and interleukin to and administered to patients without seeing a response until we modified the schedule of interleukin-2 administration knowing its pharmacokinetics that is only after half-life inside the body of about seven minutes and 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 uh 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 immunological maneuver could reproducibly cause cancer regression it was uh it was one of the few eureka moments that i've had in doing research but the realization finally that after all of those patient deaths due to it everybody had advanced cancer all would go on to die of their cancer uh survived and that uh patient now alive over 35 years later free of disease you know it reminds me a lot of um thomas starzel's work in the 1960s with liver transplantation where the number of patients who died was it was hard to keep track of before finally achieving the technical success that was was necessary both the perioperative care and the post-operative 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 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 there would be commonalities that could be could be attacked and so we were treating all kinds of histologies it was the first patient that we 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 and those two diseases turned out to be about 15 to 20 percent 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 yeah because in that situation there were technical problems that had to be overcome and it was a genius of tom starzel 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 as you can work the technical problems how to 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 direct 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 uh remission in 1984 how did you because again let's if 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 um i i just i wonder how how you coped with that what were those drives home what were the drive you know what was it like to 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 because we did not have any impact in the manipulations that we were uh that we were applying and you know 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 you uh 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 this would work you know 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 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 uh that can be effective and when that first patient responded the it all exploded in my brain it 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 um again i i know i have the 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 you had to do this very difficult thing which was uh basically uh you know have this remarkable obligation to your family which every father does and at the same time he felt like you were carrying the weight of your world 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 they 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 outside the home and alice was such a person uh never hassled me about it always understood that um 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 to work at that uh 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 to her first order apply to college beth she opened her college essay with a sentence somewhat along the lines of at our dinner table at home we're 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 uh by all of this talk of of death and suffering from these diseases so it takes a family and i doubt i could have done it without without that kind of support so once you identified this patient patient number 67 um 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 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 carcinogen 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 uh 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 other kinds of cancer types lynch syndrome but we didn't understand that with 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 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 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 percent of uh 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 uh i'd say the median very likely to be about 110. now 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 these mu cancer mutations that were being recognized by uh by the immune system well it turns out that some of these antigens that are recognized by the by t cells are recognizing the proteins that derive from driver mutations that is that caused the cancer in the first place like p53 present in half of all cancers but only about two percent of patients develop immune reactions against it k ras 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 k-ras to some extent pic3ca and breast cancer maybe b raft 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 you know more recently shown in a breast cancer patient that we we published a few years ago that we could mediate complete durable regression now over six years later uh by targeting four what appeared to be random somatic mutations none of which had a driver function but in concert caused the cancer and by attacking them you could cause cancers to disappear now i mean i still i'm struggling to understand why it is that a p53 mutation or a k-ras 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 i mean do we have any biologic insight into this so you have to get a 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 that is 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 nine to 11 amino 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 one and a half and two percent of all mutations and when you look at melanoma it's 1.3 percent when you look at the gastrointestinal cancers 1.6 percent breast cancer 2.1 percent 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 and 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 k-ras mutation that was recognized on a very rare class 1 molecule cw 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 eighty percent of patients will yes okay we haven't found and secondly outside of the k-ras 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 k-ras that's not to say that p-53 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 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 that's 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 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 find 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 let's 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 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 managements 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 to develop but when we develop 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 till unrelated but temporally related but before we do because you brought up car t cells let's let's tell the story about the diffuse b cell lymphomas that 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 but i think it's an important this is this is an illustrative case to explain how they came about uh how they differ of course from a regular t cell receptor and as you said how industry basically came in to solve a problem uh that that at the outset looked pretty daunting so pick it up wherever it makes sense with respect to uh lymphoma 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 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 that was created by some scientists at the weizmann institute about 10 or 12 years ago zelegeshar 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 on to that antigen and 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 on 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 cd19 and so with this understanding and as soon as i heard about these chimeric t-cells i invited zeligeshar 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 and 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 he developed from normal b cells expressed 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 cd19 so all the normal b cells were eliminated but so too were lymphomas and leukemias and that became the first actual cell in 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's 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 uh people develop and they developed complete regressions that were ongoing for at least seemed like several several years well once we did this and incidentally all the patients 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 june at the university of pennsylvania used these cd19 car t cells to treat leukemia patients and so 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 was 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 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 arie belgium had a different vision he said we can figure out a way to make this available and in 2012 formed what's called a crater 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 and so we just started that in 2012 we signed the crater we worked together uh we treated over 50 patients showed that this could happen and over half of patients will undergo uh durable regressions uh 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 dollars 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 you know these b-cell lymphomas uh and leukemias so it's really a pretty incredible story that evolved so rapidly yeah it it's it is i 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 cancer is 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 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 antibody 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 you were 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 you know you know 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's not it was present on normal cells and that can result in death uh of patients and so yes if you could find a 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 attract to tumors these these t cells that infiltrate uh the tumor and they're called till so after we describe i'm sorry yeah no no so how did you how did you come to understand these and understand the 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 il-2 as a t-cell growth factor was mediating reproducible regressions it seemed reasonable that is being mediated by the ability of 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 till 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 an interleukin 2 these till 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 soul modality could cause tumor regression in patients with uh 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 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 if 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 the two scientists at the nih french anderson and mike blais who were trying to develop gene therapies to replace denison deaminase deficiencies a lethal deficiency in young and 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're administering to patients we picked the gene a bacterial gene called neomycin phosphate transferase 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 and so we proposed that to investigational review boards at that point the government had established what's called the recombinant dna advisory committee the rack 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 iraq 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 rack 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 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 it was a paper we published in the english 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 modified 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 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 and 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 on that in 2014 it was a patient with a bile duct cancer calangiocarcinoma that was widespread in the lungs and liver we gave her you gave her bulk till 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 till that were not genetically modified those were you know those were not genetic so our work went in two directions genetically modifying till or figuring out ways to use natural to and these were natural till that was selected for mutation reactivity and given to a patient and whose natural immune system was temporarily eliminated and she's living disease free now eight years later all of her liver and lung disease is uh is gone and 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 k-ras 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 uh 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 are some other things we've glossed over quickly but but in 1985 you had this uh [Music] this opportunity to operate on the then president of the united states who had developed colon cancer um why is it that you were a part of the team that would take care of the president uh why is it that the the the um the chair um 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 uh at the federal level no it's it's part of the aberrancy involved in treating high government uh high government officials it turns out that there is a a set of modules in the in walter reed or bethesda naval hospital that are set aside for the treatment of of the president it's an isolated set of rooms i i learned this as a as it happened i didn't know it ahead of time uh where the kind 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 an excellent doctor an 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 on 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 it turned out to be president 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 uh so it was because the vascular surgeon was in charge and i was across the street that i got that i got called and took part in that uh 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 and i'm not telling stories out of school here about a patient because larry speaks it was public 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 handle the the questions and i had been in and uh 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 know 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 uh 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 [Music] the surgeon who led the discussion just basically read off the path report there's an adenocarcinoma just distal 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 de vita who was the director of the nci uh 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 accepted 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 had become the director of the nci which 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 never recurred from his 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 that tempted you at least where you thought you you could even do better work or continue your work because obviously you're you're so mission focused it's i 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 when was here at georgetown because of a relationship i had with a surgeon in terms of collaborating things and i 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 shortlist 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 want to be doing it i want to be guiding it because i thought i could do it well and so i actually refused any of those offers never looked at another job and actually turned 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 we they've come up now a couple of times in this discussion um you've mentioned uh anti-ctla-4 and anti-pd-1 [Music] certainly my time at the nci my second stint i got me got me very familiar with ntc tla 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 um maybe go back and explain how that system works how how the removal of brakes works um and and and of course as is part of the undercurrent of this it only works if there's a tumor antigen to be recognized in other words taking the breaks 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 breaks and when you release those breaks now the t cell can be very active and it turns out that cancer has manipulated those and by taking the breaks 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 so many mutations and it was a startling discovery that simply attacking a molecule a single molecule on the cell surface could take the breaks 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 the uh msi 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 to take advantage of but hopefully combinations of treatments using checkpoint modulators will be more effective in the future but it was a major a major step forward and the beauty of it easy to apply because all that 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 ntctla4 ntpd1 and the durable effect that they can have on patients in whom uh you have enough mutagenic burden that relieving the uh the checkpoint is enough to initiate it obviously what you've alluded to earlier with il2 high-dose il2 i i don't want to at all sound disparaging but just for the lack of 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 six 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 from multiple tumor types and as i've mentioned we've we've described it and published a 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 that'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 percent 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 we it's almost an engineering problem because since we know the receptors we've now isolated libraries of receptors against p53 k ras 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 uh 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 uh that by sufficient work uh creativity uh this is going to be a problem that is 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 percent 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 percent 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 you know 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 publish 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 has been published we now have looked at these 195 individual cancers and found regardless of histology they're there and so it's very recent this realization that mutations are the antigens and now that t cells can recognize these mutations uh it's 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 uh that those of us who've been privileged enough to to work alongside you have learned along the way um and i don't think you you never sort of pounded the table to make these lessons but it was 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 you know people from other labs i don't mean other labs at nih i mean other labs in different parts of the country would you know 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 um am i am i accurately representing that is that uh i don't think i'm overstating that no i've always been horrified by the secrecy that exists in in medicine and it's an ongoing problem the need for biotech companies pharmacologic pharma 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 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 uh 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 of cancer and there's no excuse for not doing everything you can to try to help and that means sharing what you know you know on the on the other side of that 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 uh you might even be into the thousands now if people who have come through um and trained with you is this uh how would i say it basically this idea that one never retreats from the bedside uh one of the things that struck me actually especially in medical school when i was there because i spent the entire time on the clinic i lived in the clinical ward you may recall i didn't i i had rented an apartment in bethesda which i never went to except on sundays to get new clothes but i slept and i slept on the i remember that yes um you're quite a legend at the nih with respect to that incidentally i mean i people thought i never left but you never left so it was really quite a uh quite an experience to see you in operation there but the the thing that was hard to believe and hard to process until you experienced it was nine out of ten people that walked in the door died you know eight eight or nine out of ten of the people who walked because because again what 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 those they come to the nci for those hail marys and if 20 percent of them are saved that's remarkable but it means 80 percent 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 urge 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 uh in their in their practice what and it's difficult if 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 in the right ways 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 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 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 um [Music] and i like it's 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 you know the 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 a 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 he he he you know i think i always and i've said this before i 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 uh you know he was he was maybe 26 years old um so i i certainly understand the motivation there's no lack of motivation for how you do what you do i guess i i'm amazed that you know you talked about how cancer has both these stimula or the immune system has the stimulatory and the inhibitory components well it's similar that you know taking care of patients like this there's the there's the motivation that comes from it to do more but at some level there's the depression of the the death toll um i'm not sure everybody could do that you seem to have found that balance well you know 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 that's the hardest thing to to deal with um but again given the fact that i'm doing everything that i i can reasonably do to help them uh eases the it certainly eases the burden some and if 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 uh 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 you know we spend a lot of time uh just learning uh how to help people it's a unique a unique opportunity in 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 don't work out but there clearly are sleepless nights involved in all of that process you know 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 um i know you don't like golf enough to uh hang up what you're doing for the golf course um you know i found the i i pulled this off the wall today i wasn't sure if you still recognize these guys here this this is this is us from i think this is 16 years ago we both look uh wow quite a bit younger and this is um this is the only picture of me in my office is is this picture wow and and it 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 um then you is somewhere between zero and epsilon it's uh it's a decidedly small list uh so i feel forever in your debt um 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 it what 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 thank you for listening to this week's episode of the drive if you're interested in diving 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Channel: Peter Attia MD

Views: 100,622

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Id: pVMl0LgdnOU

Length: 131min 34sec (7894 seconds)

Published: Mon Sep 27 2021