Transcript from an interview with James P. Allison

Interview with James P. Allison on 6 December 2018 during the Nobel Week in Stockholm, Sweden.

What triggered your interest in researching a new cancer therapy?

My personal experience with cancer did indeed get my attention, let’s put it that way. My mother died when I was about ten years old of lymphoma. I was with her when she passed away and shortly after two of her brothers died of cancer, one of melanoma, the other of lung cancer, so I got to see the ravages of conventional therapies. So I always wanted to do something about cancer, I didn’t really know how. I would say I went into immunology because I was fascinated by immunology, these T cells, they were just discovered when I was in college and these cells grow all over your body and go through tissues and they can detect when something there is not meant to be there. And then they eliminate it. And how do they do that?

At the time there was nothing known about it. I’ve spent the last almost forty years now trying to figure that out. But my approach was that if I can figure that out maybe we can use the knowledge somewhere along the way to think about cancer, going back and treating cancer. That’s the way I approached it. In a way I was doing the work but the idea of ultimately treating cancer… but I was really doing because I wanted to know how T cells work. So it was fundamental research I was interested in, not necessarily the cancer aspect but I was aware, always aware that it was there, you know, if I could just figure out enough, to be smart enough to come up with a new way to do it.

How does it feel to do work that saves lives?

After we first got into clinical trials, I had cured a lot of mice in my laboratory, of my own hands. When you cure mice, they bite you and I will stop there, they are not grateful at all, let’s put it that way. Of course we gave them the cancer in the first place so I guess that’s not wrong. But to me, after we started, I could sort of figure out what was going on, sort of understand that it was a good thing but it was mostly numbers to me at first. And then when I had the chance to meet the first patient which was about 2006, actually it was 2004, anyways in that era, it really changed everything. It was a patient named Sharon Belvin. She was 22 years old when she was diagnosed with metastatic melanoma, which is basically a death sentence in that time. She had just finished college, gotten engaged, you know, and wanted to start her life and Bam! she gets this diagnosis. So she started on ipilimumab and in a few months her tumours were completely gone. I met her when her doctor called me in New York and called me and said that I’ve got a patient who wants to meet you. She told her “The guy who invented this is here – do you want to meet him?” So she did.

I went over to our patient clinic and walked into this room with her doctor, she and her husband and her parents and it was just … Let’s put it this way; it was a life changing moment. That’s when it first really became clear to me exactly what was going on and I have followed her since then. She’s fourteen years out now, almost 15 years, and has two beautiful children and she told me several years ago, you know she said “They tell me I have this chronic disease that I have to keep an eye on but I say to hell with melanoma, I am done with melanoma. I am cured and I will live my life like I am cured.” And that’s when it really caused me to think about this. It isn’t just a cancer therapy, this is a way of liberating people from the burden of always every day having to be thinking about the fact that you have this disease that can come back and kill you. You are always looking over your shoulder and that’s what she taught me, that takes a bigger tool and patience than I had imagined. A lot of people don’t like to, a lot of conditions don’t want to say that and I do think you ought to be careful because you don’t want an optimism about what is happening, but the statistics on thousands of patients say that if you make it in four years … and this is just metastatic melanoma, you are probably going be good for 10 or more. So people ought to just quit worrying about it and get on with their lives.

What is the main impact of your discovery?

The main impact of our work is to show that you can effectively get your own immune system to attack cancer. It is a very radical departure from the conventional types of cancer therapies, which are radiation, surgery and chemotherapy. All of which is either to remove or kill the cancer cells. What we do has really very little to do with the cancer cell. What I figured out was a molecule that is involved in stopping T cells responses. When you respond to bacteria or cancer you’ve got to generate a huge amount of T cells. So we worked out this pathways by which they get started, but then you’ve got to stop them at some point, or they can damage your body. We had the idea maybe that is why we don’t deal well with cancer, why the immune system doesn’t deal well with cancer. It’s one particular molecule, I thought, if we can pick and inactivate it that is kind of you disable the breaks and you just let the thing keep going for a while but it has nothing to do with cancer. We are not treating the cancer.

So it has really revolutionized how you go about treating cancer where you go in with chemicals or radiation trying to kill every last tumour cell and you know that’s all you can do. But the immune system gives you a way of getting your own T cells to attack the cancer and again, the kind of cancer … You don’t need to design a different thing for every cancer, let’s just put it that way. And once you got the T cells, you got them for the rest of your life, so if the cancer comes back it can immediately rejuvenate and this memory cells can then go after the cancer. So fundamentally it is completely different than conventional therapies. The great thing about it is that it has now become clear that immunotherapy is the fourth pillar of cancer therapy but I like the other three, it can work with them, you can combine it.

And what it is going to do in the next few years, it is starting now so this is going to happen pretty rapidly, as people begin to reevaluate radiation, reevaluate genomically targeted therapies and radiation, and realise that you don’t have to kill every cancer cell. You can just give enough to kill some cancer cells whatever the treatment is and maybe get away from all the adverse events that are associated with those kinds of therapy and give them the benefits, such as memory, of immunotherapy. I would say that is beginning to happen in lung cancers, best examples so far, I think that is going to be happening more and more and I think there are going to be rapid developments pretty soon. But the main thing is again to get durable responses instead of just giving somebody several months, several years or switching drugs or approaches. That is not to say that nothing worked at all until this came along, that is not true. Even if drugs didn’t work by themselves, many types of cancer you can just keep changing them and still keep people alive for long periods of time. But that is not the same as actually curing them.

Where does your passion for science come from?

I became committed to science, although it was before I was in the eight grade, because I always liked to have my microscope, chemistry set and just mess around and I liked figuring out things. My dad was a doctor so I was on the way for a while, a little tour, but basically assuming that I was going to be a doctor. I started college as a pre-med major but I had this experience after my junior year in high school, I participated in a science program at the University of Texas at Austin where you as a high school student had lectures in the mornings, which was fantastic, biology teachers, and then worked in labs in the afternoons. For me, it was just like heaven. It was just so much fun. I said this is what I want to do.

I was thinking about it after I matured a little bit and we thought as a doctor you have to, as you are treating people you have to fill your head with facts, just an incredible number of facts and have them in there so when a patient presents to you with a particular set of symptoms you develop an algorithm to treat them and you better be right. Because if you are wrong at the very least you don’t hurt anybody. But as a scientist you are supposed to be wrong, you are supposed to be testing and questioning, saying how does this work? Does it work this way? And if you can figure it out easily and you are right every time you are probably working on boring stuff. If you are right in a big way a few times a year or a few times a decade with really big stuff that’s enough. And so that is the key to be able to identify anything important, questions and follow the experiments down the road. If you are wrong you just keep going. You just learn something. Learn more, every experiment teaches you something. So hopefully you get to the point where you have got something that you can’t prove it is wrong.

What kind of a student were you?

As a student I think I had a pretty strong will. Not that I was studious or particularly disciplined in my approach to my studies. But I think I was inquisitive and creative enough … I mean I got in trouble a lot at school and one big one was when after my experience at the University of Texas in summer working in a laboratory taking biology, I came back and I had known about evolution but I really hadn’t been exposed to this class. I realized how fundamental the ideas of Darwin about selection was fundamental to understanding biology, otherwise it is just a bunch of trees, flowers, species all these stuff, family kingdom and all this. That is a way of organizing it, but it is not a way that helps you understand. But the principals of selection can help you understand how things work and how things got to where they are going and better yet give you a worldview where you can begin to predict what is going to happen in the future. I refused to take the high school course because it didn’t have evolution in it. For religious reasons they didn’t teach it, and I said Well, I am not going to take the course and anyways it was quite a … playing chicken with the school because they said you have to take it because you need it to graduate and I said Well, I am not going to waste my time on memorizing kingdom phylum and all that stuff. And so they finally let me take biology from the University of Texas again by correspondence. I fought my way into getting proper training.

Who has influenced you?

One would be Barrie Kitto. I worked with him as an undergraduate and graduate student getting my bachelor’s degree and my PhD. He taught me something about how to do science and sort of instilled in me that we do science because we have to and we should do things that benefit mankind to pay back for allowing us to have all this fun. And then I guess the other would be Lloyd Old again for giving me insights into how you really connect laboratory science with treating people and how you need to view every patient as a source of information. They shouldn’t be wasted by not doing everything you can to understand why a drug worked or why a drug didn’t work. And that patient … something that Pam Sharma has the same feelings about which is why I think we work so good together as we really are after the same thing eventually.

One of the things that we both believed in was that it is not enough just to do a clinical trial and look at clinical signals, you need to do science, dissect what is going on, tissue specimens of the cancer and blood and just look at what is happening in respect to immune cells and so you know what the mechanisms of what you are doing is because we know that only a fraction of patients actually respond to these things, at least when you give them one at a time, and so she worked very clever way called pre-surgical therapy. Pre-surgical trials where patients that have local disease are getting the drugs before they go to surgery. Then you get the whole organ to dissect and study and just start generating amazing data from it. We started collaborating on some of that work and I just started writing grants together, sort of grew out of that, so now we work together. We each got our own labs, but we are on a big operation called immunotherapy platform at MD Anderson where we got about almost 70 people that work for us in that group.

The whole goal of it is to study what is going on in patients, right now we are involved in about 115 trials of very diverse types of cancer. Very diverse immunological drugs and also working with pharmaceutical companies to bring us the newest drugs and work with us maybe from steps that haven’t been in humans yet, mice experiments to learn about it and I think it is unique in the world actually. We are generating what I think could be just very important data and have made some progress on enhancing the effectiveness of immunotherapeutic approaches for example in kidney cancer and pretty soon perhaps in prostate cancer where it hasn’t really worked up until now.

How did you react to being awarded the Nobel Prize?

Found out, got word of the award in a pretty strange way, for some reason the committee didn’t know how to get a hold of me so about 5.30 New York time the phone rang and I went Wow! but it was my son and he was watching the press conference broadcast and said ‘Dad, you won it, you won it!’ and that was how  I found out. It was actually about an hour and a half later before I got the official word. Some people realized what was going on and heard on television that they had trouble locating me so one of the public relations guys from where I work called them and said Hey, this is his cell phone number so … But that was a pleasure getting word from my son. Several of my friends and we had a meeting of cancer immunotherapy people, there were 2-3,000 people there, so really a lot of my very closest friends and people I have worked with for three or four decades were there and so the word begins to spread even at that early hour in the morning. And people somehow got their hands on bottles of champagne and so about 6.30 there’re about 15 people in our hotel room celebrating.

How do you stay focused when people question your research?

There are a lot of points when people question your research. I have been through several episodes of that and the first is, before you say anything, you should be pretty sure you are right, you shouldn’t just go out there on a limb unless you want to. If you are wrong someone is going to prove you are wrong sooner or later, you should be the first one to do that. But I think that I have gotten into controversies before and if I am convinced enough that I am on the right track I pretty much ignore them. I’ll argue about it at meetings and stuff enough, but I just keep going and go to the next tap and just keep building up. I don’t get hung up and worrying. Try to do it so that when you get in a position with an argument you are confident enough that you are correct, you have done that experiment that tells you that there is no other explanation except the one you got. And if anybody challenges you they better have that one too.

What is your greatest achievement in science?

better I guess my greatest achievement in science so far would be I think … There has been a number of them and figuring out how details work but I think it is the realization that what this molecule CTLA4 did. You know, I didn’t discover the molecule, it was discovered by others but its function was unknown for a long time and the first function that was proposed, we showed was incorrect. In simple terms it was thought to be another positive, you know like another gas pedal that we showed acknowledges the breaks. And we had to take that and say ‘Okay, now we can treat cancer’.

Tell us about your passion for music.

I am a musician, but I don’t know about highly accomplished. I have fun at it. Ever since I was kid I loved music. I tried to learn the guitar and piano and stuff like that but it was always beyond me, I just couldn’t. But at some point I picked up the harmonica which is very easy to play, very visceral instrument. I started playing for fun and then teamed up when I was doing my post-doc studies in San Diego. I teamed up with some Texas ex-pats who were there and played honky-tonk music at country-western bars around San Diego County, California. Then they went professional. I still played for fun and listened to records. And then at an immunology meeting, maybe 12 years ago, somebody spread the word to this conference that anybody who has a musical instrument bring them and we will get together and just play. It was an odd assortment of musics, a couple of guitars and keyboards, my harmonica and a trombone and lots of other things.

Anyway we just had lot of fun, but three of us, a keyboard player, a guitar player, just had a particular good time playing, and so after a few years we started to put together a band fairly serious and I called it Checkpoints after the immune checkpoint blockade. Everybody in the band is either a physician or a scientist working in that field. We have been playing ever since. Mostly plain sort of advanced amateurs, mostly at conferences, when people are there we do fund raises for cancer charities, and things like that. I have played with Billy Nelson several times, he has been one of my favourite musicians and just people you know for a long time for forty years or more and now I have had a chance to play with him several times. The most notable was sitting in with him briefly at the Austin City Limits Festival a few years ago when there was 70,000 people in the audience. It was pretty remarkable walking out in front of that many people.

Are there similarities between scientific research and playing music?

I think there are similarities between science and music. I mean, in both you try to build a team that works. Each person has its own contribution and their own part of the overall work to do. And hopefully all of them see the big picture as well but people take care of their own individual thing. When a good science team is working it is kind of like a good band where you can communicate just with a gesture of a head or a wink or something. The other person knows exactly what is going on. So there is the communication and every now and then my lab has been so well tuned it feels like a really good band, where it’s just going to go where it’s going to go without any conscious leadership. Everybody is just doing what they are supposed to do.

What qualities are necessary to be a successful scientist?

I think to be a successful scientist, of course you need to have a high degree of intelligence and discipline. After all, science involves making hypotheses and testing them, as I said, most of the time you are wrong and one thing that a lot of people miss too and you have to … especially young people, you have to really get the /- – -/ and to do that is kind of tedious because you finally get it all together then you got to do it all again at least twice more to make sure it is reproducible. You can’t skip that step, just because something happens once, you know you got to do it all. So you just have to be able to persevere but in the same time know when you are going down the wrong track.

It takes discipline but creativity, you have got to learn how to view your datas or crystal or something, you know when you look at every facet of it, get to know it from every direction. Look at what it tells you beyond the reason you did the experiment and figure it out. And so I think that’s pretty much it; it is the ability to really study the data and really learn what it is telling you. In order to avoid to keep doing experiments that are just going to give you results that are consistent with what you thought you think you should get, your job is really to turn that on its head and say I want to design an experiment that it can’t, that there is no other explanation, except one from this experiment and then decide to try to prove yourself wrong. And try hard, not just the easy ones you know that are consistent but I think the killer experiment. And I think it is the ability to recognize those and seek those rather than just the easy stuff.

What do you hope the future holds for cancer research?

The word cancer became very shortly after it was conceived of was to really do basic science and understanding what causes cancer, what are the lesions, the genetic lesions and what are the circuits and everything. The ultimate goal was to design drugs to hit those things. The one thing that came out of that is that you can’t cure cancer doing that, because cancer cells are inherently unstable in their genomes. You can come up with a drug that treats one of those lesions but there will already be another one there that your drug doesn’t hit. But I think now where there are cases where the tumour will almost disappear, they never really or very very rarely with the drugs that came out of the official war on cancer, it will never kill all the cancer cells but then again you don’t need to kill all of them when you are treating with immunotherapy. You can use them like vaccines to kill the drugs that have the right lesion. They can be used to form a basis of a really more individualized approach to cancer therapy where you study what is going and treat them with the right drug, be it chemotherapy or the genomically targeted drugs and then come in with immunotherapy.

What’s next for you?

What’s next is working with Pam Sharma. Right now in some cancers like metastatic melanoma combinations of checkpoint blockers we give long-lived, pretty durable responses. We don’t know how long because it hasn’t been enough time yet but it looks like about 60% which is pretty good because when we started on this if you were diagnosed with metastatic melanoma the immediate life expectancy was 11 months. And no drug had ever lengthened that, so now 60% of people are going to get four years. And we will see, it may be more. We need to get that to a 100%. In other cancers maybe 30% or something so we need to just, what I call ‘raise the tail’.

If you look at a survival curve in something like melanoma or other lethal cancers, we started at 100% and with time it drops down to some level. It used to go to zero at some point and you could just move the median over with treatments but now we know that the survival curve flattens out at some level at some point. But we need to get that as high by doing the right combinations as close to 100% as we can. And in other cancers, notably pancreatic cancer and glioblastoma really haven’t responded at all, and so we need to keep working very hard with those again not by just throwing random combinations of things but by doing the science, treat them with something, if it fails it fails, but look and see why it fails, what didn’t happen. It is easy if it works to figure out why it works, it is not so easy if it didn’t work. But by figuring out why it didn’t work can help you make it work, that something is being missed so that’s our passion. That is our goal right now. We know we can benefit a lot of patients. I think overall it is 20-25 % of all cancer patients, we would like to get that up as high as we can get it.

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MLA style: Transcript from an interview with James P. Allison. NobelPrize.org. Nobel Prize Outreach AB 2021. Sat. 25 Sep 2021. <https://www.nobelprize.org/prizes/medicine/2018/allison/159229-james-allison-interview-transcript/>

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