So, thank you. This year's laureate, Jim Allison, was born in the small South Texas town of Alice in 1948.

From an early age, he was drawn to science. He played with his chemistry set and was fascinated by dissecting frogs.

His father was a doctor in the town. Jim Allison sometimes accompanied him on house calls, but when doing that, he realized that following in his father's footsteps wasn't exactly what he wanted.

During high school, he ran into a teacher who would not teach evolution.

Allison took this very, very seriously. To him, biology without Darwin was like physics without Newton. He therefore refused to take the class, and this put him in danger of actually failing high school.

Fortunately, a compromise was reached. He fulfilled the requirements by taking college biology by correspondence with the University of Texas, where he later also received bachelor's and PhD in biochemistry.

As an immunologist, Dr. James Allison's fundamental discoveries, in parallel with others, include defining the structure of the T-cell antigen receptor, demonstrating that CD28 provides co-stimulatory signals necessary for full T-cell activation, and showing that CTLA-4 is an inhibitory checkpoint which impedes activation of T-cells.

All of this was basic research, and based on his basic research, Allison was the first to propose and demonstrate that immune checkpoint blockade might be a powerful strategy to treat tumors.

As we will hear more about, he was also involved in the development of ipilimumab, a monoclonal antibody which was approved by the FDA for treatment of metastatic melanoma seven years ago.

Dr. Allison is a member of the National Academy of Sciences and the National Academy of Medicine. He has received numerous awards including the Lifetime Achievement Award from the American Association of Immunologists, the Lowy-Old Award, the Novartis Award in Clinical Immunology, the Medal of Honor in Basic Research from the American Cancer Society, the Harvey Prize in Human Health, the Breakthrough Prize in Biosciences, The Wolf Prize, and in 2015, the Lasker-DeBakey Clinical Medical Research Award.

Now, if he hadn't been and become a scientist, Jim Allison may well have become a musician.

He has played the harmonica at least casually since his youth. He told me that he became more serious in playing the harmonica during his postdoctoral years in California, and this culminated with playing on stage with Willie Nelson at the Stingaree Bar by the sea in downtown San Diego.

Now, that wouldn't be Allison's last run-in with Willie Nelson and his band. It so happened that Nelson's longtime harmonica player, Mickey Raphael, read about Allison's research in the newspaper, and he then invited him to come and play with the band.

So, in 2016, in what he calls one of the five best moments in his life, Allison and Raphael traded harmonica solos on stage with Willie Nelson, and they remained friends to this day.

Please welcome this year's laureate, Jim Allison.

Thank you, Dr. Smith, and Mr. President, and members of the selection committee and members of the Nobel Assembly.

I'm really honored to have the opportunity to speak to you all, noted guests here, and give you some insights into what we've been doing and why I've been doing it for the last several years.

I'd like to dedicate this this talk to the many students and fellows that have trained with me and really done the work that I'm going to be talking about over the years, and also to the doctors and the patients that were involved, it had no small risk to themselves in the early clinical trials.

And finally, to my partner in life and science, Dr. Padmanee Sharma, with whom much of the work I was doing to show you is done in collaboration.

And so, the people tried to list some of these people. Of course, they aren't all up there, but the people whose names are in red are people who contributed specifically to the new work I'm going to show you later today.

And what I want to try to do is show you the early stuff that we did leading up to the idea of checkpoint blockade, show you where that's at, and then finish with some mechanistic studies that have provided some surprising new insights into how this actually occurs.

So, why would you want to use immunotherapy to treat cancer? Well, I think we all know now that cancers are a disease of many diverse gene mutations.

Ultimately, the tumor cells become highly unstable with respect to genomic integrity, and so it really can be viewed as many different cancers, each independent of histotype, each of which are caused by distinct genetic mechanisms.

But one of the things we've learned since the War on Cancer started is that trying to target these single causative mutations with targeted small molecules always essentially leads to relapse after response.

And that's because there are so many mutations. By the time you target one, there's already a resistant mechanism which the tumor can use after selection to bypass it.

But T-cells, which has been my love ever since I heard about them in graduate T-cells offer three things that really other kinds of cancer treatment do not.

And the first one is specificity. I think that everybody knows that T-cells recognize peptides on the surface of the cells presented by MHC molecules that tell the immune system what's going on in them.

And we know now from work by Bob Schreiber and many others that in the case of T-cells, they're focused on the mutations, products of the mutations that occur in the tumor cell, not just the ones that cause it, which is what targeted therapies do, but pretty much any of them.

So you can get polyvalency about targeting these because the immune system doesn't know what the mutations are, doesn't know whether they're causal or not, and it doesn't matter.

They just tell the immune system something's different. The second thing is, once you've got T-cells, a number of them become for slowly renewing memory cells, and so they're there for the rest of your life basically, and can be reawakened if necessary to come after the tumor again.

And finally, the immune system is very adaptable. You've probably got 50 to 70 million different T-cells circulating around, which is that cost that can change with time since the immune system is generating new.

And still the immune system can adapt spontaneously to changes in the tumor, and so it's easily a match to cancer, which is the whole theme of this talk.

So I'm just going to condense a lot of work here to get everybody on the same page. And in 1982, we worked out the structure of the antigen receptor heterodimer.

But with antibodies, a number of labs showed after that, that soon after that, that signaling through the T-cell receptor by itself is not sufficient to activate T-cells.

You need additional co-stimulatory signals, which were provided only by very specialized cells such as dendritic cells.

In 1988, we showed that the receptor for those signals was a molecule called CD28.

And others showed that there were ligands for B7. But there was also a molecule called CTLA-4, which had an unknown function.

It was only known that it was not expressed until after T-cell activation. So the current view is when the T-cell gets a T-cell receptor signal and a CD28 co-stimulatory signal, you turn on two pathways, two programs shown in green.

There are a lot of genes associated whose products were associated with cell proliferation because we have to expand a few dozen cells of any particular type to hundreds of thousands of cells very quickly to get the soldiers in the field to attack the cancer.

But you also started, this wasn't really realized until about 1994, you also start an off program by induction of the program induced by CTLA-4 expression, which eventually accumulates in a cell and can turn T-cells off.

So without going through all the work, one of the things that we had shown in the meantime is that tumor cells, like mouse tumor cells, have plenty of antigens.

And we showed that because we put B7 molecules into them so that they can provide co-stimulation, they'll immediately get rejected.

But normally they're not rejected because they're invisible to the immune system, not because they lack antigens, because they can't give the second signal.

And so I reasoned at the time that, and you can't start it on your response until tumor cells die and the specialized dendritic cells come in, pick up the bits of dying tumors, redisplay the antigens on their surface in the context of B7.

So this cross-priming then initiates an immune response against tumor cells. But then CTLA-4, of course, is the normal process is induced.

And so it's a kind of race, you know, the tumors had a head start, and if the tumor gets to such a mass as the T cells can't generate enough to take care of it, we thought then the tumor wins because they would be turned off by CTLA-4.

So we had the idea of just disabling the brakes by putting in an antibody to CTLA-4, a very simple process, and just keeping the brakes off, letting the T cells keep running.

Well, we did this, well, anyway, what that's shown on this cartoon in the right, and there's there's a couple of features there that are that are very interesting when I first thought of this.

One is that we're not we're targeting the immune system, not the tumor cells.

So the kind of cancer doesn't make any difference, it doesn't make any difference because, you know, all tumors have neoantigens and that really doesn't matter what kind of cancer.

So we don't have to make a new drug for every cancer cell.

It's a universal therapy that can be potentially used for any kind of cancer. And the second one is, since it started by cross-priming, you can take advantage of that priming by death to use in combination with chemotherapy, radiation, hormone therapy, whatever kills some tumor cells and give agents that do those things properties of the immune therapy as well.

And so there we go. Sorry. And so the idea, of course, is a wonderful idea, but does it work.

And so this just shows one of the first experiments we did. We've got, you know, transplantable tumors growing in the backs of mice.

You see, untreated, they grow. We have to euthanize the mice. Block CD28, they'll go faster. But if we inject antibodies to CTLA-4, the tumor grows for a while, then gets rejected.

And so when I got this result, I was, I was amazed. Not expected to slow the tumor, but it just completely eliminated.

I'm covering up this one molecule out of everything that's going on was sufficient to give tumor rejection.

So, just to make a long story very short, after two years' delay because people, in part, couldn't understand how you could treat cancer by ignoring the cancer cell and treating the immune system, we worked with a company called Medarex, and later they had a human CTLA-4 antibody called ipilimumab.

And this is a patient in a phase one trial started about 2000. This is May 2001, actually, what she started.

You can see these big tumors in her lung. She had metastatic melanoma that had failed every therapy, including high-dose IL-2 and a dendritic cell vaccine.

She got one injection of three mics per kg of CTLA-4. And I happened to visit Tony Ribas, her doctor, in 2011, 10 years after she'd gotten an injection.

The CAT scan on the right is from her 10th year checkup after a single injection. And she's actually still doing fine.

She's almost 19 years out now from metastatic melanoma. And I should point out that when we started this work, the median life expectancy after diagnosis with metastatic melanoma was 11 months.

So it was essentially a death sentence, and there was no drug that had ever prolonged life at any level whatsoever.

So there are a lot of trials done resulting in a Phase 3 registration trial with overall survival as the endpoint, which took almost four and a half years to complete.

And what you can see here is this is the, if you'll remember, the line, this one, this is the placebo control here.

And what you can see is we improved the survival over about four months, which would have been sufficient for FDA approval because no drug had ever done that before.

But as you can see here, a very interesting thing happens between two and three years: the survival curve flattens out and stayed that way for the duration of the trial, which means basically nobody is dying of the disease after about three years.

And so, by 2015, there was follow-up data of several thousand patients.

What you can see here is it's the same at three years, and kind of flattens out, stays that way for ten years.

And about twenty, a little over twenty percent of the patients, so I think for all intents and purposes for this disease, people that make it past four years, I really think you can consider them to be cured and they don't have to worry about, you know, what's going to go on.

I wouldn't say that lightly; it's based again on several thousand patients. So with this, this follow-up therapy.

But the question is, why isn't it a hundred percent? You know, why isn't it just a fraction? There's a number of mechanistic reasons why that might be true.

But of course, there's another possibility that there were other checkpoints, and Dr. Honjo had discovered a molecule called PD-1.

And by about 2001, it was shown there was another checkpoint, actually, and it differs in a couple of important ways.

one of them is that one of its ligands could actually be expressed on the surface of tumor cells and induced by gamma interferon made by the CD8 cell.

What that means is that rather than working at priming like CTLA-4, it's working on fully differentiated cells at the end of their development and turning off the functional cells by interaction PD-L1 on the tumor cell with PD-1 on the T cell, and I'll come back to that in detail in a while.

Anyway, there was very quickly this way into clinical trials. This is a summary of a phase one trial done by Santa Paula and very good results in melanoma, non-small cell lung cancer, renal cancer, no responses in colorectal cancer, although later on Bert Vogelstein shows there's a subset that has genomic instability that has microsatellite instability defects and DNA damage repair.

This subset has a large number of mutations, and patients with that defect do respond. And then there's also no responses to castrate-resistant prostate cancer, and I'll show you later that we think we've figured out why that is and, you know, a way around it.

Well, obviously, combinations. You've got two different drugs that work at different stages of T-cell development, and so put them together.

So this is a trial, one of several really, put together by Jed Wolchok and others. This is the ipilimumab only arm, and you can see here the anti-PD-1, nivolumab, and here plus anti- CTLA-4, there's a 60% response rate now when you combine those two functionally different checkpoints.

And the last time I checked, the survival is out to about four years on these patients.

So we're getting close to the point of knowing whether this is going to be as durable as if you do them available and there's no reason to think that it won't be.

And so I think we've gone here's of this remarkably from an almost uniformly fatal disease to being able to get meaningful responses that last perhaps for decades as well with this combination in 60% of melanomas.

And a lot of people say, "Well, this is just a melanoma drug." That's not really true.

There are various trials have been done. The FDA's approved these these agents for non-small-cell lung cancer, for renal cell cancer, Hodgkin's lymphoma, bladder cancer, head and neck, Merkel cell, which is a very even more lethal form of skin cancer, also gastric cancer and hepatocellular carcinoma.

This is really a remarkable approval, so any tumor of any histotype that has defects in DNA damage repair and consequently has high levels of neoantigens can be treated regardless of what kind of cancer they are.

For the first time it's ever been approval for a particular genetic defect and in a class of tumors.

And so we're in a pretty good setting. We know a lot of tumors respond, not all and not all of them as high a fraction as we would like.

So to go forward really in a rational way, we need to know the cellular and molecular mechanisms of the effects so that we can, you know, design the best way to combine things and develop strategies for identifying patients who are going to respond.

And so at MD Anderson, Dr. Sharma and I built on some work that she'd been doing for some time in genitourinary cancers to develop what we call the immunotherapy platform.

And the goal of this is to do mechanistic studies on any patient with any kind of cancer that's being treated with any drug that would have impacted the immune system.

Of course, we defined that as anything basically. And the idea is to get tissue and blood from them and analyze it by all the techniques that we can to get some insight into what's going on.

And I'm not going to go through the details, but so far we've enrolled over 3,000 patients, have gotten matched samples of tissue and blood from those patients.

And so I'll just show you one brief thing about what how we've used this to study what's going on in prostate cancer.

So as I told you, there were no responses in a phase one with PD-1 with early trial, so with Ipilimumab, there were a small number but remarkable responses of men whose PSA was undetectable and had metastasis disappear and symptomatic relief.

No, thanks. So this went to a phase three trial shown here, which unfortunately failed.

Nobel Lecture: James Allison, Nobel Prize in Physiology or Medicine 2018

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Nobel Lecture: James Allison, Nobel Prize in Physiology or Medicine 2018

Nobel Lecture: James Allison, Nobel Prize in Physiology or Medicine 2018

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