Original subtitles

It's a part of Texas that was still majority Hispanic.

Football reigned, you know, everybody, Friday nights, that's what it was all

about.

And it was an oil boom town, too, although there was a lot of agriculture

as well.

My mother's family's been there since probably the 1840s, I think.

My dad was a doctor who, you know, took care of people in the neighborhood, did

house calls.

My father moved to Dallas in the 30s sometime. I don't remember exactly when,

but I was born in 1948, and we lived, I think, here, actually, because there was

a washing machine out in the yard, and I got my arm caught in the ringer one

time. It pulled me up and, you know, got stuck, and I was hanging, you know, by

my arm, and some people, neighbors came out.

I have two brothers, Murphy and Mike.

My mother,

she was a housewife.

She was a good influence on us. Just kind of give us a little discipline.

We'd get to wash the dishes on Sunday and things like that.

Of course, that may have been a little bit before Jim's time.

I think he got out of that.

I didn't really know what was going on in those days. Nobody talked about it.

I knew she was sick, and she had these burns on her throat, and,

you know, she was in bed a lot.

I remember one day I had some good friends, had a kid my age, and his

mother was going to take us to the swimming pool.

I'm just about to get in the car, and somebody came running out.

I said, hey, you've got to come back. You can't go.

So I went in, and she was dying.

So she died that morning.

And I found out later, I really didn't know what it was, but I found out later

that it was lymphoma.

She had been getting radiation therapy, hence the burns on her neck.

I sat on the bed with her and held her hand while she died.

There was a big hole, a lot of loneliness.

I was 11 years old when my mom died.

My father was just heartbroken. He seemed to lose interest in things.

Anyway, he was gone a lot.

I ended up living with sort of a foster home.

I mean, not in the sense that I was given away or everything, but a

counselor from high school teamed me up with a family who had a boy about my

age.

So that's when my dad was away. I stayed with them all the time.

I liked to wander around in the woods. I lived right at the edge of town and used

to wander in the woods by my home.

I just felt it was comforting to have a harmonica and just...

to the wagon on

behalf

of the nobel assembly at carolinska institute

I wish to convey to you our warmest congratulations.

May I now ask you to step forward to receive the Nobel Prize from the hands

of His Majesty the King.

Innovation is extremely difficult.

We were all very skeptical.

Many people said, Jim Allison, you're wasting your time.

I knew that this is a way to cure cancer. I knew that that was a way. And

I'll be damned if I'm going to let that just lay around.

I guess my dad encouraged me to mess around my Gilbert chemistry set in the

garage, you know, and dissect frogs and horned toads and things.

He told me about the bombs he used to make, so he would construct these little

bombs out in the woods, and he said, in this very Jim way, when you talk with

scientists later in life, you realize a lot of us were bomb makers in the

beginning.

When I started learning about what science really was and how to do it, you

know, I started doing more intelligent things than making bombs.

One of my teachers who taught advanced mathematics, physics, chemistry, I

thought he was one of the greatest teachers I ever had.

But I tried to have a few conversations with him about evolution, selection of

the fittest, Darwin.

And he just said, no, you know.

It's not real. I did not allow. We will not teach that here. We will not discuss

it.

I refused to take the course because I knew that there was no biology in it.

The syllabus, there was no biology in it. So it was a pretty ugly time. And it

was basically me versus him.

I was still taking advanced physics from him while I was having this fight with

the school because he was the head of the science program. He was the one that

made sure that evolution wasn't taught.

He really did start taking it out on me.

Back in those days, you know, you could use boards to paddle students, so I

seemed to be getting in trouble all the time and getting a couple of licks just

for walking by, you know.

I just thought I was a troublemaker.

I wasn't. I was just trying to do what was right.

That's the way it is, you know.

If you, uh...

don't agree with something, you need to stand your ground.

And if it hurts, it hurts, you know.

That's the way it is, you know.

When he was little, we said he was hard-headed.

We never did call Jim this to his face, but, you know, this guy, we called him

Diamond Head because his head was the hardest substance known to man.

Jim graduates from high school at age 16.

He goes to the University of Texas in Austin, determined to become a

biologist.

There was this knock on the door.

The door opens, and this scrawny kid pokes his head in and says, You got a

job?

I said, there's one job left, but you may not like it.

It's just a dishwasher.

And he said, I'll take it.

We would take a piece of cheesecloth and put a little bit of acetone on it and

rub off the number of each test tube.

And literally there were thousands of them.

And so he got the idea, well, maybe I could take those.

test tubes and spray them with a solid stream of acetone.

This was back in the 60s. And just about everybody smoked then, including in the

lab. Jim sprayed his test tubes with acetone and then sat back to have a

cigarette. And boom!

And we all run in from the lab, and here's Jim with a blackened face.

His eyebrows were all singed.

I was about to fire him, but in the short time he'd been there, Jim had just

got along and knew all the graduate students and the others, and they

besieged me on his behalf. Look, can you find something else for Jim to do?

He's quite a character. Let's keep him around.

In the summer of 1966, he came for a fraternity party that I went to with

someone else.

He was the most amazing thing I'd ever seen in my life.

I never dated anyone else in college.

We were together from then on.

It was a really kind of magical time to be in college.

It was so much fun, so much going on.

We were lucky enough to be in college in Austin just as everything was beginning

to happen there.

That really made it when Willie Nelson moved there.

I think the first time I saw him live was playing on a flatbed truck at a Ford

dealership of South Lamar in Austin.

But everyone was also real serious about their studies.

Jim was passionate about science.

When I was at the University of Texas, the number one thing I learned in the

lab was just how important it is just to persevere.

Not be so disappointed. You give up. Just keep working.

We could never go anywhere without going by the lab, checking on this or that,

experimenting process.

T-cells were discovered when I was in college, and I took an undergraduate

class, and my professor Bill Mandy taught one lecture about T-cells because

almost nothing was known about them.

The human immune system circulates in our blood.

and protects us from disease.

We now know that at the center of the immune system is the T-cell.

T-cells are a type of white blood cell.

And these are the cells that actually respond against viral infections,

bacterial infections, and they start the fight to keep you healthy.

These cells that go all over your body and manage to protect you and not kill

you.

And still, to me, just wondrous.

I wanted to try to do something, something that Barry Kiddo always

taught, was, you know, you should try to do things.

If you're going to do this stuff, you ought to at least do things that help

people.

My mother had three brothers.

One died from melanoma.

In those days, melanoma was a death sentence, so he didn't even get therapy.

When he was diagnosed, he just said, that's it. You know, had a really good

time for the months that he had.

The other brother was a former rancher who could roll a bullderm cigarette with

one hand while he was on a horse, you know, but he paid for that. He had lung

cancer and died from that. I saw him in an oxygen tent when he got to the point

that his, you know, his emphysema or whatever was so bad, he needed... helped

to breathe those made kind of an impression

my

own lab was not involved with cancer when jim came to work with this

but he had had a tremendously difficult relationship with cancer

So my graduate school, he convinced me that perhaps we could look at something

in the cancer field.

There was an enzyme called asparaginase that when injected into kids with

leukemia could induce remissions.

I first thought they were cured, but it turned out they weren't. I mean, they

were for a time, but then they always came back.

My thesis project was to find other asparaginases from other bacteria that

would be so different that they could be used in succession.

We pulled water out of the local stream and surveyed that for asparaginase

activity.

Jim purified that.

And in mice, that worked very well indeed.

Jim's work on asparaginease convinces him the immune system plays an important

role in responding to cancer.

I was a bigger kid growing up.

I really ate way too much sugar. I know that now.

I played a lot of sports.

Basketball was my thing.

I played my first year of high school and then injured my knee pretty darn

bad.

Kind of lucky that I did because I couldn't play basketball anymore, but I

joined the marching band where I ended up meeting my soon

-to-be husband.

I was finishing up my graduate year.

I had what, you know, feels like bronchitis. You were coughing, breathing

was a little bit of an issue.

Progressively over the next couple of months, I didn't get better.

I was walking up a hill one day and I could not take a deep breath.

My mother worked for a primary care doctor, and she's like, oh, sweetie,

when you get home, come on, see him, and we'll get this sorted out.

Little did I know that just a few weeks before that, I was going to develop a

mass growing out of my chest, and I thought it was breast cancer because of

where it's located.

So going to see her doctor, they noticed the tumor, and they did a biopsy, and my

world changed.

I went to Scripps because I wanted to learn about the immune system. I wanted

to ask questions about how the immune system worked.

Strangely enough, there was a group of expatriate Texans there.

And we would all go to a little bar called a Stingery.

And there was a band there that he would sometimes play harmonica with.

Columbia Records was having their annual convention in San Diego, and Willie

Nelson's record, The Red-Headed Stranger, had just gone platinum, so

they decided to have a big party for him.

The guy that was in the sheriff's department, he was a real devotee of our

band, came and told me about this, you know, and said, we're doing security for

it. He let me go in, you know, let me through security to go to this private

party.

Willie Nelson came over.

And he said, well, you know someplace we could go picking tomorrow night? Because

I got tomorrow night off, and I'd sure like to play some music.

So I said, well, it's talent night at the Stingery.

So we loaded up in our little VW camper.

We walked in, and people just fell on the floor.

Willie basically asked, you guys mad if I played?

He and his drummer and his bass player started playing.

They played for three hours at least.

And, you know, it was a little dive bar, and there was about eight people at this

place, you know.

There was one payphone on the wall, and so those eight or so went up, called

people, and pretty soon the place filled up, and people called other people, and

it was full, and the people were...

out on the street.

It was amazing. I didn't have to buy a beer at that place for about two years

after that.

An old college roommate of mine, he heard that MD Anderson was opening a new

laboratory near Austin.

To tell you the truth, the main reason I went there is because I thought I would

have freedom.

The first time I connected with Jim was I think in about 1980.

I was a postdoc in New Mexico.

I went to MD Anderson, and they asked me to give a seminar.

And they said, well, you're being live-streamed to Smithville, Texas.

And so I gave my seminar, and they said, do we have any questions from

Smithville? And I'm thinking, where in the hell is Smithville?

And then...

This voice comes over with this, you know, nice Texas accent and asked me

this incredible question.

With a given molecule on a pathway, for example, the MAP kinase pathway,

which... He got right to the heart of, you know, the hardest question he could

ask about the science I was doing at the time.

I consider Jim my brother, scientifically as well as personally.

I would consider him my best friend for the last 30-odd years.

I really wanted to understand the immune system and things, so I really wanted to

know how T-cells worked. And at the time, all we really knew was that T

-cells went around the body and took care of stuff that didn't hurt you.

Scientists know that T-cells distinguish between healthy cells and threatening

ones by using a molecule on their surface called the T-cell receptor.

But they don't know how the receptor works.

We didn't know how those white blood cells, these T cells, would actually

recognize the virus as being different and needing to be eliminated.

And that was the holy grail in the late 70s and early 80s. All the top labs in

immunology, that was the quest.

I read the literature and there was a lot of stuff that was contradictory, a

lot of stuff that seemed like fantasy.

I could not possibly imagine how some of the mechanisms that were proposed

actually... I said, well, either I'm a total moron and can't follow this

complicated stuff, or people are just, you know, it's all nonsense.

So finally I said, forget it. I'm not going to pay any attention to the

literature.

Part of Jim's success is the fact that he's an iconoclast.

You know, he doesn't care.

He doesn't care that he's not following convention.

He's following his own thoughts, his own motivations.

He's willing to do it in the face of his colleagues not necessarily believing

him.

I got a notice that Irv Weissman from Stanford, who is a very noted

immunologist, was giving a lecture.

So I drove three hours from Smithville into Houston.

I was driving back, replaying his talk in my head.

I remember it just sort of clicked. I said, I know how to find the T-cell

receptor.

Race scientists are creative people.

They're not just focused on their detailed work.

They're thinking beyond.

There's a creativity to this work, and frankly, if not for the creative

scientists, we would make little progress.

I saw miles and miles of Texas All the stars

up in the sky I saw miles and miles of

Texas

drove back that night just rolling in my head and everything and you know the

next few days just lying down the path i find the t-cell receptor

over the next few months

jim uses the latest genetic engineering techniques to test his hypothesis

Work hard all day, get an incubation period or something, go to the beer

hall, knock down some beers, go back and finish the experiment.

Go to sleep, get up, start it all over again.

I think the guy is just incredibly passionate.

So he'll spend a night going out to a honky tonk and he'll be out all night

and he'll drink and he'll have a great time.

And then there's that same energy that would put him in the lab at Smithville.

They're doing a 36 hour experiment and he's staying up for that. And he's just

as driven and turned on by that whole experience of being in the lab.

We went to a conference in California.

This is where you present your data. You're not well-known enough to be

invited to get up on the podium and give a talk at that point. You're relegated

to putting your work on a poster board.

So Jim had a poster there, and I remember walking over to look at his

poster, and we'd just kind of met recently then, and he pointed to this

spot on the poster and says, that's the T-cell receptor.

And he was right.

His contributions to our understanding of the T-cell receptor, the molecule

most centrally identified as the thing that recognizes the target and allows

for it to be eliminated.

Extremely important.

He was the first one to actually purify the molecule by which T-cells recognize

everything.

This is how T-cells recognize infectious disease.

This is how T-cells are recognizing things they shouldn't recognize when you

get autoimmune diseases.

So this was a seminal discovery.

Jim was invited to major immunology conferences, and it was recognized that

this constituted a real breakthrough.

When they came back and said, Sharon, you have melanoma, I was completely

shaken.

Unbelievable.

I couldn't believe that that was my life.

I thought I was going to die.

Good job.

The doctor canceled all his patients and shut his office door and got on the

phone and said, I have a 22-year-old patient here who needs to see you now.

And he was on the phone all day, but I had an appointment with Sloan by the end

of it.

So then I saw Dr. Walchuk just a couple days later.

Sharon Belbin, when I first met her, was 23 years old.

She was seen by an oncologist near her home in the New Jersey Shore, who called

me and said, you need to see this young woman. So I see her, and it's a room

full of very sad.

you know, family members trying to get their head around this seemingly

unbelievable situation.

We started her on chemotherapy very quickly thereafter.

So I had chemotherapy Monday, Tuesday, Wednesday, and got married that

Saturday.

We decided to go through the wedding because it's for better or worse.

I mean, we were joking around a couple days before and we were just like, okay,

well, we are going to get the worst over with right in the beginning and then the

rest of life will be great.

And Rob is really probably a saint and don't tell him I said that.

Who can look at somebody and say, here's a terminal diagnosis and I'm going to

marry you anyway?

In 1981, there was a bill that was introduced by a very conservative state

senator from East Texas saying that creationism needed to be taught in

schools.

One of his teachers from Alice had actually been elected as the state

representative from Alice, not the...

the science teacher, of course.

And she called him up and said, someone has introduced a bill to outlaw the

teaching of evolution in the public schools, and we've got a hearing coming

up, and we need someone to come and talk.

She said, he's going to have 300 people here supporting the bill, deposing

evolution, and so if we don't have somebody here speaking to the other

side, it's likely to pass a committee out to the House floor, and God knows

what's going to happen.

I tried to find other people who would do it. I only found one other scientist

that was willing to do that.

I'm here tonight speaking before this committee because I feel that in this

highly technological age, an education in science is essential if members of

our society are to be able to understand and deal with complex and diverse

problems facing them.

Science is something that you can use.

It's not just a couch for the past. It does that. It also allows you to...

understand what's going to happen in the future to situations that you've never

seen before, that have never arisen. That's what science is.

That is the chief problem with creationism, purporting to be a science.

It cannot be used to construct explanations of newly observed fact. It

does not give us any help whatsoever in understanding how bacteria acquire

resistance, how tumor cells arise, or how they are eliminated by the immune

system. He talks about using the immune system to cure cancer.

at that point, even in 1981.

I said, I challenge this man to use his creation science, such as it is, to

understand how a tumor escapes the immune system.

It's hilarious, the limits of their arguments.

Probably the best one was, if you put a Ford in a field, it rusts. It don't turn

into no Cadillac.

You know, I said, oh, yeah, okay, I got it.

Obviously, I can't be anything like evolution.

Pretty soon after that, he got an offer from the University of California at

Berkeley to go out there.

After the T-cell receptor, I was offered a full professorship at Berkeley.

And I was really happy out at Smithville, living in Austin, working in

Smithville, just doing science. It was as clean as it could get. I was doing

exactly what I wanted to. I didn't have to answer to anybody.

I didn't have to do any administration or anything.

So the idea of going into some big-time place and having to...

You know, compete was a little scary.

An old friend of mine called me up and said, what are you doing?

And I told him that I'm comfortable here. I'm happy here.

He says, yeah, in 20 years you're going to be sitting there with your feet up on

the porch saying I could have been a contender.

I kind of went, yeah, I understand what you mean.

When I decide who to hire in my lab, I always am looking for one thing, really,

and that's curiosity.

Berkeley drew me in in a lot of different ways.

It's filled with very smart people, but very freaky people, and they all sort of

intermingle, and you don't ever know what's a crazy idea and what's a great

idea.

Even at Berkeley, Jim was a standout.

He didn't look like the other people.

Berkeley has its own conservative liberal side of it, which is that, you

know, you can be liberal up to a point, but Texas is actually too far. You know,

it's like you're carrying a gun and I don't know, all kinds of things that

could be bad.

And so Jim was like just over that line and represented just the, you know,

additional frontier even of Berkeley.

But also immunology was not considered a science.

The classic people said, oh, immunology, that's sort of a pseudo-discipline.

That's really like almost like...

giving holistic medicine or something, right? It's like, what is that? You

don't even know what that is.

So Jim's lab has a feel of being like a pirate ship.

There are personalities doing their own crazy stuff, and yet there is a, you

know, dedication to the purpose of driving the boat forward.

I was working a lot.

Not as hard as the people in the lab, of course. I mean, they were working all

the time.

But we also all partied together.

You know, I just had some incredible parties.

There is the rigid thought process that is like connect the dots A to B to C to,

you know, like that. And that you do during the daytime.

But I think there's a whole element of the idea of unwinding and not letting

the mind go linear.

and just saying, what if nothing we thought was right?

Jim's work on the T-cell receptor has sparked a race to discover more secrets

of the T-cell.

Soon a French scientist finds a new protein on the surface of T-cells called

CTLA-4.

Most researchers assume that it activates the immune system like the T

-cell receptor.

But Jim doesn't assume anything.

The only right way to do science is not to do experiments to give you an answer

that's consistent with what you think you ought to get.

But do the killer experiment that can only be right if you're right.

Jim started looking at the data on CTLA-4 critically.

And he and Max Crumble, his graduate student, started saying, well, let's see

what the real data is. If we do experiments, is that true or not?

So we just had this stupid question, like, what does it do?

And it wasn't, like, just cure cancer.

It's like, what does that do?

Are you shooting, Jim?

Yes. Well, it's Christmas. It's 1991.

And we're loving up the pinata here.

To study CTLA-4 in a mouse, Cromwell must build a mouse antibody, a

Y-shaped protein that will trigger a reaction from CTLA-4.

Okay, let's go.

What made that whole three-year stretch for me very difficult was that I didn't

get any progress scientifically.

Robert's first, fourth birthday. Robert, look over here.

Are you Batman?

And this is really common. For three years, nada.

You know, like, everything I did...

really didn't amount to anything.

Running laboratories, it's not easy to have people do the experiments you want

them to do.

I regret at times not being able to motivate people to do the kinds of

experiments that I was sure needed to be done.

But Jim has that ability to do that.

So because of that, people in this lab have done things that were crazy at some

times, but he also was able to get people to do the things that he was

really passionate about.

While Max struggles to make his antibody, another lab beats him to it.

Peter Linsley, a scientist working with the drug company Bristol-Myers Squibb,

publishes results saying that CTLA-4 is an activating receptor.

When it's engaged, it revs up the immune response against targets.

Then these papers came out and said it's a positive regulator.

So, you know, that attitude was, well, we've been scooped, you know, it's done.

Except I said, I don't think so. There's something about, you know, I saw some

holes in that paper, and so we're going to test this fucker to see if it's...

really right.

You have this picture of Einstein sitting at the whiteboard, hair frayed,

you know, writing equations that no one can see.

Really what he's doing is saying there's a fundamental question, an assumption

people have made that doesn't make sense if you look at this in a clear-eyed way.

What if I step back here and just observe?

and say, these pieces of information need to be put together in a different

way. I think that is what pioneers do, and weirdly, it's childlike.

This is a hard thing. It took me a while to be able to say this to people, but I

think there was a formative moment when I was in Jim's office, and I actually

started to cry.

Because I'd been working on something for so long, and he told me something

again, a mistake that I'd made.

And, you know, I just started to cry.

And then I got over that. I mean, there was a period of that that you just have

to get through and just say, okay, go back at it.

Crummel finally makes his CTLA-4 antibody and launches Jim's experiments.

He quickly demonstrates that Linsley's idea of how CTLA-4 works is wrong.

The experiment proves that engaging CTLA-4 doesn't activate the immune

response. It stops it.

Jim and Max Crummel, as well as Jeff Bluestone and his grad students, turned

the thing completely around and said, nope, all these prior papers saying that

CTLA-4 is another gas pedal, that's not correct. It's actually a brake.

Like Jim, I was able to figure out CTLA-4, and I was shocked.

CTLA-4 was the wackiest thing in the world, right?

Nobody believed that you would actually have a whole system in place to shut

down the most important thing going on in your body, which is an immune

response, and you're going to shut this thing down and make sure it doesn't

work? The body does not want an overexuberant immune system, because if

we did have one, we would all be suffering from autoimmune disease.

Autoimmune diseases, like multiple sclerosis, are caused when the immune

system attacks healthy cells.

Jim's discovery prompts many immunologists to think about curing

these diseases.

They will engage CTLA-4 and stop T cells from going on the attack.

Jim heads in a different direction.

There's this big part of the immune system that is built on stopping itself.

Now what the heck does that have to do with cancer?

Cancers, we know they have mutations. We know they're different from normal. They

should be visible to the immune system. And for a long time we struggled.

Why can't the immune system see cancer? It can see flu.

GEM theorizes that tumors have evolved to trick the immune system.

They engage CTLA-4, turning on the T-cell's break.

This stops T-cells from attacking the tumors.

If you were a cancer, it would certainly be advantageous if you contacted that

receptor and turned off all those T-cells that might otherwise come to

kill you. This would make sense.

At the time, it was a crazy idea. Nobody thought.

Tumors were trying to turn off the immune system.

But he said, well, what if I block this?

Why don't we see what that does to certain cancers?

Jim hypothesizes that if he inserts an antibody to block the connection between

the tumor and CTLA-4, the T cell will be free to attack the tumor.

Jim had all these tumors in the freezer.

So I was making antibodies as fast as I could, and a guy named Dana Leach came.

He was a postdoc in the lab, new postdoc.

And Jim gave him the tumor models, and, you know, I gave him the antibody.

The student who was doing the experiment had put the tumors in the mice and gone

away for the holidays.

And so it was actually left to Jim to check on these mice. And, you know,

shortly before Christmas, I think, he saw the tumors are growing.

Maybe nothing's going on.

Kind of sad about that. It's not a happy thing to see, but, you know, that's what

the data was.

We had Thanksgiving and Christmas together for probably, you know, almost

20 years.

I remember that Christmas.

He was mumbling about, you know, the student taking off and going on holiday.

I had family visiting and everything, and so I did something that was

unforgivable, really. If he had done it, I would have fired him, probably.

I skipped a couple of readings for the Christmas holidays.

A few days later, though, Jim remembered, oh, yeah, I'm supposed to be

checking on this guy's mice because he's still off celebrating Christmas with his

family, and came back to find that, you know, in the mice that had received the

antibody, the tumors were gone.

Which was one of these, you know, truly one of these aha moments when I went,

oh, Jesus, you know, this is something big.

Because I've been doing tumor immunology enough by then to know this experiment

was so cool. You didn't need a statistician. They were all alive or all

dead, you know.

These tumors have disappeared.

I mean, this is impossible.

This is not possible.

That's how mind-boggling you have to think of this as, because the human

body, with 480 million years of evolution behind it, can't get rid of

this stuff.

And now the tumors have disappeared.

From then on, for the next decade, essentially he had one goal, to get that

made into a drug for cancer patients.

It didn't come out of cancer, but once it was there, it was there.

And I'd be damned if I'm going to let that just lay around.

This is a way to cure cancer. I knew that that was a way.

In my teen years and in my college days, I was the dork, the one that studied

really hard, got good grades, because I was the first in my family to go to

college. I had a lot to live up to with that, so I had to make sure that while

friends were out partying, their grades were Cs, I needed to get As, and I knew

it. Knowing what I know now of what life had in store for me, maybe I would have

had a little bit more fun.

I probably would have.

We started her on chemotherapy, and that chemotherapy really didn't work for her.

So we tried another kind of chemotherapy.

I know that chemotherapy is supposed to kill cancer. It can give you back your

life.

Chemotherapy made me feel like I had cancer.

I felt like death warmed over.

I got severe peripheral neuropathy from the chemotherapy.

That's numbness and tingling in your hands and feet.

It wasn't just hands and feet, though. It went up my leg.

And I couldn't hold a pencil to write.

Your skin peels off.

All of it.

Peels off.

So it looks like you have a massive sunburn everywhere.

I was itchy everywhere.

It was like an itch that you could never stop.

And that chemotherapy didn't work for her.

And then I sent her to get high-dose interleukin-2.

My chest started to fill up with fluid.

I remember sitting across just like this from my...

Mom, in the family room of her house, and I would have to go, Mom, what are we

going to do?

That was my breathing.

And the high-dose interleukin-2 didn't work.

At the same time, though, I had an MRI done, which I had not had done

previously, and they found a brain tumor.

So she needed radiation to her brain.

You know when you break your neck and that thing sits on your shoulders and

they screw it into your head?

That's what they put on you when you have to be bolted to a table when they

give you brain radiation.

So I had somebody come at me with a drill and screw things into my head

while fully awake and conscious.

The life expectancy of someone with metastatic melanoma at the time was

about seven months. So we are way into that at this point.

We published the paper in 1996.

Everybody kind of went, wow.

And that was kind of it.

We were all very skeptical of the science of cancer immunology. I wasn't

sure.

that what he had done successfully in a mouse, in a very controlled setting,

would ultimately translate to a method that would work in a human being.

You're going to be hearing a good deal more about something called interferon

these days.

Skepticism about an immunotherapy drug for cancer stems from the 1980s.

Researchers are now calling a new cancer treatment the most promising in 30

years. When attempts at using the immune system to fight cancer offer an enormous

promise.

called interleukin-2. And then, devastating disappointment.

Because fewer patients than expected seemed to benefit.

For years, there were clinical trials, and none of these worked. We started to

see some bad side effects. And I can tell you, these were not happy meetings

to attend.

They all started with, we did this experiment in animals in our lab, and it

looked great, and then we did a clinical trial, and nobody got better.

Years of that had led to a view that immunotherapy would just never work.

20 or 30 years ago, cancer was not a very big thing for drug companies.

The drugs didn't work that well.

The patients didn't live that long.

The much more lucrative drugs were for heart disease or diabetes.

chronic diseases that people would take drugs for for the rest of their lives.

Jim first goes to BMS who had held the patents and Peter Lindsley worked for

them at the time.

The guys at BMS had told him, we like CTLA-4 but we think it has other

applications.

But in fact they weren't doing anything clinically with it at all.

I was very disappointed in the initial response, but it got more and more

frustrating with time.

It was just no, place after place after place.

The scientists would get happy, you know, and excited, and attorneys would

say, no, no, no, no, no, you can't do this because Bristol-Myers Squibb

already has filed for a patent on their antibody.

And I said, have you read their patent? Their patent is backwards.

But still, you know, the company would say, well, BMS has got more lawyers

than...

We'd had a big company and so too bad

So there were all kinds of things that like stood in the way of this

happening and I would say You know his experiment in this was to just keep

fighting to say there's something here. There's something here something here

And that's where I really give him credit It's like a bloodhound on the

scent. He's not going to get taken off the scent until he's found the fox.

I would always

plan vacations places where he could not get a phone call and he could not be

connected to the internet.

Dad is doing a great job of shopping.

Robert, go over there and stand by dad.

Okay.

It was about two years that nobody would listen, and

so it was getting depressing.

My brother Mike had metastatic prostate cancer.

He presented with a lot of joint pain, which is how they found him.

We often had Thanksgiving with Mike for many years in Berkeley. He'd come out,

and so I got to know him quite well.

Mike got diagnosed in his 50s with metastatic prostate cancer to the bone.

That's how he was first diagnosed, and that pretty much is a death sentence.

And that also, during this time, while Jim was trying to march forward this new

therapy, he really wanted to be able to give this to his brother. I need to get

it into people. I need to get it into patients.

Jim turns his search towards smaller and smaller biotech companies, looking for

anyone willing to take a gamble on his idea.

In Boulder, Colorado, he finds Alan Korman, who is creating drugs for

autoimmune disease.

My interest was in immunology.

I didn't really know much about cancer biology or cancer therapy.

I think it was useful not to be biased by the current thinking of how to go

after cancer.

The concept of jumping into a problem and being the naive one is really

useful. The people that have been in that field very long can do the exact

same thing. I think you get tunnel vision.

Corman's job will be to take the CTLA-4 antibody that Jim and Max developed for

mice and make it into a drug that can work safely in humans.

The drug will be called ipilimumab.

I ended up collaborating with someone that I knew from graduate school, a guy

named Nils Lomberg.

Nils Lomberg works for Metarex, a small biotech company based in San Francisco.

I got a call from Alan.

We started talking about the idea of ipilimumia. Ipilimumia hadn't been

created yet, and I convinced him to let me in on this. I was fascinated.

Jim and Alan Corman and Nils Lahnberg all get together at the bar in the

basement of the Hotel Boulderado, right in downtown Boulder.

Jim's primary concern was that we move quickly.

I think he was very skeptical of the whole biotech pharmaceutical industry.

He didn't think we had the urgency.

I ended up sitting up with him most of the night with a bottle of whiskey.

Out of that conversation, we had a handshake agreement.

And with that handshake, we started work back in California, back in the lab.

466 days later, we had ipilimumab in a patient.

And I think that's a world's record.

Phase one tests a relatively small number of people, generally, for safety.

Sometimes they get a little hint of whether the drug's working, but

generally it's just to make sure that the drug is not going to harm somebody.

We picked a dose that was, you know, a coin toss that was based,

you know, somewhat loosely on what we had done in the mouse.

But clearly, you know, we didn't know enough about how to figure out its

potency.

When we were developing the phase one clinical trials, there were many stops

and starts.

There were many times when it was wondered whether or not the clinical

trial could even start.

Which tumor type should we do it in? Should it be all comers? Should we focus

on melanoma patients?

How many patients should we enroll in the phase one clinical trial? How much

of a budget did we have to enroll these patients?

What was the starting dose of the drug that we were going to give? Were we

taking the starting dose just based on mouse data? Which, by the way, is what

we did.

when drugs go into phase one trials their first trials in people nine out of

ten or more fail and that's it you pull the plug at that first stage

i ran that clinical trial at that time it was amazing

because three out of the 12 patients was a very small clinical trial three out of

the 12 patients showed that all of the tumor went away

We never see this in a phase one trial. It's so rare that it's sort of like, you

know, finding the pot at the end of the rainbow. You know, you feel like, am I

really seeing this or am I imagining it, right? It's just unbelievable.

I became aware that CTLA-4 was the focus of an early set of clinical trials that

was through the clinical trial grapevine producing a little bit of activity in

patients with advanced melanoma

Obviously, I wanted to be part of that.

I remember going Christmas shopping in a wheelchair in the mall where we grew up.

That was probably the worst Christmas ever.

I remember sitting underneath the Christmas tree with Rob, and I was a

huddling mess on the floor.

And he just held me and told me to work it out.

That Christmas was hard because I didn't think I was going to see the next one.

She comes to clinic and I say, I think that we're really at the point where the

readily available standard options are not working for you.

There is a clinical trial that you could consider participating in.

I remember Dr. Walchuk explaining it to me in very, very simple terms, that

instead of an outside agent like chemotherapy, your body then uses its

own immune system to fight off cancer.

It allows it to turn on the immune system and recognize cancer in a way

that it previously couldn't.

Sharon got four doses of ipilimumab.

The treatments were not like chemotherapy.

Chemotherapy, you go back three or four days in that week. You live at that

oncologist's office.

It's your home.

This was different.

I had a shot in my leg.

And then I had a 90-minute IV infusion. That was it.

Because I wasn't in chemotherapy either, I didn't feel nauseous. I didn't feel

the incredible fatigue that came along with it.

I noticed a difference in myself just from changing treatments.

Once a drug is proven safe in Phase I trials, it moves into Phase II and Phase

III.

These trials include far more patients studied over much longer time periods.

They can cost hundreds of millions of dollars.

We never could have developed ipilimumab as a small company, even a publicly

traded company, we never could have raised that much money.

Mederex has defined a partner with deep pockets, but the big pharma companies

are wary of the risk.

For any hope of success, ipilimumab needs a champion inside the

pharmaceutical industry.

When I left the NIH to go to industry, I went to Bayer that was building an

oncology program.

I really wanted to supervise the development of ipi. When Bayer declined,

I left Bayer after seven years specifically to bring ipilimumab

forward.

BMS was not sure they were going to take it at all. So I came at just the right

time.

And I was ready to advocate for it. I went to BMS.

I said, let me walk you through why this is important.

I must admit, I was apprehensive.

The fact that BMS had another antibody would have been one of the reasons that

a lot of companies had given for not working with us.

You know, BMS can kill you.

Stocks to watch today. A big one will be Bristol-Myers Squibb.

There were other reasons to be apprehensive of Bristol Myers Squibb.

Bristol Myers had a pretty good reputation.

Then that started to fade.

They did a deal for a drug from a small company called Imclone.

The drug sparked an insider trading scandal that led to a seven-year prison

sentence. Pessimism propelled by news that yet another corporate giant may

have accounting problems.

Today, it's Bristol-Myers Squibb in the government's crosshairs. So they went

through in the early to mid-2000s a very hard...

period bristol meyer squibb one of the leaders in the industry forecast

disappointing earnings growth for its second quarter so what we were asking

bms to do is invest a healthy amount of money into the belief that

these drugs were going to work it was against the grain a lot of our external

advisors said we were probably investing too much in immunotherapy because

nothing had worked before

My presentation focused not on the response rate, which was very low at the

time, but one patient who had received, I think it was a single dose at the

time, that now two and three years out was still in remission.

The very first public meeting, Rachel made it a point for me to come and sit

next to her.

And I'll never forget because I was sitting there and there were some

people. I had very little understanding of immunology. They were making comments

about what they thought this meant or that meant. I was just sitting there

going, oh, bullshit.

And I was just sort of under my breath, you know, going, oh, my God.

And obviously getting agitated.

And Rachel, you know, kept looking at me.

And afterwards...

She says, OK, well, I wrote down every time you started snorting and stuff. And

so what about this?

What's wrong with that?

What's wrong with this from her notes? And so we went over the notes for a

while. It was really a lot of fun.

I was part of the group of people who was following, let's call it the

conventional path of cancer research.

Jim Allison and the immunology crowd was thinking about it differently.

And the mainstream was more or less ignoring that.

Innovation is extremely difficult.

There was somebody, a regulatory person on my team, who yelled at me, screamed

at me.

We don't get it. We're wasting our time.

And it was not just the members of the team, because back in the day, most of

the doctors were not immuno-oncology believers.

That's why it was hard to get patients on the study initially.

That's why it took so long.

There was like a year where that clinical study could not be enrolled. It

was very, very slow.

No one wanted to hear about another cancer immunotherapy agent. It was, you

know, forget it. We don't want to talk to you.

And you can imagine a lot of doors slammed in his face.

You might argue that there is a defense mechanism against new ideas. They are

seen as mutations, as cancerous to a body of thought.

You don't know whether the new idea is something potent or deadly.

And that's why they're often viewed with skepticism, and that's why it takes a

really powerful idea combined with someone willing to push it forward to

make it happen.

I inherited predisposition for cancer.

My mother had melanoma, my grandfather had pancreatic cancer, and my beloved

uncle got glioma when he was 58.

So I know that cancer is coming for me.

I know it's coming from my family.

I'm just about the age my uncle was when he got his brain tumor.

The stakes are so high.

The opportunity is so great that somehow it just

didn't matter when people yelled at me or created barriers.

Because we're going to make it work.

We're going to make it happen.

I'm still in Berkeley.

But the action had moved to New York, where the companies are and a lot of the

studies were going on at Sloan Kettering.

I thought, well, there's some not-so-good stuff happening to my baby

over there.

And I better move again.

Jim decides he needs to be in New York where the major trials are going on.

When I asked Jim why he needed to be there, he said, I went there to be a

nuisance.

He wanted to stay on the scientists. He wanted to stay on the FDA. He wanted to

stay on Bristol-Myers Squibb.

Anytime a lab moves, it's always a tough decision.

especially if you're moving across the country. People have roots in a given

area. I'd been in the Bay Area for almost a dozen years at that point.

So when Jim decided to move from Berkeley to Sloan-Kettering, I think

it's a testament to how dedicated all of us were to this work and the promise we

saw in it that I would say at least 90% of the people at Jim's lab picked up and

moved cross-country.

It was a tough move in that, you know, you're moving all your stuff, you're

moving a lab. Things in the labs are delicate.

We actually lost an entire freezer full of sort of critical, unreplaceable

reagents.

Somewhere in the desert, halfway across, the refrigerated truck that it was

plugged into blew a fuse.

So there was some pain to go with that move.

Jim being in New York was truly a fish out of water.

I'm not sure Jim walked more than three blocks from his apartment on the Upper

East Side.

But, you know, he didn't move to New York to take advantage of what New York

has to offer.

He moved to take advantage of what Sloan Kettering had to offer.

Putting pressure on Jim is Pfizer, the world's largest drug company.

Seeing the progress of IPI, Pfizer has launched a competitive cancer drug,

drawing from Jeffrey Bluestone's work.

I went to Pfizer, and they got excited about it. We were on track. I was

working on them to make the drug, and things looked really good.

Tremilimumab was being developed by Pfizer, and the early signals for both

of the medicines were remarkably similar.

Pfizer came in late when they saw Reasons to Believe.

Very classic.

We think maybe you have something here. We have one just like it.

We're going to beat you.

The race is on, and watching it closely is the FDA, the U.S. government agency

that determines whether a drug is safe and effective enough for patients.

The FDA is judging the clinical trials by standards developed for evaluating

chemotherapy.

The rules said if a patient hadn't had their tumor shrink by 30% within 12

weeks, they failed.

In Pfizer's trial, the tumors don't shrink after 12 weeks.

They grow.

Failing to meet FDA standards, Pfizer decides to cut its losses.

Pfizer did this giant trial, and just everybody was watching.

It failed.

You know, a big blow.

You know, the biggest drug company in the world just abandons the whole field.

I mean, everybody, when we started out, one of the main criticisms we had is,

immunotherapy's never worked, it'll never work, it's a bunch of voodoo, and

you shouldn't even try it.

Now here's this big failure.

BMS thought there's only one other in the class.

It just failed.

We don't want to put more money in. In fact, should we be closing the studies

you're doing now?

Many of my colleagues said, this will never work.

This is a dry well.

Jim struggles to make it clear that ipilimumab is not a chemotherapy drug

and doesn't behave like one.

People go back to their community.

As soon as they got back, they'd put them on some chemotherapy drugs that had

been shown never to work. But now they're responding to such and such. I

said, yeah, right.

You know, it's another de-explanation.

They're just responding late, which is what I showed you in the mice.

You go back to Jim's early experiments in mice with CTLA-4.

Jim observed that the T cells were entering.

into the tumors and they were expanding in size before the t cells then were

able to destroy the tumors and then they would shrink in size

so

jim had to convince bristol myers-quibb to do a much more expensive much more

lengthy trial unlike jim who to

his credit

persevered and did whatever it took i felt i had done exactly what i normally

would do which is to just let the other folks make the drug little did i know at

the time that they would give up on it so quickly

jim was visibly angry he'd just go into

a tirade i've got to make this happen because the easiest you'll never get

fired for saying no if you're you know responsible for spending a lot of money

the skepticism was widespread and frankly jim experienced it probably

every day

every

time i'd see him he would just you could see his blood pressure going up that was

hard on him during those years and hard on people around him that was a trying

time jim became rather obsessed

The science and the project just consumed him, and I really couldn't be a

part of that.

With no science background of my own, our son off in college, we

had less and less in common.

That didn't mean that we didn't admire each other and care greatly for each

other, but we just decided to go our separate ways.

I was afraid the drug was going to go down.

And I invested not just myself, but my family, you know.

It was a tough time.

I think any great, big, disruptive change that you're pushing for is going

to take some single-mindedness.

Whether it has to be sacrifice, I don't know. I suppose maybe it does.

At Memorial Sloan Kettering Cancer Center, doctors are seeing in patients

exactly what Jim has predicted.

Patients were coming in and telling us that they felt well.

Even though the CAT scans are showing that the tumors are growing, these

patients said, I'm feeling really great on this treatment.

Some people, after they came off of the clinical trials of ipilimumab, began to

get better with no further therapy.

And this was quite striking.

And so at that point, clinicians like Jed Walchuk asked these kind of

immovable, implacable forces, Big Pharma and the United States government, the

FDA, to change the trial.

The risk BMS was taking at the time was we were committing to years more

of clinical study before we'd ever get approval.

In an environment where there was tremendous uncertainty about whether

this thing was going to work or not.

We were asked to do another five years of expensive, long, tedious trials.

There were investors that didn't think this was going to work.

We hadn't had a long track record of recent success.

This takes a toll.

This takes a toll.

It was in the final throes of metastatic prostate cancer.

And the drug was in trials by then.

And there were really good results coming back.

But it was just not possible.

And that was, you know, it was frustrating.

But, you know, at the time, I just wasn't so sure about whether it would

really, at the end of the day, do my brother any good because he was so sick

by then.

I remember him calling me from Dallas when, you know, Mike was dying.

And he was in his arms at the time. And you can imagine, you know, what that

would do to you.

When I was first told I had prostate cancer, I was terrified because it was a

week after my brother had died.

I had been working with the prostate group at Sloan Kettering.

So I went over to the oncologist's office. The secretary said, he's with

somebody. I said, I don't care.

I didn't read on his story.

And I said, can I talk with you? He said, let me. I said, no, now.

I need to talk to you right now.

My oncologist said, in your case, because of family history, I think we'd

better take it out.

Anyway, they caught it very early.

Sharon came back for her first set of imaging.

I got a phone call from the radiologist. Now, usually, you should know,

radiologists don't call with good news.

They call to make you aware of some awfulness that they have seen on a scan.

And this was a very serious radiologist, very well respected.

And he called and he said, Jed, I'm reading your patient Sharon's CAT scans.

He goes, I have to ask you something. He goes...

What happened to her? I'm like, what do you mean what happened? He goes, what

did she get? All the cancer went away.

And so that was an important moment for many of us.

With enough patients showing improved health, BMS decides to commit to the

full five-year study and accept the enormous financial risk.

Bristol-Myers Square made the decision with everybody in the room then to use

overall survival as the endpoint and not to use the typical sort of tumor

shrinkage immediately endpoint, but look to see how patients did over a long

period of time.

I give the team at Bristol-Myers, and Rachel was the lead of that team, credit

for... listening to us and for being open to the observations that we were

really making on the front lines and to working with us to find a way to capture

this new biology.

Most companies and most people in those companies at that time would wash their

hands and walk away.

And so I give great credit to BMS.

They went with the science. They believed the scientist and they believed

the data.

Dr. Walchuk, in his ever-so-calm voice, said, So, Sharon, the man that invented

this is here today.

Would you like to meet him?

Yes! He calls me up, says, Come down.

He didn't tell me that. You know, I found out why I was there only when I

walked into the room.

Dr. Allison walked in, and I pretty much almost lifted him up off the floor, gave

him a giant bear hug.

I just couldn't talk.

I couldn't talk. How in the world are you supposed to adequately thank

somebody standing across from you that you are 100% positive that without them,

you wouldn't be here?

There is no thank you for that.

Oh, meeting her was amazing because until then, you know, it was just

numbers. You know, it was a concept.

She was the first patient I'd ever met.

And all we could think about at the end of that was we got to get a picture.

We look around the room, and nobody has a camera.

The only camera that we could find was one that they took pictures of a

melanoma with to send out and get studied.

It's not the best quality in the world, but it definitely memorializes one of

the best days ever.

Every single scan since.

I have another MRI coming up here in about two weeks, so say a little prayer.

No evidence of disease.

In every one sense.

Now she has her family, two kids, two beautiful kids.

I still choke up when I think about that.

In 2011, 15 years after Jim Allison made his initial discovery, the

clinical trials are finally complete.

I remember the moment when we saw the data.

I can see the people around me. It is imprinted like a picture because we knew

we were changing the world.

Rachel Humphrey came running up.

the stairs, breathless, to show me the survival curves, one for the control and

one for the patients that received Ippy.

One curve stayed different for as long as we studied.

After years, you start to think that maybe you've cured these patients.

I happened to be at a melanoma meeting at Cold Spring Harbor.

I was sitting next to Harold Varmus, and I had my iPad on and kept checking it.

And he said, you know, what are you doing?

And I said, well, the FDA is supposed to announce its decision on the MP today.

All of a sudden, I got this email.

It was about 11 on the East Coast, which meant it was 8 in California. And

there's Alan in the Metarex crowd holding glasses and whiskey.

And I looked at Harold. I said, I guess, he said, I guess that's good news. I

said, I think that's good news, yes. And he said, either that or they just like

to drink in the morning.

Allison and others like him have only begun the thing. Each generation will

build on the next.

We're not nearly at the end of this story. I mean, we're somewhere in the

very first few chapters.

This happens fairly regularly. I get emails, but many times a handwritten

note.

This is from somebody I've never met.

Dear Dr. Allison, two years ago today, my 63-year-young husband Richard was

diagnosed with metastatic melanoma to the brain and everywhere else.

Thanks to you, your fortitude and determination

to prove that immunotherapy had promise, Richard is alive and well, healthy and

happy, and has been treatment-free for over a year.

And he says, the words thank you do

not begin to cover the gratitude we have for you and your persistence

through all this to see that immunotherapy be brought to people

worldwide.

Our family is eternally grateful for the extra years we've given us with Richard,

a wonderful father, husband, sincerely.

And it's from his wife.

For sure, it's knowing that we've done something like this that makes it all

worthwhile.

So... I need a drink.

Look, I'm in the eye.

I didn't come here and I ain't leaving. So don't sit around and cry. Just roll

me up and smoke me one eye.

Now you won't see no sad and teary eye.

When I get my wings and it's my time to fly.

Call my friends and tell them there's a party. Come on by and just roll me up

and smoke me one eye.

When I played with Willie Nelson at the Austin City Limits Festival, I was

scared.

It was hard to relax, you know, when I'm playing with my buddies, you know, it's

like fun.

But if you're playing with Willie, you're like, I gotta get this, I gotta

get this.

Thank you. Thank you so much. I'm so honored. You know, of course, it's a

scientist's dream.

We think that the discoveries that you have made have enabled an entirely new

principle for cancer therapy. I mean, we think it's absolutely fantastic.

Be out and build a roaring fire.

Roll me in the flames for about an hour.

Take me out and twist me up and point me toward the sky.

And just roll me up and smoke me when I die.

Roll me up and smoke me when I die.

And if anyone don't like it, look, I'm in the eye.

I didn't come here and I ain't leaving, so don't sit around and cry. Just roll

me up and smoke me when I die.

Pam Sharma was tenured at MD Anderson.

She was a big name in the cancer world in her own right.

It was talking professionally for... quite a few years, and then eventually

there was a romance.

Jim said to her one day, there's no one who can stand either of us.

Who else is going to talk about T-cells all day? We should get married.