TEDMED 2018
Carl June: A "living drug" that could change the way we treat cancer
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Carl June is the pioneer behind CAR T-cell therapy: a groundbreaking cancer treatment that supercharges part of a patient's own immune system to attack and kill tumors. In a talk about a breakthrough, he shares how three decades of research culminated in a therapy that's eradicated cases of leukemia once thought to be incurable -- and explains how it could be used to fight other types of cancer.
Carl June - Oncologist, researcher, professor
Carl June is a renowned pioneer in the fight against cancer. Full bio
Carl June is a renowned pioneer in the fight against cancer. Full bio
Double-click the English transcript below to play the video.
00:12
So this is the first time
I've told this story in public,
I've told this story in public,
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the personal aspects of it.
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Yogi Berra was a world-famous
baseball player who said,
baseball player who said,
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"If you come to a fork
in the road, take it."
in the road, take it."
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Researchers had been,
for more than a century,
for more than a century,
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studying the immune system
as a way to fight cancer,
as a way to fight cancer,
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and cancer vaccines have,
unfortunately, been disappointing.
unfortunately, been disappointing.
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They've only worked in cancers
caused by viruses,
caused by viruses,
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like cervical cancer or liver cancer.
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So cancer researchers basically
gave up on the idea
gave up on the idea
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of using the immune system
to fight cancer.
to fight cancer.
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And the immune system, in any case,
did not evolve to fight cancer;
did not evolve to fight cancer;
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it evolved to fight pathogens
invading from the outside.
invading from the outside.
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So its job is to kill
bacteria and viruses.
bacteria and viruses.
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01:03
And the reason the immune system
has trouble with most cancers
has trouble with most cancers
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is that it doesn't invade
from the outside;
from the outside;
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it evolves from its own cells.
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And so either the immune system does
not recognize the cancer as a problem,
not recognize the cancer as a problem,
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or it attacks a cancer
and also our normal cells,
and also our normal cells,
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leading to autoimmune diseases
like colitis or multiple sclerosis.
like colitis or multiple sclerosis.
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So how do you get around that?
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Our answer turned out to be
synthetic immune systems
synthetic immune systems
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that are designed to recognize
and kill cancer cells.
and kill cancer cells.
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That's right -- I said
a synthetic immune system.
a synthetic immune system.
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You do that with genetic engineering
and synthetic biology.
and synthetic biology.
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We did it with the naturally occurring
parts of the immune system,
parts of the immune system,
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called B cells and T cells.
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These were our building blocks.
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T cells have evolved to kill
cells infected with viruses,
cells infected with viruses,
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and B cells are the cells that make
antibodies that are secreted
antibodies that are secreted
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and then bind to kill bacteria.
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Well, what if you combined
these two functions
these two functions
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in a way that was designed
to repurpose them to fight cancer?
to repurpose them to fight cancer?
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We realized it would be possible
to insert the genes for antibodies
to insert the genes for antibodies
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from B cells into T cells.
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So how do you do that?
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Well, we used an HIV virus
as a Trojan horse
as a Trojan horse
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to get past the T cells' immune system.
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The result is a chimera,
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a fantastic fire-breathing creature
from Greek mythology,
from Greek mythology,
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with a lion's head, a goat's body
and a serpent's tail.
and a serpent's tail.
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So we decided that the paradoxical
thing that we had created
thing that we had created
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with our B-cell antibodies,
our T cells carrier
our T cells carrier
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and the HIV Trojan horse
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should be called "Chimeric Antigen
Receptor T cells," or CAR T cells.
Receptor T cells," or CAR T cells.
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The virus also inserts genetic information
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to activate the T cells and program them
into their killing mode.
into their killing mode.
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So when CAR T cells are injected
into somebody with cancer,
into somebody with cancer,
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what happens when those CAR T cells
see and bind to their tumor target?
see and bind to their tumor target?
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They act like supercharged killer
T cells on steroids.
T cells on steroids.
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They start this crash-defense
buildup system in the body
buildup system in the body
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and literally divide
and multiply by the millions,
and multiply by the millions,
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where they then attack and kill the tumor.
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All of this means that CAR T cells
are the first living drug in medicine.
are the first living drug in medicine.
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CAR T cells break the mold.
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Unlike normal drugs that you take --
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they do their job and get metabolized,
and then you have to take them again --
and then you have to take them again --
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CAR T cells stay alive
and on the job for years.
and on the job for years.
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We have had CAR T cells stay
in the bodies of our cancer patients
in the bodies of our cancer patients
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now for more than eight years.
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And these designer
cancer T cells, CAR T cells,
cancer T cells, CAR T cells,
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have a calculated half-life
of more than 17 years.
of more than 17 years.
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So one infusion can do the job;
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they stay on patrol
for the rest of your life.
for the rest of your life.
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This is the beginning
of a new paradigm in medicine.
of a new paradigm in medicine.
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Now, there was one major challenge
to these T-cell infusions.
to these T-cell infusions.
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The only source of T cells
that will work in a patient
that will work in a patient
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are your own T cells,
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unless you happen to have
an identical twin.
an identical twin.
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So for most of us, we're out of luck.
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So what we did was to make CAR T cells.
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We had to learn to grow
the patient's own T cells.
the patient's own T cells.
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And we developed a robust
platform for this in the 1990s.
platform for this in the 1990s.
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Then in 1997, we first tested
CAR T cells in patients
CAR T cells in patients
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with advanced HIV-AIDS.
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And we found that those CAR T cells
survived in the patients
survived in the patients
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for more than a decade.
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And it improved their immune system
and decreased their viruses,
and decreased their viruses,
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but it didn't cure them.
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So we went back to the laboratory,
and over the next decade
and over the next decade
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made improvements
to the CAR T cell design.
to the CAR T cell design.
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And by 2010, we began treating
leukemia patients.
leukemia patients.
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And our team treated three patients
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with advanced chronic
lymphocytic leukemia in 2012.
lymphocytic leukemia in 2012.
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It's a form of incurable leukemia
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that afflicts approximately 20,000 adults
every year in the United States.
every year in the United States.
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The first patient that we treated
was a retired Marine sergeant
was a retired Marine sergeant
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and a prison corrections officer.
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He had only weeks to live
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and had, in fact, already paid
for his funeral.
for his funeral.
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The cells were infused,
and within days, he had high fevers.
and within days, he had high fevers.
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He developed multiple organ failures,
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was transferred to the ICU
and was comatose.
and was comatose.
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We thought he would die,
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and, in fact, he was given last rites.
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But then, another
fork in the road happened.
fork in the road happened.
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So, around 28 days after
the CAR T cell infusion,
the CAR T cell infusion,
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he woke up,
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and the physicians finally examined him,
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and the cancer was gone.
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The big masses that
had been there had melted.
had been there had melted.
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Bone marrow biopsies found
no evidence of leukemia,
no evidence of leukemia,
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and that year, in our first
three patients we treated,
three patients we treated,
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two of three have had durable remissions
now for eight years,
now for eight years,
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and one had a partial remission.
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The CAR T cells had attacked
the leukemia in these patients
the leukemia in these patients
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and had dissolved between 2.9
and 7.7 pounds of tumor in each patient.
and 7.7 pounds of tumor in each patient.
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Their bodies had become veritable
bioreactors for these CAR T cells,
bioreactors for these CAR T cells,
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producing millions
and millions of CAR T cells
and millions of CAR T cells
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in the bone marrow,
blood and tumor masses.
blood and tumor masses.
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And we discovered that these CAR T cells
can punch far above their weight class,
can punch far above their weight class,
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to use a boxing analogy.
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Just one CAR T cell can kill
1,000 tumor cells.
1,000 tumor cells.
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That's right -- it's a ratio
of one to a thousand.
of one to a thousand.
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The CAR T cell and
its daughter progeny cells
its daughter progeny cells
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can divide and divide
and divide in the body
and divide in the body
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until the last tumor cell is gone.
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There's no precedent for this
in cancer medicine.
in cancer medicine.
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The first two patients
who had full remission
who had full remission
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remain today leukemia-free,
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and we think they are cured.
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These are people
who had run out of options,
who had run out of options,
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and by all traditional methods they had,
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they were like modern-day Lazarus cases.
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All I can say is: thank goodness
for those forks in the road.
for those forks in the road.
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Our next step was to get permission
to treat children with acute leukemia,
to treat children with acute leukemia,
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the most common form of cancer in kids.
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The first patient we enrolled
on the trial was Emily Whitehead,
on the trial was Emily Whitehead,
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and at that time, she was six years old.
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She had gone through
a series of chemotherapy
a series of chemotherapy
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and radiation treatments
over several years,
over several years,
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and her leukemia had always come back.
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In fact, it had come back three times.
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When we first saw her, Emily was very ill.
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Her official diagnosis
was advanced, incurable leukemia.
was advanced, incurable leukemia.
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Cancer had invaded her bone marrow,
her liver, her spleen.
her liver, her spleen.
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And when we infused her
with the CAR T cells
with the CAR T cells
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in the spring of April 2012,
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over the next few days,
she did not get better.
she did not get better.
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She got worse, and in fact, much worse.
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As our prison corrections
officer had in 2010,
officer had in 2010,
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she, in 2012, was admitted to the ICU,
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and this was the scariest fork
in the whole road of this story.
in the whole road of this story.
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By day three, she was comatose
and on life support
and on life support
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for kidney failure, lung failure and coma.
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Her fever was as high
as 106 degrees Fahrenheit for three days.
as 106 degrees Fahrenheit for three days.
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And we didn't know
what was causing those fevers.
what was causing those fevers.
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We did all the standard
blood tests for infections,
blood tests for infections,
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and we could not find
an infectious cause for her fever.
an infectious cause for her fever.
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But we did find something
very unusual in her blood
very unusual in her blood
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that had never been seen
before in medicine.
before in medicine.
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She had elevated levels of a protein
called interleukin-6, or IL-6,
called interleukin-6, or IL-6,
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in her blood.
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It was, in fact, more than a thousandfold
above the normal levels.
above the normal levels.
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And here's where yet another
fork in the road came in.
fork in the road came in.
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By sheer coincidence,
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one of my daughters has a form
of pediatric arthritis.
of pediatric arthritis.
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And as a result, I had been
following as a cancer doc,
following as a cancer doc,
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experimental therapies
for arthritis for my daughter,
for arthritis for my daughter,
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in case she would need them.
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And it so happened that just months
before Emily was admitted to the hospital,
before Emily was admitted to the hospital,
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a new therapy had been approved by the FDA
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to treat elevated levels of interleukin-6.
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And it was approved for the arthritis
that my daughter had.
that my daughter had.
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It's called tocilizumab.
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And, in fact, it had just been added
to the pharmacy at Emily's hospital,
to the pharmacy at Emily's hospital,
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for arthritis.
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So when we found Emily had
these very high levels of IL-6,
these very high levels of IL-6,
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I called her doctors in the ICU and said,
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"Why don't you treat her
with this arthritis drug?"
with this arthritis drug?"
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They said I was a cowboy
for suggesting that.
for suggesting that.
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And since her fever and low blood pressure
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had not responded to any other therapy,
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her doctor quickly asked permission
to the institutional review board,
to the institutional review board,
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her parents,
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and everybody, of course, said yes.
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And they tried it,
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and the results were nothing
short of striking.
short of striking.
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Within hours after treatment
with tocilizumab,
with tocilizumab,
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Emily began to improve very rapidly.
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Twenty-three days after her treatment,
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she was declared cancer-free.
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And today, she's 12 years old
and still in remission.
and still in remission.
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(Applause)
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So we now call this violent reaction
of the high fevers and coma,
of the high fevers and coma,
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following CAR T cells,
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cytokine release syndrome, or CRS.
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We've found that it occurs in nearly
all patients who respond to the therapy.
all patients who respond to the therapy.
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But it does not happen
in those patients who fail to respond.
in those patients who fail to respond.
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So paradoxically,
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our patients now hope
for these high fevers after therapy,
for these high fevers after therapy,
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which feels like
"the worst flu in their life,"
"the worst flu in their life,"
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when they get CAR T-cell therapies.
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They hope for this reaction
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because they know it's part
of the twisting and turning path
of the twisting and turning path
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back to health.
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Unfortunately, not every patient recovers.
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Patients who do not get CRS
are often those who are not cured.
are often those who are not cured.
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So there's a strong link now between CRS
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and the ability of the immune system
to eradicate leukemia.
to eradicate leukemia.
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That's why last summer,
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when the FDA approved
CAR T cells for leukemia,
CAR T cells for leukemia,
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they also co-approved the use
of tocilizumab to block the IL-6 effects
of tocilizumab to block the IL-6 effects
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and the accompanying CRS
in these patients.
in these patients.
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That was a very unusual event
in medical history.
in medical history.
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Emily's doctors have now
completed further trials
completed further trials
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and reported that 27 out of 30 patients,
the first 30 we treated,
the first 30 we treated,
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or 90 percent,
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had a complete remission
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after CAR T cells, within a month.
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A 90 percent complete remission rate
in patients with advanced cancer
in patients with advanced cancer
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is unheard of
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in more than 50 years of cancer research.
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In fact, companies often declare
success in a cancer trial
success in a cancer trial
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if 15 percent of the patients
had a complete response rate.
had a complete response rate.
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A remarkable study appeared in the
"New England Journal of Medicine" in 2013.
"New England Journal of Medicine" in 2013.
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An international study
has since confirmed those results.
has since confirmed those results.
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And that led to the approval by the FDA
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for pediatric and young adult
leukemia in August of 2017.
leukemia in August of 2017.
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So as a first-ever approval
of a cell and gene therapy,
of a cell and gene therapy,
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CAR T-cell therapy
has also been tested now
has also been tested now
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in adults with refractory lymphoma.
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This disease afflicts about 20,000
a year in the United States.
a year in the United States.
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The results were equally impressive
and have been durable to date.
and have been durable to date.
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And six months ago, the FDA approved
the therapy of this advanced lymphoma
the therapy of this advanced lymphoma
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with CAR T cells.
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So now there are many labs and physicians
and scientists around the world
and scientists around the world
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who have tested CAR T cells
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across many different diseases,
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and understandably, we're all thrilled
with the rapid pace of advancement.
with the rapid pace of advancement.
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We're so grateful to see patients
who were formerly terminal
who were formerly terminal
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return to healthy lives, as Emily has.
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We're thrilled to see long remissions
that may, in fact, be a cure.
that may, in fact, be a cure.
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At the same time, we're also concerned
about the financial cost.
about the financial cost.
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It can cost up to 150,000 dollars
to make the CAR T cells for each patient.
to make the CAR T cells for each patient.
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And when you add in the cost
of treating CRS and other complications,
of treating CRS and other complications,
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the cost can reach
one million dollars per patient.
one million dollars per patient.
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We must remember that the cost
of failure, though, is even worse.
of failure, though, is even worse.
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The current noncurative therapies
for cancer are also expensive
for cancer are also expensive
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and, in addition, the patient dies.
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So, of course, we'd like to see
research done now
research done now
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to make this more efficient
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and increase affordability
to all patients.
to all patients.
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Fortunately, this is a new
and evolving field,
and evolving field,
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and as with many other new
therapies and services,
therapies and services,
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prices will come down as industry learns
to do things more efficiently.
to do things more efficiently.
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When I think about
all the forks in the road
all the forks in the road
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that have led to CAR T-cell therapy,
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there is one thing that strikes me
as very important.
as very important.
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We're reminded that discoveries
of this magnitude don't happen overnight.
of this magnitude don't happen overnight.
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CAR T-cell therapies came to us
after a 30-year journey,
after a 30-year journey,
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along a road full of setbacks
and surprises.
and surprises.
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In all this world of instant gratification
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and 24/7, on-demand results,
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scientists require persistence,
vision and patience
vision and patience
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to rise above all that.
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They can see that the fork in the road
is not always a dilemma or a detour;
is not always a dilemma or a detour;
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sometimes, even though
we may not know it at the time,
we may not know it at the time,
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the fork is the way home.
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Thank you very much.
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(Applause)
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ABOUT THE SPEAKER
Carl June - Oncologist, researcher, professorCarl June is a renowned pioneer in the fight against cancer.
Why you should listen
Carl June's revolutionary leukemia therapy, which was recently approved by the FDA, uses genetically engineered versions of a patient’s own T cells and is the first personalized cell therapy for cancer to be sanctioned in America. Developed by June and his colleagues, this method has the potential to help patients with many other types of cancers.
June is currently Director of the Center for Cellular Immunotherapies at the Perelman School of Medicine and Director of the Parker Institute for Cancer Immunotherapy at the University of Pennsylvania. A graduate of the Naval Academy in Annapolis and Baylor College of Medicine, he has published more than 350 manuscripts and is the recipient of numerous prizes and honors, including election to the Institute of Medicine in 2012 and the American Academy of Arts and Sciences in 2014, as well as being named one of TIME Magazine's 100 Most Influential People in 2018.
Carl June | Speaker | TED.com