B1 Intermediate US 345 Folder Collection
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So this is the first time I've told this story in public,
the personal aspects of it.
Yogi Berra was a world-famous baseball player who said,
"If you come to a fork in the road, take it."
Researchers had been, for more than a century,
studying the immune system as a way to fight cancer,
and cancer vaccines have, unfortunately, been disappointing.
They've only worked in cancers caused by viruses,
like cervical cancer or liver cancer.
So cancer researchers basically gave up on the idea
of using the immune system to fight cancer.
And the immune system, in any case, did not evolve to fight cancer;
it evolved to fight pathogens invading from the outside.
So its job is to kill bacteria and viruses.
And the reason the immune system has trouble with most cancers
is that it doesn't invade from the outside;
it evolves from its own cells.
And so either the immune system does not recognize the cancer as a problem,
or it attacks a cancer and also our normal cells,
leading to autoimmune diseases like colitis or multiple sclerosis.
So how do you get around that?
Our answer turned out to be synthetic immune systems
that are designed to recognize and kill cancer cells.
That's right -- I said a synthetic immune system.
You do that with genetic engineering and synthetic biology.
We did it with the naturally occurring parts of the immune system,
called B cells and T cells.
These were our building blocks.
T cells have evolved to kill cells infected with viruses,
and B cells are the cells that make antibodies that are secreted
and then bind to kill bacteria.
Well, what if you combined these two functions
in a way that was designed to repurpose them to fight cancer?
We realized it would be possible to insert the genes for antibodies
from B cells into T cells.
So how do you do that?
Well, we used an HIV virus as a Trojan horse
to get past the T cells' immune system.
The result is a chimera,
a fantastic fire-breathing creature from Greek mythology,
with a lion's head, a goat's body and a serpent's tail.
So we decided that the paradoxical thing that we had created
with our B-cell antibodies, our T cells carrier
and the HIV Trojan horse
should be called "Chimeric Antigen Receptor T cells," or CAR T cells.
The virus also inserts genetic information
to activate the T cells and program them into their killing mode.
So when CAR T cells are injected into somebody with cancer,
what happens when those CAR T cells see and bind to their tumor target?
They act like supercharged killer T cells on steroids.
They start this crash-defense buildup system in the body
and literally divide and multiply by the millions,
where they then attack and kill the tumor.
All of this means that CAR T cells are the first living drug in medicine.
CAR T cells break the mold.
Unlike normal drugs that you take --
they do their job and get metabolized, and then you have to take them again --
CAR T cells stay alive and on the job for years.
We have had CAR T cells stay in the bodies of our cancer patients
now for more than eight years.
And these designer cancer T cells, CAR T cells,
have a calculated half-life of more than 17 years.
So one infusion can do the job;
they stay on patrol for the rest of your life.
This is the beginning of a new paradigm in medicine.
Now, there was one major challenge to these T-cell infusions.
The only source of T cells that will work in a patient
are your own T cells,
unless you happen to have an identical twin.
So for most of us, we're out of luck.
So what we did was to make CAR T cells.
We had to learn to grow the patient's own T cells.
And we developed a robust platform for this in the 1990s.
Then in 1997, we first tested CAR T cells in patients
with advanced HIV-AIDS.
And we found that those CAR T cells survived in the patients
for more than a decade.
And it improved their immune system and decreased their viruses,
but it didn't cure them.
So we went back to the laboratory, and over the next decade
made improvements to the CAR T cell design.
And by 2010, we began treating leukemia patients.
And our team treated three patients
with advanced chronic lymphocytic leukemia in 2012.
It's a form of incurable leukemia
that afflicts approximately 20,000 adults every year in the United States.
The first patient that we treated was a retired Marine sergeant
and a prison corrections officer.
He had only weeks to live
and had, in fact, already paid for his funeral.
The cells were infused, and within days, he had high fevers.
He developed multiple organ failures,
was transferred to the ICU and was comatose.
We thought he would die,
and, in fact, he was given last rites.
But then, another fork in the road happened.
So, around 28 days after the CAR T cell infusion,
he woke up,
and the physicians finally examined him,
and the cancer was gone.
The big masses that had been there had melted.
Bone marrow biopsies found no evidence of leukemia,
and that year, in our first three patients we treated,
two of three have had durable remissions now for eight years,
and one had a partial remission.
The CAR T cells had attacked the leukemia in these patients
and had dissolved between 2.9 and 7.7 pounds of tumor in each patient.
Their bodies had become veritable bioreactors for these CAR T cells,
producing millions and millions of CAR T cells
in the bone marrow, blood and tumor masses.
And we discovered that these CAR T cells can punch far above their weight class,
to use a boxing analogy.
Just one CAR T cell can kill 1,000 tumor cells.
That's right -- it's a ratio of one to a thousand.
The CAR T cell and its daughter progeny cells
can divide and divide and divide in the body
until the last tumor cell is gone.
There's no precedent for this in cancer medicine.
The first two patients who had full remission
remain today leukemia-free,
and we think they are cured.
These are people who had run out of options,
and by all traditional methods they had,
they were like modern-day Lazarus cases.
All I can say is: thank goodness for those forks in the road.
Our next step was to get permission to treat children with acute leukemia,
the most common form of cancer in kids.
The first patient we enrolled on the trial was Emily Whitehead,
and at that time, she was six years old.
She had gone through a series of chemotherapy
and radiation treatments over several years,
and her leukemia had always come back.
In fact, it had come back three times.
When we first saw her, Emily was very ill.
Her official diagnosis was advanced, incurable leukemia.
Cancer had invaded her bone marrow, her liver, her spleen.
And when we infused her with the CAR T cells
in the spring of April 2012,
over the next few days, she did not get better.
She got worse, and in fact, much worse.
As our prison corrections officer had in 2010,
she, in 2012, was admitted to the ICU,
and this was the scariest fork in the whole road of this story.
By day three, she was comatose and on life support
for kidney failure, lung failure and coma.
Her fever was as high as 106 degrees Fahrenheit for three days.
And we didn't know what was causing those fevers.
We did all the standard blood tests for infections,
and we could not find an infectious cause for her fever.
But we did find something very unusual in her blood
that had never been seen before in medicine.
She had elevated levels of a protein called interleukin-6, or IL-6,
in her blood.
It was, in fact, more than a thousandfold above the normal levels.
And here's where yet another fork in the road came in.
By sheer coincidence,
one of my daughters has a form of pediatric arthritis.
And as a result, I had been following as a cancer doc,
experimental therapies for arthritis for my daughter,
in case she would need them.
And it so happened that just months before Emily was admitted to the hospital,
a new therapy had been approved by the FDA
to treat elevated levels of interleukin-6.
And it was approved for the arthritis that my daughter had.
It's called tocilizumab.
And, in fact, it had just been added to the pharmacy at Emily's hospital,
for arthritis.
So when we found Emily had these very high levels of IL-6,
I called her doctors in the ICU and said,
"Why don't you treat her with this arthritis drug?"
They said I was a cowboy for suggesting that.
And since her fever and low blood pressure
had not responded to any other therapy,
her doctor quickly asked permission to the institutional review board,
her parents,
and everybody, of course, said yes.
And they tried it,
and the results were nothing short of striking.
Within hours after treatment with tocilizumab,
Emily began to improve very rapidly.
Twenty-three days after her treatment,
she was declared cancer-free.
And today, she's 12 years old and still in remission.
So we now call this violent reaction of the high fevers and coma,
following CAR T cells,
cytokine release syndrome, or CRS.
We've found that it occurs in nearly all patients who respond to the therapy.
But it does not happen in those patients who fail to respond.
So paradoxically,
our patients now hope for these high fevers after therapy,
which feels like "the worst flu in their life,"
when they get CAR T-cell therapies.
They hope for this reaction
because they know it's part of the twisting and turning path
back to health.
Unfortunately, not every patient recovers.
Patients who do not get CRS are often those who are not cured.
So there's a strong link now between CRS
and the ability of the immune system to eradicate leukemia.
That's why last summer,
when the FDA approved CAR T cells for leukemia,
they also co-approved the use of tocilizumab to block the IL-6 effects
and the accompanying CRS in these patients.
That was a very unusual event in medical history.
Emily's doctors have now completed further trials
and reported that 27 out of 30 patients, the first 30 we treated,
or 90 percent,
had a complete remission
after CAR T cells, within a month.
A 90 percent complete remission rate in patients with advanced cancer
is unheard of
in more than 50 years of cancer research.
In fact, companies often declare success in a cancer trial
if 15 percent of the patients had a complete response rate.
A remarkable study appeared in the "New England Journal of Medicine" in 2013.
An international study has since confirmed those results.
And that led to the approval by the FDA
for pediatric and young adult leukemia in August of 2017.
So as a first-ever approval of a cell and gene therapy,
CAR T-cell therapy has also been tested now
in adults with refractory lymphoma.
This disease afflicts about 20,000 a year in the United States.
The results were equally impressive and have been durable to date.
And six months ago, the FDA approved the therapy of this advanced lymphoma
with CAR T cells.
So now there are many labs and physicians and scientists around the world
who have tested CAR T cells
across many different diseases,
and understandably, we're all thrilled with the rapid pace of advancement.
We're so grateful to see patients who were formerly terminal
return to healthy lives, as Emily has.
We're thrilled to see long remissions that may, in fact, be a cure.
At the same time, we're also concerned about the financial cost.
It can cost up to 150,000 dollars to make the CAR T cells for each patient.
And when you add in the cost of treating CRS and other complications,
the cost can reach one million dollars per patient.
We must remember that the cost of failure, though, is even worse.
The current noncurative therapies for cancer are also expensive
and, in addition, the patient dies.
So, of course, we'd like to see research done now
to make this more efficient
and increase affordability to all patients.
Fortunately, this is a new and evolving field,
and as with many other new therapies and services,
prices will come down as industry learns to do things more efficiently.
When I think about all the forks in the road
that have led to CAR T-cell therapy,
there is one thing that strikes me as very important.
We're reminded that discoveries of this magnitude don't happen overnight.
CAR T-cell therapies came to us after a 30-year journey,
along a road full of setbacks and surprises.
In all this world of instant gratification
and 24/7, on-demand results,
scientists require persistence, vision and patience
to rise above all that.
They can see that the fork in the road is not always a dilemma or a detour;
sometimes, even though we may not know it at the time,
the fork is the way home.
Thank you very much.
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【TED】Carl June: A "living drug" that could change the way we treat cancer (A "living drug" that could change the way we treat cancer | Carl June)

345 Folder Collection
林宜悉 published on October 3, 2019
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