A "living drug" that could change the way we treat cancer | Carl June

123,057 views ・ 2019-10-02

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So this is the first time 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,
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"If you come to a fork in the road, take it."
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Researchers had been, for more than a century,
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studying the immune system as a way to fight cancer,
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and cancer vaccines have, unfortunately, been disappointing.
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They've only worked in cancers 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
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of using the immune system to fight cancer.
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And the immune system, in any case, did not evolve to fight cancer;
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it evolved to fight pathogens invading from the outside.
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So its job is to kill bacteria and viruses.
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And the reason the immune system has trouble with most cancers
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is that it doesn't invade 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,
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or it attacks a cancer and also our normal cells,
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leading to autoimmune diseases 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
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that are designed to recognize and kill cancer cells.
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That's right -- I said a synthetic immune system.
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You do that with genetic engineering and synthetic biology.
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We did it with the naturally occurring 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,
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and B cells are the cells that make 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
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in a way that was designed to repurpose them to fight cancer?
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We realized it would be possible 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
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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,
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with a lion's head, a goat's body and a serpent's tail.
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So we decided that the paradoxical thing that we had created
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with our B-cell antibodies, 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.
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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.
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So when CAR T cells are injected into somebody with cancer,
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what happens when those CAR T cells see and bind to their tumor target?
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They act like supercharged killer T cells on steroids.
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They start this crash-defense buildup system in the body
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and literally divide 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.
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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 --
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CAR T cells stay alive and on the job for years.
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We have had CAR T cells stay 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,
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have a calculated half-life 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.
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This is the beginning of a new paradigm in medicine.
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Now, there was one major challenge to these T-cell infusions.
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The only source of T cells 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.
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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.
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And we developed a robust platform for this in the 1990s.
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Then in 1997, we first tested 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
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for more than a decade.
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And it improved their immune system 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
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made improvements to the CAR T cell design.
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And by 2010, we began treating leukemia patients.
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And our team treated three patients
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with advanced chronic 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.
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The first patient that we treated 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.
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The cells were infused, 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.
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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.
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So, around 28 days after 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.
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Bone marrow biopsies found no evidence of leukemia,
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and that year, in our first three patients we treated,
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two of three have had durable remissions 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
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and had dissolved between 2.9 and 7.7 pounds of tumor in each patient.
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Their bodies had become veritable bioreactors for these CAR T cells,
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producing millions and millions of CAR T cells
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in the bone marrow, blood and tumor masses.
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And we discovered that these CAR T cells 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.
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That's right -- it's a ratio of one to a thousand.
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The CAR T cell and its daughter progeny cells
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can divide and divide 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.
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The first two patients 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,
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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.
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Our next step was to get permission 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,
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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
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and radiation treatments 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.
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Cancer had invaded her bone marrow, her liver, her spleen.
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And when we infused her 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.
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She got worse, and in fact, much worse.
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As our prison corrections 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.
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By day three, she was comatose 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.
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And we didn't know what was causing those fevers.
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We did all the standard blood tests for infections,
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and we could not find an infectious cause for her fever.
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But we did find something very unusual in her blood
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that had never been seen before in medicine.
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She had elevated levels of a protein 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.
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And here's where yet another 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.
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And as a result, I had been following as a cancer doc,
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experimental therapies 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,
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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.
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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,
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for arthritis.
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So when we found Emily had 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?"
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They said I was a cowboy 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,
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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.
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Within hours after treatment 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.
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(Applause)
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So we now call this violent reaction 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.
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But it does not happen 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,
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which feels like "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
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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.
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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.
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That's why last summer,
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when the FDA approved CAR T cells for leukemia,
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they also co-approved the use of tocilizumab to block the IL-6 effects
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and the accompanying CRS in these patients.
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That was a very unusual event in medical history.
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Emily's doctors have now completed further trials
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and reported that 27 out of 30 patients, 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
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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
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if 15 percent of the patients had a complete response rate.
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A remarkable study appeared in the "New England Journal of Medicine" in 2013.
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An international study 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.
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So as a first-ever approval of a cell and gene therapy,
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CAR T-cell therapy 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.
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The results were equally impressive and have been durable to date.
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And six months ago, the FDA approved 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
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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.
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We're so grateful to see patients 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.
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At the same time, we're also concerned 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.
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And when you add in the cost of treating CRS and other complications,
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the cost can reach one million dollars per patient.
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We must remember that the cost of failure, though, is even worse.
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The current noncurative therapies 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
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to make this more efficient
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and increase affordability to all patients.
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Fortunately, this is a new and evolving field,
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and as with many other new therapies and services,
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prices will come down as industry learns to do things more efficiently.
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When I think about 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.
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We're reminded that discoveries of this magnitude don't happen overnight.
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CAR T-cell therapies came to us after a 30-year journey,
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along a road full of setbacks 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
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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;
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sometimes, even though 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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