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How scientists built a "living drug" against cancer

In 2010, Emily Whitehead was diagnosed with acute lymphoblastic leukemia, a cancer of certain cells of the immune system.

This is the most common form of childhood cancer. and Emily had a good chance of getting it on chemo. The remission rate for the most common variety was about 85 percent.

It would take them 20 months to understand the shadow behind these sunny statistics and the appalling prospect of voluntarily providing their daughter as a zero patient for the world's first living medicine.

From the Book The Breakthrough: Immunotherapy and the Race for the Cure of Cancer, Copyright (c) 201

8 by Charles Graeber. Buy at Amazon.

Twelve Publishing

Emily began using 26-month chemotherapy. She lost her hair and most of her childhood energy, but the medicine seemed to do its job and make her body too sick, as it killed the disease. Nevertheless, her cancer lived like all cancers, a constellation of mutant cells that continued to transform into new variations. Some of these new mutants were immune to chemo and continued to flourish.

By October 2011, Emily had relapsed; In the language of immunotherapists her cancer had "escaped". Her doctors at Hershey Medical Center in Pennsylvania could only offer more chemo more aggressively. In February 2012, however, a renewed relapse occurred.

It was painfully clear now that Emily was among the 15 percent of children with leukemia for whom chemotherapy was not a cure. The cancer doubled daily in her bloodstream and it was too late for a bone marrow transplant – she was too ill. Oncologists now called Emily's cancer "terminal." She was 6 years old.

Cancer is shitty and unfair, but this shitty inequality reaches a completely different level when the cancer happens to a child. Tom and Kari Whitehead were told that they needed to consider hospice for their daughter. Or if she wanted, she could die at home. Traditional medicine had nothing else to offer. But a researcher at the Philadelphia Children's Hospital could do it if Emily's parents were ready to take the risk.

The Whiteheads learned of this possibility on a Sunday. Until Monday they were in Philadelphia. Emily Whitehead would be the first child in the world to try an experimental cancer therapy called CAR-T. The researchers offered to reprogram their immune cells into a clone army of carcinogenic serial killers.

A CAR-T cell is a revised T-cell that was removed from the cancer patient and optimized in the laboratory to detect the patient's cancer, and then injected back into the patient. Since each of these reworked cells is a monstrous robocop-like accumulation of parts of immune cells, the researchers gave their invention the equally monstrous name "chimeric antigen receptor T cell" (in Greek mythology, the chimera is a patchwork monster that integrates aspects of Lion, a goat and a snake) But "CAR-T" sounds a lot better.

CAR-T is often referred to as the "most complex drug ever made", but it's not a real drug in the traditional sense. Unlike an inert molecule that has been introduced into the body for a transient effect, CAR-T lives. If it worked as planned, this "living drug" would live on in Emily's bloodstream like a cancer-killing superpower, giving her some sort of immunity to her illness. And it would give humanity a revolutionary new weapon in the fight against cancer.

And if it had not worked? If the released cellular serial killers attack the girl's healthy cells instead of cancer? Well, the Whiteheads decided not to think about it. At that time, her only daughter had nothing to lose.

The hundreds of millions of T-cells that patrol our bloodstream and lymph nodes are experts at detecting and killing off-body cells. And although the idea has been rejected by most scientists over the last 100 years, they have recently accepted that a handful of these T cells are also predisposed to recognize and kill cancer.

So why do you always know when? You have a cold or the flu, but cancer also comes without a cold? Why does a test have to be done to find out if we have this deadly disease?


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The answer to this question came in a series of groundbreaking discoveries on how cancer tricks out our immune response, hiding from it and overwhelming it. Krebs shuts down T cells before being given the opportunity to demand reinforcements, multiply into an overwhelming clone army, and get their work done. But what if there was a way to overwhelm cancer and block it with a large number of immune cells that could recognize and kill it?

The research group that considered this option was called Cancer Immunotherapist and
at the time Emily Whitehead emerged in the hospital, having already spent decades dealing with the problem.

However, before they could hope to create a clone army from the perfect killer T-cell, they had to find that perfect T-cell somewhere in the blood of the cancer patient stream, one or the other among hundreds of millions who was tuned to it to recognize exactly the cancer of this patient.

It was not surprising that Mr. Perfect was hard to find. In fact, even cancer immunotherapists were not sure that Mr. Perfect existed until the 1980s.

Identifying, extracting, fertilizing, cultivating, cloning and then activating the perfect T cell – this was largely trial and error, done with little financial resources and little understanding of the overwhelming biological complexity of cancer or the immune system. The science was all incredibly new; T cells were discovered only in the late 1960s.

There was no roadmap. Cancer immunotherapists have wavered for decades and have failed to prove that the immune system can be assisted in the detection and killing of cancer cells.

Meanwhile another group of cancer immunotherapists had begun to consider a different approach: instead of somehow hoping that the perfect cancer would kill the T cells in a patient's body, they would make their own Mr. Perfect and construct a Frankenstein T-cell sewn together from different parts of the lab. The Weird Science T-Cell has been specifically designed to find and destroy the specific cancer of a patient.

The engineering is complex, but the concept is simple. A single T-cell recognizes only the particular diseased cell protein (termed antigen) to whose "vision" it was born, as determined by a random assignment process. The business end of this "seeing" is called T-cell receptor or TCR.

If you change the TCR, you may be able to change what this T-cell targets. Change it to the right one, and you may even be able to target it for a specific disease. And that's exactly what a charismatic Israeli researcher named Zelig Eshhar came up with.

In the early '80s, this apiculture thesis began thinking about the commercial end of the TCR – the part that stretches like a red thread through the surface of the T-cell Grabby protein antenna and "sees" specific antigen Aims.

For Eshhar it looked very much like the grabby protein claws of an antibody. It seemed to work the same way. These Y-shaped immune structures are available in many flavors (hundreds of millions) each linked to a different disease-specific protein. Everyone was a key in search of his castle.

Eshhar could imagine jumping off the end of the TCR and jumping on a new antibody like a vacuum attachment. Change the antibody, and possibly change what the T-cell targets. Theoretically, there could be an almost infinite number of new appendages, each specific to recognize and bind to another antigen, thus targeting another disease. Such technology would create a whole new class of drugs.

Making Eshar's theory a reality required a bit of bioengineering, but in 1985 he somehow managed to create a simple proof of concept.

He called his primitive CAR a T-body. It was a T-cell that was retooled to recognize a relatively obvious antigenic target that he had selected, a telltale protein borne by the fungus Trichophyton mentagrophytes better known as athlete's foot. This modest experiment obscured incredible possibilities. And it caught the attention of those who had spent their lifetime working in the trenches of cancer immunotherapy.

In 1989, Eshhar was persuaded to spend a sabbatical year in the lab of pioneering immunotherapist Steve Rosenberg. Rosenberg first became convinced in the 1960s of the ability of the immune system to kill cancer after examining a former stage IV patient whose immune system had spontaneously cured his own disease. Rosenberg wondered if the man's charged immune cells could help other cancer patients.

In today's unthinkable experiments, Rosenberg had tried exactly that and transferred the blood of the healed man to the veins of a cancer patient in the next bed. It did not work, but the promise of cell transfer therapy stuck to him.

Over the next five decades, the lab would serve the Rosenberg's National Institutes of Health (and that of Philip Greenberg at the Fred Hutchinson Cancer Research Center in Seattle) as a sort of hive and refuge for immunotherapy talents.

There, Eshhar joined another brilliant young NIH researcher named Patrick Hwu to develop an updated version of the so-called adoptive cell therapy.

Examination of a patient Tumors under the microscope showed that even after the failure of the larger immune attack, some T cells were able to successfully recognize and invade tumor antigens. These were her Mr. Perfect T cells and hopefully seeds for her clone army of targeted cancer killers.

Hwu's goal was to arm this subgroup of successful "tumor infiltrating lymphocytes" (TILs) by packing the small missiles with an additional load of powerful tumor-killing hormones.

They needed a guidance system that researchers could choose and modify to fight various cancers. "Zelig had shown that an antibody and a T-cell can be combined to target something," says Hwu, who heads the department of cancer medicine at the Anderson Cancer Center in Houston, Texas. "Now the question was whether we can target cancer cells?"

Starting with a series of T cells that proved to be Mr. Perfect TILs against melanoma, Hwu and Eshhar Frankenstein replaced them with new TCR targets for ovarian, colon, and breast cancer. "Zelig made the receptor, I put it in T cells," recalls Hwu. "That was really difficult in the 1990s."

Without the benefits of retroviral vectors or CRISPR, a small needle had to be inserted into a T cell and the new TCR genes individually microinjected. "We spent a lot of time together," says Hwe with a laugh. "Lots of night owls in the lab."

None of the results was perfect, but the TILs they used to detect ovarian cancer proved to be the best of the three, and the team was able to release the result and announce the new name CAR-T and the tantalizing effects of technology.

They had not healed cancer, but pushed science forward. They had successfully replaced the T-cell steering wheel and controlled it specifically against a specific cancer. "When I first brought this to work, I was so excited," recalls Hwu. But he knew that retargeting was only part of the development of a cancer-killing machine.

To be effective, these new cells also needed to thrive and replicate themselves, as do normal T cells. It seemed that something essential had been lost during the retrofit, resulting in Lemon CARs that did not run long enough to replicate themselves or stop the task of killing cancer. Her Frankenstein would rise from the table and fall over.

It would be up to the researcher Michel Sadelain to find the clever solution to this and some other technical problems and to create a truly "living drug," as Sadelain called it. a second-generation CAR that can detect a target, expand clonally, and maintain its other T-cell functionality, with a life span equal to that of the patient.

Sadelain (a laconic scientific intellectual who does that) worked in his lab. The founding director of the Memorial Sloan Kettering Cancer Center of Cell Engineering also gave his new CAR an important new target – a protein called CD19, which is located on the surface certain blood cancer cells is unique.

CD-19 seemed like a good CAR target. It has been found abundantly on the surface of certain cancers. Unfortunately, it was also expressed by some normal B cells, but if the CAR also attacked them, it was a survivable collateral damage.

In a healthy human, B cells are essential aspects of the normal immune system; In patients like Emily, these B cells had mutated and become cancerous. (B cells appear white when centrifuged in bulk.) The science used Greek roots to turn white [leuk] blood cells [cytes] into "leukocytes." We call cancer these cells "leukemia." To survive,

Fortunately, doctors had long ago learned to keep patients without B-cells alive. "If you're in late-stage cancer," says Sadelain, "it's not so bad your B-cells

Sadelain now owns a sleek, elegant and self-replicating second-generation car with plenty of fuel and a realistic cancer target.His group shared the sequence of their new car with Rosenberg's group at the National Cancer Institute and the Laboratory of the University of Pennsylvania Researcher and Physician Carl June. (June in turn tested aspects of his CAR design that he received from Dr. Dario Campagna of St. Jude's Children & # 39; 39; s Research Hospital had borrowed.)

The three groups are now pushing for experiments with people complex and powerful new cancer py were competitors, and yet they worked together, borrowed each other and improved their ideas.

Sadelain's group had first launched CAR-19 T-cell clinical trials, Rosenberg's first, which were published. her successful CAR-T study shrank tumors in a lymphoma patient. But it would be Carl June's process with Emily Whitehead, who would determine if there is a future for CAR-T.

June believed he could save her. But if the little girl died of the experiment and his strong Franconian drug attacked her body instead of the cancer, the result would be terrible and tragic. He knew that too. And he was equally sure that the ability to develop CART into an FDA-approved drug for hundreds of other children was likely to kill her.

In the 1990s June was a certified leukemia specialist commissioned by the National Institutes to work on new approaches to treating HIV. This led to collaboration in an experimental CAR-like treatment in which killer T cells were rerouted to detect infected T cells in AIDS patients. The first clinical CAR study in humans would be for HIV. June had developed techniques to grow T cells from human donors that were robust enough to last for decades.

Early data looked good, June said. But before the work was completed, it became unnecessary to develop the first protease inhibitors in 1997, drugs that blocked the replication of the HIV virus.

Overnight, these drugs changed the prognosis for millions of people and the direction of June's career. Now he transferred his work and practice to a laboratory in UPenn and the Children's Hospital in Philadelphia to focus more on a disease that had recently become very personal.

Junes wife Cynthia was diagnosed with ovarian cancer in 1996. When Cindy June did not respond to traditional therapies, June had turned to immature immunotherapy approaches that were still in its infancy and equipped his laboratory with a customized version of the promising immunotherapy vaccine from another lab.

It Was GVAX, a Personalized Approach A portion of a patient's tumor provided him with additional genes that code for cytokines that would alert the immune system and re-injected the result into the patient. June held GVAX a huge potential.

"I had no idea how difficult it was to make a clinical trial out of a lab experiment," said June. He believed that his wife had a good response to her personalized vaccine. But as with all cancer vaccines of the era, the response did not last. June rightly suspected that the tumors shut off this immune response in some way.

This suspicion was fueled in part by the pioneering work of Jim Allison, a harmonica-playing Texas immunology researcher. In 1987, Allison had found one of the tricks that cancer uses to shut down immune responses and developed an antibody that blocks this trick in mice and triggers their immune system to kill cancer. Thirty-one years later, this discovery was recognized as a breakthrough in our war on cancer and Allison won the Nobel Prize for Medicine. But in 1999, Allison's work had not yet been turned into a drug. It had not even been tested on humans.

June had no choice but to push ahead blindly, hoping to save his wife. "I knew that his antibodies in mice improve the effects of immunotherapy," said June. The combination of Allison's antibody discovery with GVAX "was a breeze," says June. He repeatedly tried to obtain a sample of the precious anti-CTLA-4 antibody Allison had discovered from the manufacturer, and was repeatedly rejected. They did not allow a single experimental use of the unapproved antibody, as this was considered too dangerous.

"It was very frustrating," says June. He could not imagine how the result of Mary's hail experiment with an experimental drug might be more dangerous than the specific outcomes of untreatable cancer.

When Cindy June died in 2001 at the age of 46, June moved his grief for the mother of her three children into his work, shifting his full-time focus to a CAR for cancer "to the top". Nine years later it was time.

In the June lab technology was concerned with the placement of genes into cells that had come a long way since Hwu started injecting them by hand. The foreman in this modernized CAR production line was the rebuilt envelope of the AIDS-causing virus.

Viruses are essentially only genes with legs in a protein envelope and are at the edge of our definition of life. These slimmed down DNA carriers also lack the tools to reproduce themselves.

In order to make more copies of themselves, viruses deposit the work on the cell machinery of the larger, more complex cells that infect them, and inject their own viral genetic blueprints into their host's cellular production facilities. In the case of the human immunodeficiency virus, this host cell is a T cell.

HIV is devastatingly effective in fighting T cells. This usually causes the virus to infect this T cell with instructions to produce more HIV. This makes them useless for the defense against diseases and leads to an interruption of adaptive immunity in the body, the disease we know as acquired immunodeficiency syndrome or AIDS.

However, this ability to alter DNA from T cells also makes HIV an ideal transport system for the genetic blueprints of a CAR-T. Theoretically, this killer could become a life-saving technology.

In UPenn's June lab, an HIV virus was emptied and given new genetic instructions. It was then introduced into Emily's T cells, which had been carefully centrifuged from their collected blood. Instead of delivering a disease, June's transfected virus "infected" Emily's T cells with new genetic instructions and reprogrammed them to target only the CD19 protein on the surface of their cancerous B cells.

19 T-cells were taken to the Children's Hospital and taken to the room where Emily Whitehead was sitting on a hospital bed, a little girl, bald and unbowed in a sparkling purple dress. ,

A line was inserted and its reprogrammed T cells slowly reintroduced into their native veins. Only with the third pack did the side effects begin.

The extreme toxicity of new T-cell therapy was unknown to physicians at this time. Now they know it under several names; The most scientific "Cytokine Release Syndrome" (CRS), especially "Cytokine Storm", most commonly "shaking and baking".

As the names suggest, it is a whirlwind of exhausting and dangerous symptoms caused by the flow of the immune system signaling hormones released during a T-cell feeding rage, a tremendously enhanced version of the debilitating side effects an immune fight against the flu.

Emily's CRS was "severe" in the language of her medical reports. Children have a stronger immune system effect than adults; As the first pediatric CAR-T patient, Emily's CRS was more extreme than anyone would have thought.

Powerful cytokines, triggered by the turbocharged immune attack that flew through Emily's system. Soon she was sweating and trembling and had trouble breathing. Her blood pressure dropped dangerously and her temperature rose to 105 degrees. At the age of 106, Emily was taken to intensive care. She stayed there, a tube in her throat, another in her nose, in a coma, breathing mechanically. Days passed. She did not improve.

On the fifth day she received steroids. Emily's symptoms calmed for a moment, only to gain strength like an offshore cyclone and come back. On the seventh day, the little girl who climbed the pump of a fan motor was swollen like a hot water bottle. She had multiple organ failure. It seemed that healing, not illness, was killing her.

Stephan Grupp, her oncologist and clinical trial leader, desperately ordered a series of blood tests covering all the immunological molecules he could think of.

Blood returned two hours later. Two numbers stood out. Both their interferon gamma (INFγ) and interleukin-6 levels were remarkably high. Grupp introduced the ad to his 15 o'clock lab meeting, where a group gathered to work out the problem and identify possible options for brainstorming. Nobody saw any.

It was clear that their interleukin-6 level had increased a thousand times over normal levels. Whether it was a disease or a symptom, a cause of the problem, or an aspect of the body's attempt to alleviate it, they were not sure. The interpretation of the notes and melodies within the chemical symphony of the immune response was still in its infancy, and interleukin-6 was known to be a cytokine with a variety of roles in normal immune function, both anti-inflammatory and anti-inflammatory, push and pull. It has also been known to be involved in the inflammation of rheumatoid arthritis.

And here, Emily Whitehead was very lucky.

As it happened, June was well acquainted with the debilitating effects of childhood rheumatoid arthritis. His own daughter suffered. He'd followed the literature for years, keeping an eye on a promising new antibody that seemed to block the interleukin-6 receptors and seemed to lower the volume of the cytokine call for inflammation and swelling. "No one working on cancer would have had a reason to know about it," June said. "It was just pure luck that I did it." He had even awarded a prize to the Japanese professor who discovered this antibody.

Just a few months earlier, it had completed clinical trials and was now approved by the FDA as a tocilizumab drug. June had gotten ready with the stuff just in case his daughter was experiencing a flare-up of her illness.

Now, June wondered if this new arthritis drug would help a child with cancer.

There were no experts to seek advice – they were the experts who urgently groped their way through foreign territory. The decision had to be made immediately. Emily's fever had struck 107. Tom and Kari Whitehead had been instructed to consider an order to revive their unconscious daughter.

Grupp wrote a recipe for tocilizumab. He ran it down to Emily, who was languishing in intensive care, and told the doctors what he was up to. The drug was new, it had never been tested against CRS patients; So far no one had ever treated the side effects of CAR-T therapy. Grupp believed the drug would help Emily. He also knew that it could do nothing or worse.

"(The doctors in the ICU) called him a cowboy," recalls June. This was Wild West, new territory. But without a map, without precedent, an untested, unproven answer was the only possible one. Grupp prepared an injection and injected the tocilizumab directly into Emily's IV port. And gradually, the anti-interleukin-6 antibodies blocked their receptors and calmed Emily's cytokine storm. Over the next few days, Emily was weaned off the ventilator and blood pressure medication, but remained in a coma.

The wait was difficult for everyone, especially their parents. Finally, a week later, Emily opened her eyes to the tune of "Happy Birthday," sung by the hospital staff. She was exactly 7 years old. And she was alive.

A single CAR-T cell can remove up to a hundred thousand cancer cells and cause an instantaneous remission that surprises even the most passionate immunotherapist. Sadelain calls her "a living drug". June sometimes calls her a "serial killer" for cancer.

Only four weeks after her first CAR infusion, Emily's lab results showed no cancer – apparently a laboratory error, so June ordered a second biopsy. But there was no mistake. The procedure had been a success – as a drug for Emily and as a proof of concept. That was good, but not the end. Emily was not the only childhood leukemia patient to be treated experimentally.

June also had another teenage ALL patient treated at the Children's Hospital, a 10-year-old girl. Her leukemia had responded to CAR-T therapy and she had gone into remission, only to relapse two months later.

Biopsies showed that the leukemia of this girl was mutated and escaped on B cells that did not carry the CD19 target protein. The crab had changed the uniforms, but they had no other car to get.

And so, in September 2012, Emily Whitehead returned to school with a medical certificate signed by President Obama. Sie war eine niedliche nationale Erfolgsgeschichte, die auf Good Morning America gefeiert wurde und ein Symbol der Hoffnung und des Fortschritts im Kampf gegen Krebs war. Das andere Mädchen starb an ihrem Krebs, eine traurige und demütigende Erinnerung an die noch zu erledigende Arbeit.

Emily Whiteheads vollständige Remission sorgte für Schlagzeilen und brachte das gesamte Feld in Schwung, was die Finanzierung und Entwicklung von CAR-T beschleunigte.

Jedes der Forschungsteams – einst Kollaborateure, jetzt Konkurrenten – schloss sich schnell mit einem pharmazeutischen Partner zusammen, um die Technologie in Medizin umzuwandeln. Das National Cancer Institute hat sich für Kite Pharma entschieden (das die Zulassung für sein CAR-T mit der Bezeichnung Yescarta für große B-Zell-Lymphome erhalten hat). Das Memorial Sloan Kettering Cancer Center hat zusammen mit dem Fred Hutchinson Cancer Research Center und der Seattle Children’s Research Group eine Partnerschaft mit Juno Therapeutics geschlossen.

Der Arzneimittelriese Novartis hat die CAR-T-Technologie von der University of Pennsylvania lizenziert. Es erhielt die FDA-Zulassung für die Therapie von Emily Whitehead, die es jetzt unter dem Markennamen Kymriah vertreibt. Diese Zulassung kam im Jahr 2017, aber die CD-19 CAR-T-Therapie hat bereits Tausenden von Menschen geholfen, darunter Hunderten von krebskranken Kindern.

Selbst die 85 Prozent der Kinder, bei denen ALL mit einer Chemotherapie behandelt werden kann, sind Kandidaten für die neue Therapie . Für Kinder ist eine solche Heilung mit versteckten Kosten verbunden. Zwei Jahre Chemotherapie kosten die Entwicklung von Körper und Geist.

Die jetzt als Kymriah bekannte experimentelle Behandlung ist sowohl ein Medikament als auch ein Produkt. Es wird aus einer hübschen durchscheinenden Packung mit einer blutorangen Leuchtkraft abgegeben. Jedes wird für den Patienten angepasst und aus den eigenen T-Zellen des Patienten hergestellt.

Derzeit kostet jede dieser maßgeschneiderten einmaligen Infusionen 475.000 USD. Wenn die Krankenhauskosten addiert werden, belaufen sich die Gesamtkosten auf 1 Million USD pro Patient. Die nächstbeste Behandlung für akutes B-Lymphom ist eine Knochenmarktransplantation, die mehr als 100.000 USD kostet. Diese "ökonomische Toxizität" ist gegenwärtig eine weitere schwerwiegende Nebenwirkung von hochmodernen Krebsheilverfahren wie der Immuntherapie von Krebs, die noch zu behandeln ist.

Für einen CAR-T-Patienten sieht der Behandlungsprozess ungefähr so ​​aus: Ein in Frage kommender Patient fährt zu einem angeschlossenen medizinischen Zentrum. Dort wird mindestens 15 Minuten lang bei 2.200 bis 2.500 U / min Blut entnommen und zentrifugiert, um die T-Zellen von Plasma, Thrombozyten und dem Rest zu trennen.

Anschließend werden die T-Zellen kryogen gefroren und in einem speziellen Kryovac-Behälter verpackt. und zur 180.000 Quadratmeter großen Mutterschiff-Einrichtung von Novartis in Morris Plains, New Jersey, verschifft, wo sie aufgetaut und überarbeitet werden, um ein für den Krebs des Patienten spezifisches Protein zu erkennen.

Dies erfolgt schrittweise. Zuerst werden die T-Zellen aktiviert. Dann werden sie mit einem Virus transduziert, der neue genetische Anweisungen enthält. Dann werden sie angebaut und vermehrt, bis sie Hunderte von Millionen erreichen. Die Klonarmee der Supersoldat-T-Zellen wird dann erneut kryokonserviert, zum zertifizierten medizinischen Zentrum zurückgesandt und wieder aufgetaut, um wieder in den Patienten getropft zu werden.

Durch die Kryokonservierung können Patienten aus der ganzen Welt die Behandlung nutzen. Die Bearbeitungszeit vom begehbaren Zentrum bis zur fertigen maßgeschneiderten T-Zell-Behandlung beträgt 22 Tage. Vorläufige Daten deuten darauf hin, dass Therapien mit diesen maßgeschneiderten T-Zellen dauerhafte Ansprechraten für ehemals hoffnungslose Fälle liefern. Emily und ihre Mutter Kari Whitehead Jeff Swensen / The New York Times / Getty Images Emily ist Teil von diese glückliche Statistik. Ab Juli 2019 bleibt sie in Remission. Das strahlend kleine kranke Mädchen ist jetzt ein Tween. Sie spielt Ukulele und fährt Straßenrennen. But mostly, she’s a kid again.

There is great danger, of course, in any engineered fiddling with the hair triggers, feedback loops, and checks and balances of an immune system evolved over millennia, and great trepidation in using experimental therapies on any patient, especially a child. At the same time, the worst possible side effect of these treatments is death; untreatable leukemia ends the same way.

Those first experimental treatments, and the new approach to treating cytokine storm, quickly demonstrated that for these patients, the rewards far outweighed the risks. For such patients, CAR-T has changed the numbers seemingly overnight.

Before CAR, kids like Emily had a zero percent survival rate. Currently, that estimated survival rates now stand at 83 percent or higher, and combination therapies—combining a CAR with another immunotherapy drug that blocks the tricks cancer uses to shut down immune response—are driving that rate even higher. The goal, of course, is a cure.

Developing this cancer-killing technology is one thing, getting access to it is another. For cancer patients, delays and bureaucracy can be deadly. It’s understandable that extra caution is still exercised when considering the ethics of giving experimental therapies to kids.

June understands that, but he’s also seen first hand the price paid when potentially lifesaving but experimental drugs are denied. That happened with his wife. Something similar almost happened to Emily too. She couldn’t start her CAR treatment until a lengthy ethical review. By the time it was finished, it was nearly too late.

This highlights one of the other challenges of such rapid discovery and technology: how to properly regulate it, while getting it into the hands and bodies of the patients who need it as quickly as possible. In this breakthrough age, clinical trials are more important than ever. And yet many patients don’t fully realize it. Remarkably, not all doctors do either.

Researchers increasingly understand cytokine storm and how to control it, making CAR-T therapies far less of a rough ride, and a safer one. An additional safeguard now comes standard in the new experimental CARs as well, in the form of built-in cellular “kill switches”; if Frankenstein goes crazy, researchers can just pull the plug.

It’s only been two years since CARs were FDA approved as a medicine, but already the design permutations are exploding. Several of them make versions of CAR-T that use donated T cells (rather than a patient’s own), for off-the-shelf solutions. The others would take a separate article to enumerate.

But customizable variations, collaboration, and combinations seem to be the logical response to a this confounding disease; a mutating answer to a mutating problem. What’s clear as we understand how complex and personal both our cancers and our immune systems truly are, what we now specify as “personalized’ medicine will one day just be called medicine.

So far, CAR-T has been proven effective in some “liquid” cancers, like lymphomas and leukemias. The next challenge is to move that success to treat solid tumors as well—liver masses, lung cancers, brain lesions and many more.

To do that, researchers have needed to identify antigens unique to such cancers, and create CAR’s that can recognize them.

One of the antigens showing promise is a protein called mesothelin, recently found to be commonly and uniquely expressed by the cancers of an estimated 2 million cancer patients in the US alone.

Results from a phase I study targeting this antigen with CAR-T, unveiled at the end of April, suggested promise; Michel Sadelain was lead author of the study supported by the Parker Institute of Cancer Immunotherapy, founded by Napster legend Sean Parker. The technology has since been licensed to Atara Biotherapeutics for development and, hopefully, a new breakthrough drug that widens the circle of cancer immunotherapy responders.

Other new targets include other (non-CD19) antigens expressed by various leukemias and non-Hodgkin lymphoma, as well as solid tumor targets; promise has been shown in a number of cancers—metastaic melanoma, neuroblastoma and synovia cell sarcoma, recurrent glioblastoma, advanced ovarian cancer, colorectal cancer and mesothelioma.

And clinical trials are ongoing for cancers including lung, cervical, esophageal, liver, breast stomach, prostate pancreatic—with nearly 500 such studies presently running, any list is incomplete, and growing quickly, up 84 percent in the last two years.

We’re still a long way from what anyone might consider a “cure” for cancer, but the expert consensus is that hope is warranted, especially regarding cancers (such as pancreatic cancer and triple negative breast cancer) against which we’ve not seen progress in generations.

For 100 years most scientists were dead certain that the immune system couldn’t target cancer. And they were dead wrong. The immunotherapy breakthrough against cancer is bigger than just CAR-T or any single cancer therapy or drug; the real breakthrough is in our scientific understanding of the disease and ourselves and the validation of cancer immunotherapy as the most likely road to progress—and perhaps a cure.

The discovery that cancer uses tricks to shut down or hide from the immune system has made sense of generations of failed attempts to get immunotherapy to work. And now that we can block those tricks, some of those therapies are getting a second look. Including the approaches that fall under the general term of “adoptive T cell transfer.”

For example last August, Steve Rosenberg’s National Institutes of Health lab announced the results of their TIL therapy trial for a group of women with late stage metastatic breast cancer and no other options.

Most were not helped by the therapy, but one went into complete remission. Judy Perkins knows she was one of the lucky ones. Now the race is on to figure out how to reproduce what happened to Perkins in everyone else. These are early days, and CAR-T and other adoptive cell therapies are only one small arm of an immunotherapy breakthrough researchers refer to as our “penicillin moment” against cancer.

Whatever happens, there’s reason to hope that more patients like Emily Whitehead will be around to see it.

From the book THE BREAKTHROUGH: Immunotherapy and the Race to Cure Cancer. Copyright (c) 2018 by Charles Graeber. Reprinted by permission of Twelve/Hachette Book Group, New York, NY. All rights reserved. Buy on Amazon.

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