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Home https://server7.kproxy.com/servlet/redirect.srv/sruj/smyrwpoii/p2/ Health https://server7.kproxy.com/servlet/redirect.srv/sruj/smyrwpoii/p2/ How scientists built "live drugs" to defeat cancer

How scientists built "live drugs" to defeat cancer



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

This is the most common form of cancer in childhood, her parents said; and Emily had a good chance of defeating him with chemotherapy. The remission rate for the most common variety was around 85%.

It will take 20 months before they understand the shadow behind this solar statistics, as well as the chilling outlook for their volunteer daughter as a zero patient for the first living animal in the world.

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

8 by Charles Graeber. Buy on Amazon

Twelve Publishers

Emily began a 26-month hemological regime. She lost her hair and most of her child's energy, but the healing poison seemed to do her job, she was abusing her body while she was killing the disease. However, her cancer, like all types of cancer, was a living constellation of mutant cells that continued to mutate in new variations. Some of these new mutants are immunized against chemotherapy and continue to thrive.

By October 2011, Emily had a relapse; In the language of immunotherapists her cancer "escaped". Her doctors at the Hershey Medical Center in Pennsylvania could offer more chemotherapy, more aggressive. But in February 2012 she came back again.

Now it was painfully obvious that Emily is one of 15 percent of children with leukemia for whom chemotherapy is not mild. The cancer doubled daily in her blood, and it was too late for a bone marrow transplant – she was too sick. Now oncologists have indicated Emily's cancer as a "terminal." She was 6 years old.

Cancer is nasty and unfair, but this nasty injustice reaches another level when cancer happens to a child. Tom and Carrie Whitehead were told they had to think of a hospice for their daughter. Or, if they wanted to, he could have died at home. Traditional medicine had nothing else to offer. But a researcher at the Philadelphia Children's Hospital may be, if Emily's parents are willing to take the risk.

The White Head learned about this opportunity on Sunday. By Monday they were in Philadelphia. Emily Whitehead will be the first child in the world to experience experimental cancer therapy called CAR-T. Researchers propose to reprogram its immune cells in a cloning army of serial killers targeting cancer.

CAR-T cell is a re-engineered T cell that has been removed from the cancer patient altered in the laboratory to recognize. patient's cancer and then injected back into the patient. Because each of these re-engineered cells is a monstrous combination of parts of immune cells similar to robofop, the researchers have given their invention the monstrous name of the "T-cell of chimeric antigenic receptors" (in Greek mythology the chimera is a combination of monsters combining aspects of lion, goat and snake) But "CAR-T" sounds much better.

CAR-T is often called the "most sophisticated medicine ever created," but it is not actually a drug in the traditional sense of the word. Unlike an inertial molecule introduced into the body for some temporary effect, CAR-T is alive. If it works as planned, this "live drug" will continue to live in Emily's bloodstream as a superpower that kills cancer that gives her immunity against her illness. And in this process, it will give humanity a new revolutionary weapon in the war on cancer.

And if he did not act? If the released cell serial killers turned to the girl's healthy cells and not to cancer? Well, the Whiteheads decided, best not to think about it. At this point their only daughter had nothing to lose The hundreds million T-cells that patrol our bloodstream and lymph nodes are experts in detecting sick cells and killing them. And while the idea has been rejected by most scientists over the past 100 years, they have recently assumed that a handful of these T-cells are prone to cancer recognition and killing.

So why do you always know when you have a cold or flu, but the cancer arrives, but not as much as snorting? Why do we need a test to find out if we have this lethal disease?

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The answer to this question came in a series of breakthroughs about how cancer uses tricks to exclude, hide and defeat our immune response. Cancer closes the T cells before they get the opportunity to call for reinforcements, replicate in a huge clone army and do their job. But what if, instead, there was a way to overcome cancer, block it with a huge number of immune cells capable of recognizing and killing it?

The group of researchers exploring this opportunity were called cancer immunotherapists and
at the time of Emily. Whitehead appeared in the hospital, they had spent the decades in the problem. But before they could make a cloned army of the perfect T cell, they had to find the perfect T cell somewhere in the patient's blood. flow, one or two of the hundreds of millions that happened to be tuned to recognize the exact cancer of this patient.

Not surprisingly, Mr Perfect was hard to find. In fact, until the 1980s, even immunotherapists of cancer were not entirely sure that Mr. Perfect was there. Identifying, harvesting, fertilizing, growing, cloning, and then activating the perfect T cell against cancer – this was largely a trial and error done with little funding and little understanding of the enormous biological complexity of cancer or the immune system. Science was impossible new; T cells were only discovered in the late 1960s.

There was no road map. Immune therapists for cancer have been struggling for decades, laughing at the research community who have failed to prove their theory that the immune system can be assisted in recognizing and killing cancer cells. Meanwhile, another group of cancer immunotherapists began to consider a different approach: Instead of hoping to somehow find the perfect cancer that kills the T cells in the patient's body, they would make their own. The Weird Science T will be specifically designed to look for and destroy the specific cancer of the patient.

Engineering is complicated, but the concept is simple. An individual T-cell recognizes only the individual diseased cellular protein (called antigen) that they were born to "see" as determined by a random identification process. The business of this "vision" is called the T-cell receptor, or the TCR

TCR change, and you may be able to change what the T cell targets. Change it to the right one and you may even be able to target it to a particular illness. And that's what happened to a charismatic Israeli researcher named Zeljg Eshhar.

In the early 1980s, this beekeeping doctor began to think about the TCR's business end – the portion that extends across the surface of the T cell as a protector antenna and "sees" specific antigenic targets.

For Eshhar, it looks very similar to the protein-binding fingernail of an antibody. It seemed to work the same way. These Y-shaped immune structures come in many flavors (hundreds of millions), each of which is sticky to a different disease-specific protein. Each of them was a key in the search for her lock. Eshhar could have imagined he was breaking away from the edge of the TCR and spraying a new antibody as a vacuum attachment; the change of the antibody and can change what the T-cell aims. In theory, you could have an infinite number of new attachments, each recognizing and linking to a different antigen, and thus targeting a different disease. Such technology would create a whole new class of drugs.

The conversion of Eshhar's theory into reality required a fantasy of bioengineering, but somehow, in 1985, he was able to produce a simple proof of the concept. T-body. Transforming T cells to recognize a relatively obvious antigenic target that he has chosen, a publishing protein carried by the fungi Trichophyton mentagrophytes better known as the athlete's foot. This humble experiment concealed unbelievable possibilities. And this has attracted the attention of those who have spent their lives working in the bundles of cancer immunotherapy.

In 1989, Eshar was convinced to spend a Saturday in the laboratory of pioneering immunotherapist Steve Rosenberg. Initially, Rosenberg has convinced the immune system's potential to kill cancer in the 1960s after exploring a former stage IV cancer whose immune system spontaneously cured its own illness. Rosenberg wondered if the man's loaded immune cells could help other cancer patients

In experiments that they do not think about today, Rosenberg tried just that, overflowing the blood of the cured person into the veins of a terminal cancer patient in the next bed. It did not work, but the promise of cellular transfer therapy remained with it

In the next five decades the laboratory of the Rosenbergs National Health Laboratories (and that of Phillip Greenberg at Fred Hutchinson's Cancer Research Center in Seattle) will serve. like some kind of hive and a refuge for talent for immunotherapy.

There Eshhar will join another brilliant young NIH researcher named Patrick Hvu to create up-to-date information on what ultimately will be known as "host cell therapy"

tumors under the microscope showed that even when the bigger immune attack has failed, several T-cells still manage to successfully recognize the tumor antigens and penetrate them. That would be their Mr. Perfect T cells and, hopefully, seeds for their cloned army of target cancer killers.

Hwu's focus was to try to arm this subgroup of successful "tumor-infiltrating lymphocytes" or TILs by packing small hand-held missiles with an extra load of powerful hormones that kill the tumor.

They needed a guidance system that researchers could choose and change to target different types of cancer. "Zelig had shown that an antibody and a T cell could be combined to focus on something," says Hvu, who serves as Head of the Cancer Medicine Unit at the Anderson Cancer Center in Houston, Texas. "The question now is whether we can direct it to cancer cells?"

Starting with a group of T cells, they found that they are Mr Perfect TILs active against melanoma, Hwu and Eshhar Franken, who wear them with new TCR instead of ovarian, colon and breast cancer. "Zelig made the receptor, I put it in the T cells," Hugh recalls. "It was really hard to do that in the 1990s."

Without the benefit of retroviral vectors or CRISPR, the task required sticking a small needle into a T cell and microinjecting new TCR genes one cell at a time. "We spent a lot of time together," says Hve with a laugh. "There were many nightdresses in the lab.

None of the results were perfect, but the backs that were redirected to recognize ovarian cancer were the best of the three, and the team managed to publish the result. the new name of CAR-T and the seductive effects of technology.

They did not cure cancer, but they did improve science. They successfully replaced the T-cell's steering wheel by targeting it to specific cancer. "The first time I started working, I was so excited," recalls Haw. But he knew the redirection was only part of the engineered machine for killing cancer.

To be effective, these new cells also have to develop and reproduce as normal T-cells. It seemed as though during the modernization something essential, missing essence had been lost, as a result of which lemon CARs did not escape long enough to repeat or complete the work of killing cancer. Their Frankenstein would rise from the table just to overturn.

Researcher Michelle Sadein had to provide a clever solution to this and a number of other engineering problems, creating a real "living drug", as he called it Sadeinel, the second generation of CAR that can recognize the goal of expanding the branch and preserving the other T cell function, with a life span as long as the patient.

Working in his laboratory, Sadelain (the laconic intellectual intellectual who is the founding director of the Memorial Sloan Kettering Center for Cell Engineering, among other things, has also given his new CAR an important new goal – a protein called CD19, uniquely the surface of some blood cancer cells

The CD-19 seemed to be a good target for KAR, found in the abundance of the surface of some types of cancer, also expressed by some normal B-cells, but this is acceptable. If CARD attacks healthy cells as well as cancer, side damage is estimated In a healthy person, cells are essential aspects of the normal immune system, but in patients like Emily these B-cells are mutated and become cancerous, and in order to survive, they will have to lose them

Fortunately, doctors have long have learned to keep patients alive without B-cells. "If you encounter terminal cancer," says Sadelain, "the loss of B cells is not that bad."

Sadelain now had a sleek, stylish and self-replicating second-generation car with a lot of fuel and a realistic cancer target. His group shared the sequence of their new CAR with the Rosenberg group at the National Cancer Institute, as well as in the laboratory of the University of Pennsylvania researcher and physician Carl Junny. (June in turn also based aspects of his CAR design on a sample borrowed from Dario Campagna at St. Jude Children's Research Hospital.)

These three groups – all insisting on the human trials of this complex and powerful new cancer therapy – now competitors. At the same time, they work together, borrow and improve the ideas of others.

The Sadelain Group is the first to initiate clinical trials of CAR-19 T cells, the first published Rosenberg; their successful CAR-T trial shortened the tumors in a patient with lymphoma. But it will be Carl Jun's process with Emily Whitehead, who will take the spotlight and determine if there is a future for CAR-T.

June did not think so in such a heroic way, but deep inside she believed she could save Emily. That was his job.

But if the little girl died from the experiment, if her strong Frankenson drug attacks her body, not cancer, he is equally sure the result will be terrifying and tragic. And any chance that CART will ever cure cancer in hundreds of other children dying from the VCI will probably die with her.

In the 90s June was a certified leukemia specialist but appointed by the National Institute of Health to work out new approaches to HIV treatment. This difficulty has led to collaborative experimental treatment, similar to CAR, which has redirected killer T cells to target infected T-cells in AIDS patients and the first clinical trial of KAR in HIV-infected people. But before the work was completed, it became unnecessary, due to the development of the first protease inhibitors, drugs that blocked the replication virus HIV in 1997.

At night, these drugs changed the forecast for millions of people and the direction of the Career in June. Now he moves his work and practice to a lab at UPenn and the Children's Hospital in Philadelphia, and he finally strengthens his focus on a disease that has recently become extremely personal.

In 1996, Cynthia's wife, in June, was diagnosed with ovarian cancer. When Cindy Junney did not respond to traditional therapies, June's lab turned to immunotherapeutic approaches early in the day, adapting a version of a promising immunotherapeutic vaccine to another laboratory.

It is called GVAX, an individual approach that took part of the patient's tumor, supplemented with additional genes encoding cytokines that would alert the immune system and reinject the patient's result. June considered that GVAX had a tremendous potential but, he says, "I had no idea how difficult it was to turn a laboratory experiment into a clinical trial."

When he started treating his wife, he thought he had a good answer to her personalized vaccine. But, as with all cancer vaccines in the age, the answer did not go on. June suspected that tumors had somehow turned this immune response

This suspicion is partly due to the pioneering work of Jim Alison, playing harmonica in the Islamic immunological researcher. През 1987 г. Алисън е открила един от раковите пътища, използван за затваряне на имунния отговор, и е разработил антитяло, което да блокира този трик при мишките, като импулсира имунната им система, за да убие рака. пробив в нашата война с рак и спечели Алисън Нобелова награда. Но през 1999 г. работата на Алисън все още не е била превърната в лекарство. Дори не беше тестван при хората.

За да спаси жена си, юни нямаше друг избор, освен да продължи напред сляпо. „Знаех, че в мишки неговото антитяло прави имунотерапиите да работят по-добре“, каза ми юни. Комбинирането на откритието на Алисън с антитялото GVAX „не е никак трудно“, казва Юн. Той многократно се е опитвал да вземе проба от скъпоценното анти-CTLA-4 антитяло – откритието на Алисън – от фармацевтичния производител и многократно му е отказано. Отпускането на нерегламентирания им наркотик беше твърде опасно.

„Беше много разочароващо“, казва Юн. Той не можеше да си представи как резултатът от опита на Мария с експериментален наркотик би могъл да бъде по-опасен от някои резултати от нелечимия рак.

Когато Синди Юни умира през 2001 г. на 46-годишна възраст, Юни запълниха скръбта му за майка на трите им деца в работата си и премести пълния си фокус върху CAR за рака “пред предната горелка”.

Отне девет години, но технологията на поставяне на гени в клетките е изминала дълъг път, тъй като Hwu започна да ги инжектира на ръка. През юни UPenn лабораторията, бригадирът в тази модернизирана поточна линия на CAR беше преправената обвивка на вируса, причиняваща СПИН.

Вирусите са по същество само гени с крака в протеинова обвивка и съществуват на ръба на нашата дефиниция за живот , Тези съкратени ДНК носители също нямат инструменти за самостоятелно размножаване.

За да направят повече копия от себе си, вирусите възлагат работата на клетъчната машина на по-големите, по-сложни клетки, които заразяват, като инжектират свои собствени вирусни генетични планове. в клетъчните производствени предприятия на техния домакин. В случая на вируса на човешка имунна недостатъчност, тази гостоприемна клетка е Т клетка.

ХИВ е опустошително ефективен при насочване на Т клетки. Обикновено това води до инфектиране на вируса на Т-клетката с инструкции да направи повече ХИВ, което го прави безполезен в защита срещу болести и води до изключване на адаптивния имунитет в организма, болестта, която познаваме като синдром на придобитата имунна недостатъчност или СПИН. Но тази способност за промяна на ДНК на Т-клетките също е точно това, което прави ХИВ идеална система за доставка на генетичните чертежи на CAR-T. На теория този убиец може да се превърне в спасителна технология.

В лабораторията на юни в UPenn, вирусът на ХИВ беше изпразнен и снабден с нови генетични инструкции. След това беше въведена в Т-клетките на Емили, които бяха внимателно центрофугирани от изтеглената й кръв. Вместо да доставят болест, вирусът, пренасочен от юни, „зарази” Т-клетките на Емили с нови генетични инструкции, като го препрограмира, за да насочи само протеина CD19 на повърхността на нейните ракови В-клетки. 19 Т-клетки бяха отведени в Детската болница. Лекарите го отнесли в стаята, където седеше Емили Уайтхед, подпряна на болнично легло, малко момиченце, плешиво и безцветно в блестяща пурпурна рокля. Нейните препрограмирани Т клетки бяха бавно повторно въведени в техните естествени вени. Докато третата чанта не е започнала страничните ефекти

По онова време лекарите не са били запознати със силата и токсичността на новата Т-клетъчна терапия. Сега те го познават с няколко имена; най-научно „синдромът на освобождаване на цитокини” (или CRS), най-вече „цитокиновата буря”, най-небрежно „разклаща и пече”.

Както подсказват имената, това е вихрушка от изтощителни и опасни симптоми, причинени от потока на имунната система. сигнализиращи хормони, освободени по време на лудост на хранене на Т-клетки, чудовищно засилена версия на инвалидизиращите странични ефекти от имунната борба с грипа

На езика на нейните медицински доклади Емили беше "тежка". е нормално. Децата имат по-силна имунна система от възрастните; като първият педиатричен пациент CAR-T, CRS на Емили беше просто по-екстремна, отколкото всеки можеше да очаква.

Мощни цитокини, предизвикани от имунната атака с турбокомпресор, пропускаха системата на Емили. Скоро тя се потеше и трепереше и имаше проблеми с дишането. Кръвното й налягане падна опасно и температурата й се повиши до 105 градуса. На 106 г. Емили беше притисната към интензивното отделение. Тя остана там, тръбичка по гърлото й, друга в носа, кома и дишаща с машина. Минали дни. На петия ден й бяха давали стероиди. Симптомите на Емили се успокоиха за миг, само за да придобият сила като офшорни циклони и да дойдат назад. На седмия ден малкото момиченце, издигнало се до помпата на вентилаторния двигател, беше подуто като бутилка с гореща вода. Тя имаше няколко органна недостатъчност. Изглеждаше, че лекът, а не болестта, щеше да я убие.

Отчаяни, нейният онколог и водещият изследовател на клиничното изпитване, Стефан Груп, наредиха батерия от кръвни тестове, обхващащи всяка имуно-свързана молекула, за която можеше да се сети. Кръв се върна два часа по-късно. Два номера се откроиха. Нивата на интерферон гама (INFy) и интерлевкин-6 са забележително високи. Групата пренесе показанието в лабораторната си среща от 15:00 часа, група, събрана, за да работи по проблема и да направи възможни опции. Никой не видя нищо.

Това, което беше ясно, че нейното ниво на интерлевкин-6 се е увеличило хиляда пъти над нормалното. Дали това е болест или симптом, източник на проблема или аспект от опита на тялото да го подобри, те не бяха сигурни. Интерпретирането на бележките и мелодиите в рамките на химическата симфония на имунния отговор е все още изкуство в детството му и интерлевкин-6 е бил известен като цитокин с множество роли в нормалната имунна функция, както възпалителна, така и противовъзпалителна, тласкане и издърпване. , Известно е също, че частично е отговорен за възпалението на ревматоидния артрит.

И това е мястото, където Емили Уайтхед е имала много късмет. деца. Неговата собствена дъщеря страдаше от това и той бе следвал литературата от години. Юни наблюдаваха обещаващо ново антитяло, което сякаш блокира рецепторите на интерлевкин-6 и намаляваше обема на цитокиновия призив за възпаление и подуване. „Никой, който работи с рак, нямаше причина да знае за това“, каза Джун. – Това беше просто чист късмет, който направих. – Той дори бе връчил награда на японския професор, който беше открил това антитяло.

Само няколко месеца по-рано той най-накрая изчисти клиничните проучвания и сега беше одобрен от FDA като лекарство тоцилизумаб. Джун веднага бе натрупал нещата, в случай, че дъщеря му избухне от болестта си.

Сега, Джон се чудеше, този нов артрит ще помогне ли на дете с рак?

Нямаше експерти, които да се консултират. – те бяха експерти, които спешно си проправяха път през непозната територия. Решението трябваше да бъде незабавно. Треската на Емили е ударила 107. Том и Кари Уайтхед е било казано да обмислят заповед за невъзстановяване на своята несъзнателна дъщеря.

Grupp написа рецепта за тоцилизумаб. Прокара го до мястото, където Емили потъваше в интензивното отделение, и каза на лекарите какво планира да направи. Наркотикът е нов, никога не е бил съден срещу пациенти с CRS; никой досега не е лекувал страничните ефекти от терапията с CAR-T. Групата вярваше, че лекарството ще помогне на Емили. Той също така знаеше, че това не може да направи нищо, или още по-лошо.

„(Лекарите от интензивното отделение) го нарекоха каубой“, спомня си юни. Това беше неща от Дивия Запад, неизследвана територия. Но без карта, без прецедент, един непроверен, недоказан отговор беше единственият възможен отговор.

Grupp приготви спринцовка и инжектира тоцилизумаб директно в IV порта на Емили. Постепенно, анти-интерлевкин-6 антителата блокират рецепторите си и успокояват цитокиновата буря на Емили. През следващите дни Емили бе отбита от дихателния апарат и медикаментите за кръвно налягане, но остана в кома.

Чакането беше трудно за всички, особено за родителите. Най-накрая, седмица по-късно, Емили отвори очи към мелодията на „Честит рожден ден“, изпълняван от болничния персонал. Тя беше точно на 7 години. И тя беше жива.

Една клетка CAR-T може да извади до сто хиляди ракови клетки и да произведе необичайно бърза ремисия, която изненада дори най-пламенния имунотерапевт. Саделайн ги нарича "живо наркотик". Юни понякога ги наричат ​​"серийни убийци" на рак.

Само четири седмици след първата си инфузия в CAR, лабораторните резултати на Емили не показват честота на рак – лабораторна грешка, очевидно, поръча втора биопсия. Но нямаше грешка. Процедурата беше успешна – като лекарство за Емили и като доказателство за концепцията. Това беше добро, но не и краят. Емили не беше единственият пациент в детска левкемия, който е получил експериментално лечение.

Юни също е лекувал друг непълнолетен ВСИЧКИ пациент в Детската болница, 10-годишно момиче. Левкемията й се повлиява от терапията с CAR-T и тя е влязла в ремисия само два месеца по-късно.

Биопсиите показват, че левкемията на това момиче е мутирала и е избягала от В-клетките, които не са носители на протеина CD19. Ракът беше променил униформите, но нямаше друг КАР, който да й даде.

И така през септември 2012 г. Емили Уайтхед се върна в училище с болна бележка, подписана от президента Обама. Тя беше сладка национална история на успеха, отбелязана в Добро утро Америка, символ на надежда и напредък във войната срещу рака. Другото момиче умряло от рака си, тъжно и смирено напомняне за работата, която предстои да бъде свършена

Цялостното опрощаване на Емили Уайтхед направи заглавията и зареждаше цялата област, задвижвайки финансирането и развитието на CAR-T в овърдрайв.

Всеки изследователски екип – след като сътрудници, сега конкуренти – бързо се свързва с фармацевтичен партньор, за да превърне технологията в медицина. Националният раков институт отиде с Kite Pharma (който получи одобрение за CAR-T, наречен Yescarta за голям B-клетъчен лимфом); Центърът за рак на Memorial Sloan Kettering, заедно с Центъра за изследване на рака на Фред Хътчинсън и Детската изследователска група в Сиатъл, си партнираха с Juno Therapeutics.

Лекарският гигант Novartis лицензира технологията CAR-T от Университета на Пенсилвания. Тя получи одобрение от FDA за терапията, използвана при Емили Уайтхед, която сега се продава под търговската марка Kymriah. Това одобрение е направено през 2017 г., но CD-19 CAR-T терапията вече е помогнала на хиляди хора, включително стотици деца с рак.

Дори 85% от децата, за които ALL се лекува с химиотерапия, са кандидати за новата терапия. , За децата такова лечение идва със скрита цена; две години химиотерапия оказва влияние върху развиващите се органи и умове.

Експерименталното лечение, сега известно като Кимрия, е едновременно лекарство и продукт. Изхвърля се от красив полупрозрачен пакет с кръвно-оранжева светлина. Всяка от тях е персонализирана за пациента, проектирана от собствените Т-клетки на пациента.

В момента всеки един от тези еднократни инфузии струва $ 475,000. Когато се добавят болнични такси, общите разходи достигат 1 милион долара на пациент. Следващото най-добро лечение за остра B-лимфома е трансплантация на костен мозък, която струва повече от $ 100,000. Тази "икономическа токсичност" понастоящем е друг сериозен страничен ефект от най-съвременните лекарства за лечение на рак като имунотерапията на рака, която все още не е лекувана. пътува до свързан медицински център. Там се изтегля кръв и се центрофугира в продължение на най-малко 15 минути при 2200 до 2500 об / мин, за да се разделят Т клетките от плазмата, тромбоцитите и останалите.

Т клетките след това се замразяват криогенно, опаковани в специален cryovac контейнер, и изпратени до съоръжението за майчинство Novartis на 180 000 квадратни метра в Морис Плейнс, Ню Джърси, където те се размразяват и реинженерират, за да разпознаят протеин, специфичен за рака на пациента. Първо се активират Т клетките. След това се трансдуцират с вирус, съдържащ нови генетични инструкции. Тогава те се отглеждат и умножават, докато наброяват стотици милиони. Клонираната армия от свръхзвездни Т-клетки след това се ре-криоконсервира, изпраща обратно в сертифицирания медицински център и се преосмисва, за да се капе обратно в пациента

Криоконсервация позволява на пациентите от цял ​​свят да използват лечението. Времето за изпълнение, от центъра за разходка до завършеното третиране с Т клетки, е 22 дни. Предварителните данни показват, че терапиите, използващи тези Т-клетки, дават трайни отговори за предишни безнадеждни случаи.

Емили и майка й, Кари Уайтхед

Джеф Свенсен / Ню Йорк Таймс / Getty Images

Емили е част от тази щастлива статистика. От юли 2019 г. тя остава в ремисия. Яркоокото малко болно момиче сега е вълнуващо. Тя играе на укулеле и управлява пътни състезания. Но най-вече, тя отново е дете.

Разбира се, има голяма опасност, разбира се, при всякакви манипулации с пулсации за коса, обратни връзки и проверки и баланси на имунната система, които се развиват в продължение на хилядолетия, и голям трепет в 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 has only been two years since CARs were FDA approved as a medicine, but already the technology is blossoming with new permutations on the original design. Some base their new CARS on donated T cells (rather than a patient’s own), in hopes of creating off-the-shelf solutions that are cheaper and more readily available than the current bespoke CAR models. Other labs are tricking out their CARs with add-on customizations and combining them with other forms of cancer immunotherapy, multiplying their effectiveness.

Researchers at Massachusetts General Hospital, publishing in Nature Biotechnology,
recently announced the results of just such a creative combo approach to getting CAR to target glioblastoma, the most common and deadly form of brain cancer. Tumors like those of gliobastoma are extra tricky, both because they live on the other side of the blood/brain barrier and because not all of the cancer cells express the same antigen.

In the new approach, their compact CAR is ferried across the blood brain barrier, then deploys a tethered secondary antibody guidance system, like a dragster popping a parachute. The CAR now has two separate guidance systems and two different means to “see” the cancer target. In preclinical models of human glioblastoma, this additional "bi-specific T-cell engager" (or BiTE) helped the CAR clear 80 percent of the tumors.

In theory, you could attach other guidance systems as well or other cancer-killing payloads or continue to refine and customize and soup up ad infinatum, an evolving design guided by both imagination and biology. CAR-T is really a gateway technology, and there’s no reason to imagine that those of the near future will bear any more resemblance to these first designs than a Tesla Model X does to a Ford Model T.

Customizable variations, collaboration, and creative combinations are a logical response to a this confounding disease; a mutating answer to a mutating problem. What’s clear is that as we increasingly come to understand how complex and personal both our cancers and our immune systems truly are, what we now think of 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. Всички права запазени. Buy on Amazon.


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