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

譯者: Harper Chang 審譯者: 易帆 余

So this is the first time I've told this story in public,

這是我第一次在公衆面前

the personal aspects of it.

以個人角度說這件事。

Yogi Berra was a world-famous baseball player who said,

世界著名的棒球運動員 尤奇貝拉曾說，

"If you come to a fork in the road, take it."

「當你遇到人生的岔道，承擔起來吧。」

Researchers had been, for more than a century,

一個世紀以來，

科學家們都在研究 用免疫系統對抗腫瘤的方法，

studying the immune system as a way to fight cancer,

and cancer vaccines have, unfortunately, been disappointing.

但腫瘤疫苗的效果卻不如人意，

They've only worked in cancers caused by viruses,

它們只對病毒引起的腫瘤起作用，

like cervical cancer or liver cancer.

比如子宮癌和肝癌。

So cancer researchers basically gave up on the idea

所以腫瘤科學家基本上放棄了

of using the immune system to fight cancer.

利用免疫系統對抗腫瘤的方法。

And the immune system, in any case, did not evolve to fight cancer;

而且免疫系統的職責 從來不是對付腫瘤，

it evolved to fight pathogens invading from the outside.

而是對抗外來的病原體。

So its job is to kill bacteria and viruses.

所以它的工作是殺死細菌和病毒。

And the reason the immune system has trouble with most cancers

之所以免疫系統無法對付大多數腫瘤，

is that it doesn't invade from the outside;

是因為腫瘤並不源於外界，

it evolves from its own cells.

而是從體內細胞產生的。

And so either the immune system does not recognize the cancer as a problem,

所以免疫系統要不就是 識別不出腫瘤細胞，

or it attacks a cancer and also our normal cells,

要不就是同時攻擊其它正常細胞，

leading to autoimmune diseases like colitis or multiple sclerosis.

引發自體免疫疾病， 例如結腸炎或多發性硬化症。

So how do you get around that?

所以有什麼解決方法呢？

Our answer turned out to be synthetic immune systems

我們的回答是「人造免疫系統」，

設計出識別能力，用來殺死癌細胞。

that are designed to recognize and kill cancer cells.

That's right -- I said a synthetic immune system.

沒錯——我說人造免疫系統。

You do that with genetic engineering and synthetic biology.

它透過基因工程 與合成生物學來實現。

We did it with the naturally occurring parts of the immune system,

我們使用免疫系統的自體成分，

called B cells and T cells.

也就是 B 細胞和 T 細胞。

These were our building blocks.

這些是基本組件。

T cells have evolved to kill cells infected with viruses,

T 細胞用於殺死 被病毒侵染的細胞，

and B cells are the cells that make antibodies that are secreted

B 細胞用於合成並釋放 殺死細菌的抗體。

and then bind to kill bacteria.

Well, what if you combined these two functions

現在，如果要整合兩者的功能

in a way that was designed to repurpose them to fight cancer?

並設計出專門對付 腫瘤的人工細胞，要怎麼做呢？

We realized it would be possible to insert the genes for antibodies

我們意識到，我們有可能 可以把 B 細胞中的抗體基因

from B cells into T cells.

插入到 T 細胞中。

So how do you do that?

但怎麼實現呢？

Well, we used an HIV virus as a Trojan horse

我們將 HIV 病毒包裝成特洛伊木馬，

to get past the T cells' immune system.

來騙過 T 細胞的免疫系統。

The result is a chimera,

結果創造出了一個喀邁拉，

a fantastic fire-breathing creature from Greek mythology,

這種希臘神話中的噴火獸 融合了獅頭、羊身、蛇尾，

with a lion's head, a goat's body and a serpent's tail.

由此引申出「嵌合」之義。

So we decided that the paradoxical thing that we had created

於是我們決定把創造出的這個

with our B-cell antibodies, our T cells carrier

結合了 B 細胞抗體、T 細胞載體

and the HIV Trojan horse

與特定的 HIV 特洛伊木馬病毒，

should be called "Chimeric Antigen Receptor T cells," or CAR T cells.

稱為「嵌合抗原受體 T 細胞」， 也叫 CAR T細胞。

The virus also inserts genetic information

這種細胞還插入了 激活 T 細胞消滅功能的基因。

to activate the T cells and program them into their killing mode.

So when CAR T cells are injected into somebody with cancer,

CAR T細胞進入癌症患者體內後，

what happens when those CAR T cells see and bind to their tumor target?

它們會如何搜尋和附着腫瘤呢？

They act like supercharged killer T cells on steroids.

它們會像火力全開的殺手

They start this crash-defense buildup system in the body

在身體中建起防禦系統，

and literally divide and multiply by the millions,

並分裂增殖至上百萬，

where they then attack and kill the tumor.

然後攻擊並殺死腫瘤細胞。

All of this means that CAR T cells are the first living drug in medicine.

這些都說明 CAR T細胞 是首種「活體藥」。

CAR T cells break the mold.

CAR T細胞殺死黴菌。

Unlike normal drugs that you take --

它不像平時服用的普通藥，

they do their job and get metabolized, and then you have to take them again --

不會發揮作用後隨代謝失效， 然後必須再次攝取。

CAR T cells stay alive and on the job for years.

CAR T細胞會在人體中 保持活性的時間長達數年，

We have had CAR T cells stay in the bodies of our cancer patients

我們有參與實驗的癌症患者 體內的 CAR T 細胞

now for more than eight years.

至今已存活超過八年。

And these designer cancer T cells, CAR T cells,

針對癌症而設計的 CAR T細胞

have a calculated half-life of more than 17 years.

生物半衰期預計超過 17 年。

So one infusion can do the job;

只需要一次輸注，

they stay on patrol for the rest of your life.

它們就能守護你的餘生。

This is the beginning of a new paradigm in medicine.

這是醫藥新典範的開端。

Now, there was one major challenge to these T-cell infusions.

但是，這些 T 細胞的 其中一個重大挑戰是：

The only source of T cells that will work in a patient

能在體內發揮作用的 T 細胞

are your own T cells,

只能是自體的 T 細胞，

unless you happen to have an identical twin.

除非你剛好是同卵雙胞胎。

So for most of us, we're out of luck.

因此，我們大多數人的運氣背極了。

So what we did was to make CAR T cells.

我們改造了 CAR T 細胞。

We had to learn to grow the patient's own T cells.

我們必須學會如何培養 患者的自體 T 細胞。

And we developed a robust platform for this in the 1990s.

我們在 90 年代 搭建了一個很厲害的平臺。

Then in 1997, we first tested CAR T cells in patients

1997 年，我們首次 對晚期愛滋病患者

with advanced HIV-AIDS.

測試 CAR T 細胞。

And we found that those CAR T cells survived in the patients

我們發現這些 CAR T 細胞

在患者體內存活超過十年。

for more than a decade.

And it improved their immune system and decreased their viruses,

它們增強了免疫系統， 減少了體內病毒，

but it didn't cure them.

但並沒有治癒愛滋病。

So we went back to the laboratory, and over the next decade

於是我們重新進行實驗室實驗，

用十年的時間改進了 CAR T 細胞的設計。

made improvements to the CAR T cell design.

And by 2010, we began treating leukemia patients.

2012 年，我們開始治療白血病患者。

And our team treated three patients

我們團隊負責治療三位

with advanced chronic lymphocytic leukemia in 2012.

晚期 B 細胞慢性淋巴性白血病患者。

It's a form of incurable leukemia

這是一種無法治癒的白血病，

that afflicts approximately 20,000 adults every year in the United States.

每年折磨著大約兩萬名美國成人。

The first patient that we treated was a retired Marine sergeant

我們治療的第一位患者

是一位退休的海軍陸戰隊中士獄警，

and a prison corrections officer.

He had only weeks to live

他的生命只剩下幾週，

and had, in fact, already paid for his funeral.

事實上，他已經準備好了葬禮。

The cells were infused, and within days, he had high fevers.

CAR T 細胞輸注後的幾天內， 他出現了高燒，

He developed multiple organ failures,

並發展出多個器官衰竭，

was transferred to the ICU and was comatose.

他被轉移到加護病房，重度昏迷。

We thought he would die,

我們以為他會死，

and, in fact, he was given last rites.

甚至給他做了臨終聖事。

But then, another fork in the road happened.

就在此時，岔道出現，要他做決定了。

So, around 28 days after the CAR T cell infusion,

在輸注 CAR T 細胞的 28 天後，

he woke up,

他甦醒過來。

and the physicians finally examined him,

醫生對他做了檢查，

他的腫瘤消失了。

and the cancer was gone.

The big masses that had been there had melted.

原來的腫瘤塊溶解了。

Bone marrow biopsies found no evidence of leukemia,

骨髓檢查沒有白血病的跡象，

and that year, in our first three patients we treated,

那一年，在首批治療的三位患者中，

two of three have had durable remissions now for eight years,

其中兩位癌症完全緩解， 至今已達八年，

and one had a partial remission.

一位癌症部分緩解。

The CAR T cells had attacked the leukemia in these patients

CAR T 細胞攻擊白血病細胞，

and had dissolved between 2.9 and 7.7 pounds of tumor in each patient.

消滅了每位患者 2.9 到 7.7 磅的腫瘤。

Their bodies had become veritable bioreactors for these CAR T cells,

身體為這些 CAR T 細胞 提供了絕佳的環境，

producing millions and millions of CAR T cells

CAR T 細胞得以繁殖至百萬，

in the bone marrow, blood and tumor masses.

遍佈骨髓、血液和腫瘤塊。

And we discovered that these CAR T cells can punch far above their weight class,

我們發現 CAR T 細胞 會使用「拳擊技巧」

來擊倒重量級的對手。

to use a boxing analogy.

Just one CAR T cell can kill 1,000 tumor cells.

一個 CAR T 細胞 能殺死一千個腫瘤細胞，

That's right -- it's a ratio of one to a thousand.

沒錯，這是一比一千的比率。

The CAR T cell and its daughter progeny cells

CAR T 細胞和子代細胞

can divide and divide and divide in the body

在體內會不斷分裂分化，

until the last tumor cell is gone.

直到最後一個腫瘤細胞被消滅。

There's no precedent for this in cancer medicine.

這在癌症治療上是史無前例的。

The first two patients who had full remission

首批中兩位癌症完全緩解的患者

remain today leukemia-free,

到今天仍然沒有白血病復發的跡象，

and we think they are cured.

我們判斷他們已然痊癒。

These are people who had run out of options,

這是一些走投無路的人，

and by all traditional methods they had,

在所有傳統療法以失敗告終後，

they were like modern-day Lazarus cases.

他們淪落為現代的拉撒路案例。 （一部反應醫療困境的文學作品）

All I can say is: thank goodness for those forks in the road.

我只能說：感謝那些岔道。

Our next step was to get permission to treat children with acute leukemia,

我們的第二步是治療晚期白血病患兒，

the most common form of cancer in kids.

這是幼兒中最常見的癌症。

The first patient we enrolled on the trial was Emily Whitehead,

首位試驗患者是艾美莉·懷特海，

and at that time, she was six years old.

當時她六歲。

She had gone through a series of chemotherapy

她在過去幾年裡

and radiation treatments over several years,

接受了一系列化療和輻射治療，

and her leukemia had always come back.

但白血病每次都會復發，

In fact, it had come back three times.

事實上，她已復發了三次。

When we first saw her, Emily was very ill.

第一次看到她時，她病得很重。

Her official diagnosis was advanced, incurable leukemia.

她的診療結果是晚期、 不可治癒的白血病。

Cancer had invaded her bone marrow, her liver, her spleen.

腫瘤擴散到她的骨髓、肝和脾臟。

And when we infused her with the CAR T cells

我們在 2012 年 4 月

in the spring of April 2012,

給她輸注了 CAR T 細胞，

over the next few days, she did not get better.

接下來的幾天，她的病情沒有好轉，

She got worse, and in fact, much worse.

反而惡化，變得更嚴重。

As our prison corrections officer had in 2010,

像 2010 年那位獄警一樣，

she, in 2012, was admitted to the ICU,

她被轉移到加護病房。

and this was the scariest fork in the whole road of this story.

這是整個故事最驚險的岔道。

By day three, she was comatose and on life support

第三天時，她陷入昏迷， 依靠呼吸機維持生命，

for kidney failure, lung failure and coma.

出現腎衰竭、肺衰竭並陷入昏迷，

Her fever was as high as 106 degrees Fahrenheit for three days.

連續三天高燒至 41 攝氏度。

And we didn't know what was causing those fevers.

但我們不知道發熱原因。

We did all the standard blood tests for infections,

我們做了所有標準的 血液感染物檢查，

and we could not find an infectious cause for her fever.

但找不到高燒感染的原因。

But we did find something very unusual in her blood

不過我們發現她血液中的不尋常之處，

that had never been seen before in medicine.

這種症狀在醫學上從未見過。

She had elevated levels of a protein called interleukin-6, or IL-6,

她血液中的間白素-6（IL-6）含量過高，

in her blood.

It was, in fact, more than a thousandfold above the normal levels.

事實上已超過正常含量的一千倍。

And here's where yet another fork in the road came in.

這時，另一個岔道出現了。

By sheer coincidence,

機緣巧合，

one of my daughters has a form of pediatric arthritis.

我的一個女兒患上了 兒童特發性關節炎。

And as a result, I had been following as a cancer doc,

於是作為腫瘤醫生，

experimental therapies for arthritis for my daughter,

我跟進關節炎實現性療法的研究發展，

in case she would need them.

以便她要用到。

And it so happened that just months before Emily was admitted to the hospital,

正巧艾美莉接受治療的幾個月前，

a new therapy had been approved by the FDA

一種新的療法獲美國藥物管理局通過，

to treat elevated levels of interleukin-6.

它有治療間白素-6 含量升高的功效，

And it was approved for the arthritis that my daughter had.

可以用來治療我女兒的關節炎。

It's called tocilizumab.

一種叫托珠單抗（Tocilizumab）的藥。

And, in fact, it had just been added to the pharmacy at Emily's hospital,

它剛被納入艾美莉所在醫院的藥房，

for arthritis.

以治療關節炎。

So when we found Emily had these very high levels of IL-6,

當我們發現艾美莉的 高間白素 -6 含量時，

I called her doctors in the ICU and said,

我聯繫她的加護病房醫生，說，

"Why don't you treat her with this arthritis drug?"

為什麼不用這種關節炎藥來治療呢？

They said I was a cowboy for suggesting that.

他們說我太大膽了。

And since her fever and low blood pressure

由於她的高燒和低血壓

had not responded to any other therapy,

對其它任何療法都沒有反應，

her doctor quickly asked permission to the institutional review board,

她的醫生迅速申請研究倫理審查會 和她的父母的批准，

her parents,

and everybody, of course, said yes.

當然，每個人都同意了。

And they tried it,

於是他們著手嘗試，

and the results were nothing short of striking.

結果令人驚訝。

Within hours after treatment with tocilizumab,

使用托珠單抗藥物後的幾小時內，

Emily began to improve very rapidly.

艾美莉開始迅速好轉。

Twenty-three days after her treatment,

治療後的第 23 天，

she was declared cancer-free.

她的癌症完全緩解。

And today, she's 12 years old and still in remission.

今天，她已 12 歲，病情仍未復發。

(Applause)

（掌聲）

So we now call this violent reaction of the high fevers and coma,

我們現在把 CAR-T 細胞輸注後 出現的發熱和昏迷反應

following CAR T cells,

cytokine release syndrome, or CRS.

稱為 CRS 。

We've found that it occurs in nearly all patients who respond to the therapy.

我們發現對療法有反應的患者 大多出現了這些症狀，

But it does not happen in those patients who fail to respond.

反之，對療法無反應的患者都沒出現。

So paradoxically,

所以矛盾的現象就是，

our patients now hope for these high fevers after therapy,

我們的患者盼望在輸注後 出現這些症狀，

which feels like "the worst flu in their life,"

像是「這輩子最痛苦流感」的高燒。

when they get CAR T-cell therapies.

接受 CAR T 細胞治療後，

They hope for this reaction

他們希望出現這些症狀，

because they know it's part of the twisting and turning path

因為他們知道這是條看似曲折

back to health.

卻通往健康的路。

Unfortunately, not every patient recovers.

不幸的是，不是每位患者都能被治癒，

Patients who do not get CRS are often those who are not cured.

沒有出現 CRS 的患者， 病情通常不會好轉。

So there's a strong link now between CRS

所以 CRS 和 CAR T 細胞 清除白血病腫瘤之間

and the ability of the immune system to eradicate leukemia.

有著強烈的關聯。

That's why last summer,

因此去年夏季，

when the FDA approved CAR T cells for leukemia,

美國藥物管理局在通過 CAR T 細胞療法的同時，

they also co-approved the use of tocilizumab to block the IL-6 effects

也通過了托珠單抗藥物，

以治療間白素含量過高 以及 CRS 症狀。

and the accompanying CRS in these patients.

That was a very unusual event in medical history.

這在藥物史上很少見。

Emily's doctors have now completed further trials

艾美莉的醫生完成了進一步實驗，

and reported that 27 out of 30 patients, the first 30 we treated,

並報告第一批治療的 30 位患者中，

有 27 位，或者說 90%

or 90 percent,

had a complete remission

癌症完全緩解。

after CAR T cells, within a month.

在 CAR T 細胞治療後的一個月內，

A 90 percent complete remission rate in patients with advanced cancer

晚期癌症的痊癒率達 90%，

is unheard of

這在超過 50 年的 癌症研究中聞所未聞。

in more than 50 years of cancer research.

In fact, companies often declare success in a cancer trial

事實上若療法對 15% 的 患者完全起作用，

if 15 percent of the patients had a complete response rate.

藥物公司通常宣佈療法有效。

A remarkable study appeared in the "New England Journal of Medicine" in 2013.

2013 年，《新英格蘭醫學雜誌》 發表了一篇出色的相關研究，

An international study has since confirmed those results.

此後國際研究證實了研究結果。

And that led to the approval by the FDA

這使得美國藥物管理局

for pediatric and young adult leukemia in August of 2017.

在 2017 年 8 月准許了 用該療法治療小兒和青少年白血病。

So as a first-ever approval of a cell and gene therapy,

作為首個獲准的細胞基因療法，

CAR T-cell therapy has also been tested now

CAR T 細胞療法目前也在試驗

in adults with refractory lymphoma.

對成人難治性淋巴瘤的治療。

This disease afflicts about 20,000 a year in the United States.

這種病每年折磨著兩萬位美國公民。

The results were equally impressive and have been durable to date.

治療結果同樣顯著，且效果持久。

And six months ago, the FDA approved the therapy of this advanced lymphoma

6 個月前，美國藥物管理局通過了

針對這種晚期淋巴瘤的 CAR T 細胞療法。

with CAR T cells.

So now there are many labs and physicians and scientists around the world

現在，全世界衆多實驗室和醫師

who have tested CAR T cells

在多種疾病上測試 CAR T 細胞療法。

across many different diseases,

and understandably, we're all thrilled with the rapid pace of advancement.

當然，飛速的進展令人激動。

We're so grateful to see patients who were formerly terminal

我們高興的看到， 那些原本已至絕路的患者

return to healthy lives, as Emily has.

回歸到了健康的生活， 就像艾美莉那樣。

We're thrilled to see long remissions that may, in fact, be a cure.

我們看到了長期的完全緩解， 而這有可能意味著徹底治癒。

At the same time, we're also concerned about the financial cost.

但同時，我們也關注著治療費用，

It can cost up to 150,000 dollars to make the CAR T cells for each patient.

接受 CAR T 細胞治療， 病人要花上十五萬美元。

And when you add in the cost of treating CRS and other complications,

若加上治療 CRS 和其它併發症的費用，

the cost can reach one million dollars per patient.

每位患者的支出可達一百萬美元。

We must remember that the cost of failure, though, is even worse.

我們還要知道， 若療法失敗，費用更高。

The current noncurative therapies for cancer are also expensive

其它療效甚微的癌症療法 同樣費用高昂，

and, in addition, the patient dies.

並且患者還會死亡。

So, of course, we'd like to see research done now

所以，我們當然希望研究馬上完成，

to make this more efficient

讓療法更高效、

讓更多患者負擔得起治療費用。

and increase affordability to all patients.

Fortunately, this is a new and evolving field,

很幸運地，這是個新的進化性領域，

and as with many other new therapies and services,

隨著其它新療法和服務的出現，

prices will come down as industry learns to do things more efficiently.

產業的高效化將降低治療費用。

When I think about all the forks in the road

當我想到這些岔道，

that have led to CAR T-cell therapy,

通往 CAR T 細胞療法的岔道，

there is one thing that strikes me as very important.

有一件事情對我意義非凡：

We're reminded that discoveries of this magnitude don't happen overnight.

我們領悟到，重大發現 不是一蹴而就的，

CAR T-cell therapies came to us after a 30-year journey,

CAR T 細胞療法 走過 30 年才得以問世，

along a road full of setbacks and surprises.

這條路上有挫折也有驚喜。

In all this world of instant gratification

這個世界熱愛即時滿足，

and 24/7, on-demand results,

崇拜急功近利，

scientists require persistence, vision and patience

但科學家需要毅力、視野和耐心，

to rise above all that.

來讓這些成為現實。

They can see that the fork in the road is not always a dilemma or a detour;

這些岔道不總是艱難抉擇或者險徑，

sometimes, even though we may not know it at the time,

有時候，或許當時未曾得知，

the fork is the way home.

但那是條通向終點的路。

Thank you very much.

謝謝大家。

(Applause)

（掌聲）