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

翻译人员: Li Ying (Amelia) Hu 校对人员: Wanna Shi

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

这是我第一次在公众场合

the personal aspects of it.

从个人层面来讲这件事。

约吉·贝拉（Yogi Berra）是一名 世界著名的棒球运动员，他曾说：

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

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

“当你遇到时机，请把握住它吧。”

一个多世纪以来， 研究人员一直在

Researchers had been, for more than a century,

studying the immune system as a way to fight cancer,

研究用免疫系统来抗癌，

and cancer vaccines have, unfortunately, been disappointing.

但不幸的是，癌症疫苗 的开发一直不尽如人意。

They've only worked in cancers caused by viruses,

这些疫苗只对由病毒 引起的癌症起作用，

like cervical cancer or liver cancer.

如宫颈癌或肝癌，

So cancer researchers basically gave up on the idea

所以癌症研究人员 基本上放弃了

of using the immune system to fight cancer.

用免疫系统来抗癌的思路。

无论如何，免疫系统都没能 进化到足以抗癌的地步，

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

it evolved to fight pathogens invading from the outside.

只能对抗 外来入侵的病原体。

So its job is to kill bacteria and viruses.

它的职责就是 杀灭细菌和病毒。

And the reason the immune system has trouble with most cancers

免疫系统之所以难以 对抗大多数的癌症，

is that it doesn't invade from the outside;

是因为引起癌症的 并不是外来入侵的病原，

it evolves from its own cells.

而是人体自身细胞出现了癌变。

所以免疫系统 要么没有识别癌症，

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

要么既攻击癌细胞， 又攻击正常细胞，

or it attacks a cancer and also our normal cells,

leading to autoimmune diseases like colitis or multiple sclerosis.

结果引发了自身免疫性疾病， 如结肠炎或多发性硬化症。

So how do you get around that?

那该怎么办呢？

Our answer turned out to be synthetic immune systems

我们的解决办法是 设计合成免疫系统，

that are designed to recognize and kill cancer cells.

用它来识别并杀死癌细胞。

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

对，我说的是合成免疫系统，

You do that with genetic engineering and synthetic biology.

可以通过基因工程 和合成生物学来实现，

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

使用免疫系统中 自然产生的部分，

called B cells and T cells.

即 B 细胞和 T 细胞。

These were our building blocks.

这些是构建免疫系统的基本单位。

T cells have evolved to kill cells infected with viruses,

T 细胞可以杀死 染上病毒的细胞，

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

而 B 细胞则可以分泌出抗体，

and then bind to kill bacteria.

通过与细菌相结合来消灭细菌。

如果把这两种功能结合起来，

Well, what if you combined these two functions

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

改变其功能用来抗癌， 那会怎样？

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

我们发现，可以将 B 细胞的抗体基因

from B cells into T cells.

注入 T 细胞。

So how do you do that?

那该怎么做呢？

我们用一个艾滋病病毒（HIV） 作为特洛伊木马，

Well, we used an HIV virus as a Trojan horse

to get past the T cells' immune system.

避开 T 细胞的免疫系统，

The result is a chimera,

结果造出了个喀迈拉（嵌合体），

a fantastic fire-breathing creature from Greek mythology,

那是古希腊故事中

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

狮头、羊身、蛇尾的吐火怪物。

So we decided that the paradoxical thing that we had created

我们用 B 细胞的抗体、 以 T 细胞为载体，

with our B-cell antibodies, our T cells carrier

以 HIV 为特洛伊木马造出了

and the HIV Trojan horse

一个自相矛盾的东西，

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

我们决定把它叫做 “嵌合抗原受体 T 细胞”或 CAR-T 细胞。

The virus also inserts genetic information

该病毒还插入了基因信息，

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

以激活 T 细胞，并将其编程， 使其进入杀灭模式。

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

我们将 CAR-T 细胞 注入癌症患者体内，

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

当这些细胞看到并粘附于 其肿瘤靶点，会发生什么？

They act like supercharged killer T cells on steroids.

它们就像类固醇上 强悍的 T 细胞杀手，

They start this crash-defense buildup system in the body

开始在体内建立防撞系统，

and literally divide and multiply by the millions,

分裂并繁殖出 数百万个细胞，

where they then attack and kill the tumor.

然后攻击 并杀死肿瘤细胞。

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

这些都意味着 CAR-T 细胞 是医学史上首款活体药物。

CAR-T 细胞击破霉菌，

CAR T cells break the mold.

Unlike normal drugs that you take --

它们不像患者服用的普通药物——

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

普通药物在发挥药效后 会被代谢掉，然后患者得再服药，

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

而 CAR-T 细胞则可存活多年， 且药效很持久。

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

我们的癌症患者 其体内的 CAR-T 细胞

now for more than eight years.

至今已存活了 8 年多。

这些定制的癌症 T 细胞， 即 CAR-T 细胞，

And these designer cancer T cells, CAR T cells,

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

其半衰期预计超过 17 年，

So one infusion can do the job;

所以输一次药液就可以

they stay on patrol for the rest of your life.

守护病人的余生。

This is the beginning of a new paradigm in medicine.

这是医学新模式的开始。

但这种 T 细胞疗法 面临着一个巨大的挑战。

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

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

能在患者体内 起作用的 T 细胞，

are your own T cells,

其唯一来源是 自体的 T 细胞，

unless you happen to have an identical twin.

除非患者碰巧 有个同卵双胞胎。

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

所以对于大多数人来说， 我们都没这么幸运。

所以为了创造 CAR-T 细胞，

So what we did was to make CAR T cells.

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

我们得学会培育 患者自体的 T 细胞。

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

20 世纪 90年代， 我们开发了一个强大的平台，

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

1997 年，我们首次 在晚期艾滋病患者身上

with advanced HIV-AIDS.

测试了 CAR-T 细胞。

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

我们发现，这些 CAR-T 细胞在病人体内

for more than a decade.

存活了十多年。

And it improved their immune system and decreased their viruses,

它增强了患者的免疫系统， 并减少了病毒，

but it didn't cure them.

但它并没能治愈患者。

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

所以我们又回到实验室， 在接下来的十年里，

made improvements to the CAR T cell design.

我们改进了 CAR-T 细胞的设计。

And by 2010, we began treating leukemia patients.

到了 2010 年，我们开始 治疗白血病患者。

And our team treated three patients

2012 年，我们的团队治疗了

with advanced chronic lymphocytic leukemia in 2012.

三位晚期慢性 淋巴细胞白血病患者。

It's a form of incurable leukemia

这是一种无法治愈的白血病，

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

在美国，每年折磨着约两万名成人。

The first patient that we treated was a retired Marine sergeant

我们治疗的第一位病人

and a prison corrections officer.

是位退役海军中士、前狱警，

He had only weeks to live

他只有几周可活了，

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

实际上，他已经为自己 筹备好了葬礼。

在给他注入了 CAR-T 细胞后， 几天内，他发起了高烧，

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

He developed multiple organ failures,

多个器官开始衰竭，

was transferred to the ICU and was comatose.

被转到重症监护室， 他昏迷不醒。

We thought he would die,

我们以为他要死了，

and, in fact, he was given last rites.

他接受了临终祷告。

But then, another fork in the road happened.

但后来出现了转机，

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

在注射了 CAR-T 细胞 大约 28 天后，

he woke up,

他醒了，

and the physicians finally examined him,

医生给他做了最终检查，

and the cancer was gone.

他的癌症消失了，

The big masses that had been there had melted.

原来在那里的 大肿块已经消肿了，

Bone marrow biopsies found no evidence of leukemia,

骨髓活检未发现 白血病迹象。

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

那一年，在我们首批治疗的 三位患者中，

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

其中两位的病情持续缓解， 至今已八年了，

and one had a partial remission.

一位病情得到了部分缓解。

The CAR T cells had attacked the leukemia in these patients

这种 CAR-T 细胞攻击了 这些患者的白血病细胞，

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

并且使每位患者的肿瘤 消减了 2.9-7.7 磅。

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

他们的身体已经成为这些 CAR-T 细胞 名副其实的生物反应器，

producing millions and millions of CAR T cells

在骨髓、血液和肿瘤组织中

in the bone marrow, blood and tumor masses.

繁殖出数百万个 CAR-T 细胞。

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

用拳击来打个比方，我们发现， 这些 CAR-T 细胞可以与远远超过

to use a boxing analogy.

他们重量等级的对手对打。

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

一个 CAR-T 细胞就能杀死 1000 个肿瘤细胞，

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

没错，这是一对一千的比率。

The CAR T cell and its daughter progeny cells

CAR-T 细胞及其子代细胞

can divide and divide and divide in the body

可以在体内不断分裂，

until the last tumor cell is gone.

直到最后一个肿瘤细胞消失。

There's no precedent for this in cancer medicine.

这在癌症医学史上 前所未有。

The first two patients who had full remission

最先的两位病人的病情完全好转，

remain today leukemia-free,

至今一直 没再出现白血病细胞，

and we think they are cured.

我们相信， 他们已经痊愈了。

These are people who had run out of options,

他们用尽了 所有的传统方法，

均告无效， 他们一筹莫展，

and by all traditional methods they had,

they were like modern-day Lazarus cases.

而现在他们就像是现代的拉撒路病例。 【注：泛指医学上“起死回生”的现象】

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

我只能说：谢天谢地，时来运转。

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

我们的下一步是要得到批准， 治疗儿童急性白血病，

the most common form of cancer in kids.

这是最常见的 儿童肿瘤性疾病。

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

我们收治第一位参加试验的病人 是艾米莉 · 怀特黑德（Emily Whitehead），

and at that time, she was six years old.

当时，她年仅六岁。

She had gone through a series of chemotherapy

在过去几年里，

她接受了 一系列的化疗和放疗，

and radiation treatments over several years,

and her leukemia had always come back.

但她的白血病总是复发。

In fact, it had come back three times.

实际上，复发了三次。

When we first saw her, Emily was very ill.

我们第一次看到艾米丽时， 她病得很重。

Her official diagnosis was advanced, incurable leukemia.

她的正式诊断是 白血病晚期，没得治了，

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

癌症细胞已侵入她的骨髓、 肝脏和脾脏。

And when we infused her with the CAR T cells

我们在 2012 年 4 月春

in the spring of April 2012,

为她进行了 CAR-T 细胞治疗，

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

在接下来的日子里， 她的病情不见好转，

She got worse, and in fact, much worse.

反而每况愈下，事实上， 她的病情出现了恶化。

As our prison corrections officer had in 2010,

就像 2010 年那位狱警 所经历的那样，

she, in 2012, was admitted to the ICU,

2012 年， 她进了重症监护室，

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

这是整个故事中 最可怕的一个关口。

By day three, she was comatose and on life support

到了第三天，她出现了 肾衰竭、肺衰竭，她昏迷不醒，

for kidney failure, lung failure and coma.

得靠仪器来维持生命，

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

她一连三天发高烧， 高达 41 摄氏度，

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

而我们却不知道 她发烧的原因。

We did all the standard blood tests for infections,

我们做了所有的 标准血液检查，排查感染，

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

却未发现引起 发烧的感染病因。

But we did find something very unusual in her blood

但我们的确在她的血液中 发现了异常，

that had never been seen before in medicine.

这在医学史上前所未见。

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

她血液里一种叫 白细胞介素-6（IL-6）的蛋白质

in her blood.

含量过高。

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

事实上，比正常水平 高出一千多倍，

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

这又是一个关口。

By sheer coincidence,

非常巧合的是，

one of my daughters has a form of pediatric arthritis.

我有一个女儿得了小儿关节炎，

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

因此，作为一名癌症医生， 为了我的女儿，

experimental therapies for arthritis for my daughter,

我一直在关注 关节炎实验性疗法，

in case she would need them.

以备她会用到。

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

就在艾米丽入院前几个月， 美国食品药品监督管理局（FDA）

a new therapy had been approved by the FDA

批准了一种治疗

to treat elevated levels of interleukin-6.

白细胞介素-6含量过高的新疗法。

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

这种疗法获得批准，用于治疗 我女儿所得的这类关节炎，

It's called tocilizumab.

名为 IL-6 受体单克隆抗体注射剂 （tocilizumab），

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

该药刚被添加到 艾米丽所住医院的药房，

for arthritis.

用来治疗关节炎。

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

所以当我们发现 艾米丽的 IL-6 含量这么高，

I called her doctors in the ICU and said,

我打电话给她的重症监护室医生，

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

我说：“你不妨用这种关节炎药 给她治疗一下吧？”

They said I was a cowboy for suggesting that.

他们说，我提这么个建议， 简直就是个莽夫。

And since her fever and low blood pressure

由于其他治疗

had not responded to any other therapy,

对她的高烧和低血压都没效，

her doctor quickly asked permission to the institutional review board,

她的医生很快向 机构审查委员会申请了许可，

her parents,

并征求了她父母的同意，

and everybody, of course, said yes.

自然，大家都同意了。

And they tried it,

于是他们尝试了这种药，

and the results were nothing short of striking.

结果疗效非常惊人。

Within hours after treatment with tocilizumab,

接受 IL-6 受体单克隆抗体治疗

Emily began to improve very rapidly.

几个小时后， 艾米丽开始迅速好转。

Twenty-three days after her treatment,

治疗 23 天后，

她体内已经没有癌细胞了。

she was declared cancer-free.

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

现在，她 12 岁了， 仍然在康复中。

(Applause)

（掌声）

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

我们现在把这种在注入 CAR-T 细胞后出现高烧和昏迷

following CAR T cells,

的强列反应

cytokine release syndrome, or CRS.

称为细胞因子释放综合征（CRS）。

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

我们发现，几乎所有对该治疗 有反应的病人都出现了这种症状，

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

但那些（对治疗）没有反应的病人 则没有这些症状。

So paradoxically,

所以这很矛盾，

our patients now hope for these high fevers after therapy,

现在，我们的病人在接受 CAR-T 细胞 治疗时，都希望能发高烧，

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

这种感觉就像是

when they get CAR T-cell therapies.

“得了有生以来最严重的流感”。

They hope for this reaction

他们希望有这种反应，

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

因为他们知道这是迈向 恢复健康之路上

back to health.

必经的坎坷与曲折。

Unfortunately, not every patient recovers.

不幸的是， 并不是每位病人都能康复。

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

没有出现 CRS 症状的病人 通常无法治愈。

So there's a strong link now between CRS

所以 CRS 与免疫系统

and the ability of the immune system to eradicate leukemia.

清除白血病细胞的能力 紧密相关。

That's why last summer,

所以，去年夏天，

when the FDA approved CAR T cells for leukemia,

FDA 在批准用 CAR-T 细胞 治疗白血病时，

还批准了使用 IL-6 受体单克隆抗体注射剂 来阻断这些患者出现的 IL-6 影响

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

and the accompanying CRS in these patients.

和伴随而来的 CRS 症状。

That was a very unusual event in medical history.

这在医学史上极不寻常。

Emily's doctors have now completed further trials

艾米丽的医生们已经 完成了进一步的试验，

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

并在报告中指出，在首批治疗的 30 位病人中，有 27 位，

or 90 percent,

或者说 90% 的病人，

had a complete remission

在用 CAR-T 细胞 治疗后的一个月内，

after CAR T cells, within a month.

病情得到了完全缓解。

A 90 percent complete remission rate in patients with advanced cancer

晚期癌症患者病情 完全缓解率达 90%，

is unheard of

这在 50 多年的癌症研究中

in more than 50 years of cancer research.

闻所未闻。

In fact, companies often declare success in a cancer trial

事实上，如果癌症试验的结果 有 15% 的患者获得完全缓解，

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

制药公司一般就会 宣布该癌症试验成功。

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

2013 年，《新英格兰医学杂志》 发表了一项令人瞩目的研究。

An international study has since confirmed those results.

此后，一项国际性研究 证实了这些研究结果。

And that led to the approval by the FDA

FDA 因而于 2017 年 8 月批准了

for pediatric and young adult leukemia in August of 2017.

将该疗法用于治疗 儿童和年轻人的白血病。

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

作为首个获得批准的 细胞与基因疗法，

CAR T-cell therapy has also been tested now

CAR-T 细胞疗法现在 也已用于试验性

in adults with refractory lymphoma.

治疗患有难治性淋巴瘤的成年人。

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

这种疾病每年折磨着 近 2 万名美国患者，

治疗结果也同样令人瞩目， 且效果持久至今。

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

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

六个月前，FDA 批准了 用 CAR-T 细胞

with CAR T cells.

治疗晚期淋巴瘤。

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

现在世界上有很多实验室、 医生和科学家都在

试用 CAR-T 细胞

who have tested CAR T cells

across many different diseases,

治疗许多不同的疾病，

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

毫无疑问，我们大家都 为迅猛的进展感到振奋。

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

我们很高兴看到， 那些以前得了绝症的病人，

return to healthy lives, as Emily has.

像艾米丽一样康复， 健康地生活。

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

我们很兴奋地看到，病情长期 得到缓解，实际上可能是治愈了。

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

同时，我们也在关注着医疗费。

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

为一位病人合成 CAR-T 细胞的 费用高达 15 万美元，

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

加上治疗 CRS 和 其他并发症的费用，

the cost can reach one million dollars per patient.

每个病人的治疗费 高达一百万美元。

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

但是，我们还要记住， 如果治疗失败，费用会更高。

The current noncurative therapies for cancer are also expensive

目前，对癌症无疗效的治疗 费用也十分高昂，

and, in addition, the patient dies.

而且病人依然会面临死亡。

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

我们当然希望看到 我们现在所做的研究

to make this more efficient

能更有效，

并让所有病人 都能付得起治疗费。

and increase affordability to all patients.

Fortunately, this is a new and evolving field,

所幸，这是个新领域， 仍在不断地发展，

and as with many other new therapies and services,

随着许多其他 新疗法和服务的出现，

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

行业效率会提高， 治疗价格会下降。

When I think about all the forks in the road

我想着这一路走来， 在研制 CAR-T 细胞治疗中

that have led to CAR T-cell therapy,

所遇到的各种重大关头，

there is one thing that strikes me as very important.

有一件事我觉得非常重要。

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

我们意识到，这些重大发现 并非一蹴而就。

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

我们花了 30 年， CAR-T 细胞疗法才得以问世，

along a road full of setbacks and surprises.

这一路走来，虽道路曲折， 但不乏惊喜。

In all this world of instant gratification

当今世界， 人们追求即时满足，

and 24/7, on-demand results,

全天候按需出结果，

scientists require persistence, vision and patience

在这样的世界里，科学家需要 坚持不懈、有远见、有耐心，

to rise above all that.

才能战胜这一切，

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

才能看清，岔道口并不总是 进退两难的困境，或者要绕道而行；

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

有时，在当时可能还不知道，

the fork is the way home.

这个路口就是通往成功之路。

Thank you very much.

感谢大家。

(Applause)

（掌声）