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免疫疗法,癌症患者的新希望?

更新时间:2016-8-3 10:01:06 来源:纽约时报中文网 作者:佚名

Harnessing the Immune System to Fight Cancer
免疫疗法,癌症患者的新希望?

Steve Cara expected to sail through the routine medical tests required to increase his life insurance in October 2014. But the results were devastating. He had lung cancer, at age 53. It had begun to spread, and doctors told him it was inoperable.

2014年10月,史蒂夫·卡拉(Steve Cara)为了增加人寿保险,去做了标准体检。但结果令人震惊。53岁的他患上了肺癌,已经开始扩散,医生说他不适宜动手术。

A few years ago, they would have suggested chemotherapy. Instead, his oncologist, Dr. Matthew D. Hellmann of Memorial Sloan Kettering Cancer Center in New York City, recommended an experimental treatment: immunotherapy. Rather than attacking the cancer directly, as chemo does, immunotherapy tries to rally the patient’s own immune system to fight the disease.

几年前,医生会建议他做化疗。但如今,他的主治医生、纽约市纪念斯隆·凯特琳癌症中心(Memorial Sloan Kettering Cancer Center)的肿瘤学医师马修·D·霍尔曼博士(Dr. Matthew D. Hellmann)推荐了尚在实验中的免疫疗法。这种疗法并不是像化疗那样直接攻击癌细胞,而是试图让患者自身的免疫系统来抗击疾病。

Uncertain, Cara sought a second opinion. A doctor at another major hospital read his scans and pathology report, then asked what Hellmann had advised. When the doctor heard the answer, Cara recalled, “he closed up the folder, handed it back to me and said, ‘Run back there as fast as you can.'”

卡拉对此并不确定,他想听听其他的意见。另一家大医院的医生看了他的扫描片和病理报告后,问他霍尔曼是怎么建议的。卡拉回忆,那位医生听完,“他关上文件夹递给我,说‘赶快回去吧,能跑多快跑多快’。”

Many others are racing down the same path. Harnessing the immune system to fight cancer, long a medical dream, is becoming a reality. Remarkable stories of tumors melting away and terminal illnesses going into remissions that last years — backed by solid data — have led to an explosion of interest and billions of dollars of investments in the rapidly growing field of immunotherapy. Pharmaceutical companies, philanthropists and the U.S. government’s “cancer moonshot” program are pouring money into developing treatments. Medical conferences on the topic are packed.

其他很多病人也在同一条道路上奔跑。利用免疫系统来抗击癌症是医学界长久以来的梦想,如今它正在变为现实。近年来,肿瘤消失、末期疾病得到缓解的惊人故事不断传来——都有可靠数据作为支持——迅速成长中的免疫疗法吸引了人们的极大兴趣,以及数十亿美元的投资。制药公司、慈善家和美国政府的“癌症登月计划”项目都在这项疗法的研发上大举投资。关于这个主题的医学研讨会也层出不穷。

“This is a fundamental change in the way that we think about cancer therapy,” said Dr. Jedd Wolchok, chief of melanoma and immunotherapeutics services at Memorial Sloan Kettering.

“这从根本上改变了我们对癌症疗法的认识,” 纪念斯隆·凯特琳癌症中心的黑色素瘤与免疫疗法学主任杰德·沃尔柯克(Jedd Wolchok)医生说。

Hundreds of clinical trials involving immunotherapy, alone or combined with other treatments, are underway for nearly every type of cancer. “People are asking, waiting, pleading to get into these trials,” said Dr. Arlene Siefker-Radtke, an oncologist at the University of Texas MD Anderson Cancer Center in Houston, who specializes in bladder cancer.

如今,有几百起和免疫疗法有关的临床试验正在进行中,有的患者单独接受免疫疗法,有的患者还同时接受其他疗法,范围几乎涉及了癌症的所有种类。“人们都在询问和等待,请求接受这些这些实验,”休斯敦德克萨斯大学MD安德森癌症中心(University of Texas MD Anderson Cancer Center)的肿瘤学医师、主攻膀胱癌的阿琳·西弗克-拉特克博士(Dr. Arlene Siefker-Radtke)说道。

The immune system — a network of cells, tissues and biochemicals they secrete — defends the body against viruses, bacteria and other invaders. But cancer often finds ways to hide from the immune system or block its ability to fight. Immunotherapy tries to help the immune system recognize cancer as a threat, and attack it.

免疫系统由免疫细胞、免疫组织和它们所分泌的生化物质构成,它保护着身体不受病毒、细菌和其他入侵者的干扰。但是癌症经常能找到办法躲开免疫系统,或是令其失去战斗能力。免疫疗法能帮助免疫系统把癌症视为一种威胁,并对它展开攻击。

A widely used type of immunotherapy involves drugs that free immune cells to fight cancer by blocking a mechanism — called a checkpoint — that cancer uses to shut down the immune system.

一种被广泛使用的免疫疗法是通过药物屏蔽一种名为“检查点”的机制,令免疫细胞恢复抗击癌症的能力;癌细胞正是利用检查点机制来关闭免疫系统的。

These drugs, called checkpoint inhibitors, have been approved by the Food and Drug Administration to treat advanced melanoma, Hodgkin lymphoma and cancers of the lung, kidney and bladder. More drugs in this class are in the pipeline. Patients are clamoring for checkpoint drugs, including one, Keytruda, known to many as “that Jimmy Carter drug” which, combined with surgery and radiation, has left the former president with no sign of recurrence even though melanoma had spread to his liver and brain.

这类药物名叫检查点抑制剂,已经被食品与药物管理局批准,用于治疗晚期黑色素瘤、霍奇金淋巴瘤,以及肺癌、肾癌和膀胱癌。更多此类药物也在研制过程中。患者迫切希望得到检查点药物,其中包括一种名为Keytruda的药,很多人都称之为“那种吉米·卡特(Jimmy Carter)的药”——前总统卡特使用这种药,配合外科手术和放射疗法,目前没有出现复发迹象,尽管黑色素瘤已经扩散到他的肝部和脑部。

Checkpoint inhibitors have become an important option for people like Cara, with advanced lung cancer.

检查点抑制剂对于卡拉这样的晚期肺癌患者来说是一种非常重要的选项。

“We can say in all honesty to patients, that while we can’t tell them we can cure metastatic lung cancer right now, we can tell them there’s real hope that they can live for years, and for a lot of patients many years, which really is a complete game-changer,” said Dr. John V. Heymach, a lung cancer specialist and chairman of thoracic/head and neck medical oncology at MD Anderson.

“我们可以诚实地对患者说,虽然我们不能保证可以马上治愈转移性肺癌,但我们可以告诉他们:他们有希望再活若干年,许多患者可以活很多年,这真的是一大突破,”肺癌专家和MD安德森癌症中心(MD Anderson)胸部/头颈部医药肿瘤科主任约翰·V·海马克博士(Dr. John V. Heymach)说。

Yet for all the promise and excitement, the fact is that so far, immunotherapy has worked in only a minority of patients, and researchers are struggling to find out why. They know they have their hands on an extraordinarily powerful tool, but they cannot fully understand or control it yet.

然而,尽管有如此前景,也令人兴奋,但现实是,免疫疗法目前只对一小部分病人生效。为什么会这样,研究者还在努力寻找答案。他们知道,他们找到了一种非常强大的工具,但他们尚不能充分理解和掌握它。

One Patient’s Story

一个病人的故事

Cara, an apparel industry executive from Bridgewater, New Jersey, had non-small-cell lung cancer, the most common form of the disease. The diagnosis shattered what had been an idyllic life: a happy marriage, sons in college, a successful career, a beautiful home, regular vacations, plenty of golf.

卡拉是新泽西州布里奇沃特一个服装公司的行政管理人员,他患上的是非小细胞肺癌,是肺癌中最常见的一种。他原本过着田园诗般的生活:婚姻幸福,儿子们已经进入大学、事业有成、漂亮的家、定期度假,经常打高尔夫。这一切都被这个诊断打碎了。

In December 2014, he began treatment with two checkpoint inhibitors. They cost about $150,000 a year, but as a study subject he did not have to pay.

2014年12月,他开始使用两种检查点抑制剂。这些药一年要花15万美元,但他是研究对象,所以无需付费。

These medicines work on killer T-cells, white blood cells that are often described as the soldiers of the immune system. T-cells are so fierce that they have built-in brakes — the so-called checkpoints — to shut them down and keep them from attacking normal tissue, which could result in autoimmune disorders like Crohn’s disease, lupus or rheumatoid arthritis. One checkpoint stops T-cells from multiplying; another weakens them and shortens their life span.

这些药物作用于免疫T细胞,这种白细胞经常被描述为免疫系统的士兵。T细胞非常凶猛,因此它们有内置的“刹车”——就是所谓检查点——以便在必要时关闭它们,以免它们攻击正常组织。一旦T细胞攻击正常组织,就会引发自体免疫性疾病,比如克罗恩病、狼疮或类风湿性关节炎。一种检查点用来阻止T细胞成倍增长,另一种检查点用来削弱它们的力量,缩短它们的生命周期。

As the name suggests, checkpoint inhibitors block the checkpoints, so cancer cannot use them to turn off the immune system.

顾名思义,检查点抑制剂可以解除检查点的作用,这样癌细胞就不能利用它们来关闭免疫系统。

Cara took drugs to inhibit both types of checkpoints. Every two weeks, he had intravenous infusions of Yervoy and Opdivo, both made by Bristol-Myers Squibb. He had no problems at first, just a bit of fatigue the day after the infusion. He rarely missed work.

卡拉使用的药物能抑制这两种检查点。每两周,他接受一次静脉Yervoy和Opdivo注射,两种药都是由百时美施贵宝公司(Bristol-Myers Squibb)制造的。一开始他没什么问题,只是在注射后的第二天觉得有点疲惫。工作也基本不受影响。

But turning the wrath of the immune system against cancer can be a risky endeavor: Sometimes the patient’s own body gets caught in the crossfire. About two months into the treatment, Cara broke out in a rash all over his arms, back and chest. It became so severe that he had to go off the drugs. A steroid cream cleared it up and he was able to resume treatment — but with only one drug, Opdivo. Doctors stopped the other in hopes of minimizing the side effects.

但是激发免疫系统的强大力量去抗击癌症可能是很危险的:有时候,患者的身体也会在激烈交锋中受到伤害。治疗进行了两个月后,卡拉的胳膊、后背和胸前长出了大片皮疹。皮疹十分严重,他不得不停药。用类固醇药膏治好皮疹后,他恢复了免疫治疗,但是只使用Opdivo。医生停掉了另一种抑制剂,希望能把副作用降到最低限度。

Checkpoint inhibitors can take months to begin working, and sometimes cause inflammation that, on scans early in treatment, can make it look like the tumor is growing. But Cara’s first scans, in March 2015, were stunning.

检查点抑制剂可能要几个月才能生效,有时候还会造成炎症,在治疗初期,从扫描结果上看,这可能会造成癌细胞在增长的假象。但是2015年3月,卡拉的初次扫描结果很惊人。

His tumor had shrunk by a third.

他的肿瘤缩小了三分之一。

By August, more than half of the tumor had vanished. The rash came back, however, and worsened. Steroids worked again, but in October a far more alarming side effect set in: breathing trouble.

到了8月,一多半的肿瘤都消失了,但皮疹又复发,并且恶化了。类固醇药膏再次生效,但是到了10月,又发生了另一种更让人担忧的副作用:呼吸困难。

Doctors diagnosed pneumonitis, a lung inflammation caused by an attack from the immune system — a known risk of checkpoint drugs. Continuing the treatment posed too great a danger.

医生诊出了肺炎,这是一种由免疫系统攻击肌体造成的感染——也是检查点药物的一种已知风险。继续治疗的风险太大。

Cara stopped the infusions, but the months of treatment seemed to have transformed his cancer to stage 2 from stage 4, meaning that it was now operable. This spring surgeons removed about a third of his right lung, and discovered that the cancer was actually gone.

卡拉停止了注射,但是这几个月的治疗令他的癌症从四期变成了二期,也就是说可以手术治疗了。今年春天,他通过手术切除了三分之一的右肺,并且发现癌细胞完全消失了。

“No cancer was seen in any of the tissue they took out,” Hellmann said. “'One hundred percent treatment effect,'” he read from the pathology report. “It was pretty cool.”

“切除的组织中没有发现癌细胞,”霍尔曼恩说。“完全是免疫疗法的功效,”他读着病理报告。“太酷了。”

As of now, he needs no further treatment, but he will be monitored regularly. He is back to work, and golf.

目前,他不再需要进一步治疗了,但还是需要定期观察。他又开始工作,也恢复了打高尔夫球。

“He’s had the best possible response,” Hellmann said. “I hope that remains permanent. Only time will tell, and I think he’s conscious of that.”

“他的疗效是最好的,”霍尔曼恩说。“我希望能持久。这还需要时间检验,我觉得他清楚这一点。”

Helping Some, but Not Others

对一些人奏效,对另一些人无效

When checkpoint inhibitors work, they can really work, producing long remissions that start to look like cures and that persist even after treatment stops. Twenty percent to 40 percent of patients, sometimes more, have good responses. But for many patients, the drugs do not work at all. For others, they work for a while and then stop.

检查点抑制剂生效时,效果会非常好,带来很长的缓解期,看上去很像得到了治愈,甚至在治疗停止后,也会维持下去。20%到40%的患者,有时候甚至更多患者,能够收到很好的疗效。但是对于很多患者来说,这类药物却根本不起作用。对于另一些患者来说,它们会生效一段时间,之后就不起作用了。

The vexing question, and the focus of research, is, why?

为什么?这个问题让人恼火,同时也是研究的焦点。

One theory is that additional checkpoints, not yet discovered, may play a role. The hunt is on to find them, and then make new drugs to act on them.

一种解释认为,还有目前尚未发现的检查点在起作用。研究者在努力寻找它们,然后开发针对它们的新药物。

Despite the gaps in knowledge, checkpoint inhibitors are coming into widespread use and are being tried in advanced types of cancer for which standard chemotherapy offers little hope.

尽管人们的认识还存在不足,但检查点抑制剂正在被广泛应用,试用于各种常规化疗希望渺茫的晚期癌症中。

While the drugs initially were given only to people with advanced disease, especially those who had little to lose because chemotherapy had stopped working, Heymach of MD Anderson predicted that soon some patients — including some with earlier stages of lung cancer — will receive checkpoint inhibitors as their first treatment.

这种药最初只在晚期患者身上使用,特别是那些化疗已经不起作用,只能背水一战的患者;但MD安德森中心的海马克医生预言,不久后,有些患者(包括较早期的肺癌患者)会在一开始就接受检查点抑制剂治疗。

But the potential for dangerous side effects cannot be overemphasized, doctors say. A 2010 article in a medical journal reported that a few melanoma patients had died from adverse effects of Yervoy.

但是,医生们说,潜在的危险副作用不可轻视。一篇2010年的医学期刊文献报告,几名黑色素瘤患者死于Yervoy带来的副作用。

In addition to causing lung inflammation, checkpoint inhibitors can lead to rheumatoid arthritis and colitis, a severe inflammation of the intestine — the result of an attack by the revved-up immune system that over-the-counter remedies cannot treat. Patients need steroids like prednisone to quell these attacks. Fortunately — and mysteriously, Wolchok said — the steroids can halt the gut trouble without stopping the immune fight against the cancer. But if patients delay telling doctors about diarrhea, Wolchok warned, “they could die” from colitis.

除了导致肺部炎症,检查点抑制剂还可能导致类风湿关节炎和结肠炎——一种严重的肠道系统感染;这些由活跃的免疫系统攻击所导致的疾病是非处方药无法治疗的。患者需要强的松等类固醇药物来抵御这些攻击。沃尔科克说,幸运而且神秘的是,类固醇可以治疗肠道问题,同时又不会停止免疫系统攻击癌细胞。但是,沃尔科克警告,如果患者没有及时把腹泻的情况告知医生,“他们可能会死于结肠炎”。

Checkpoint inhibitors can also slow down vital glands — pituitary, adrenal or thyroid — creating a permanent need for hormone treatment. Cara, for instance, now needs thyroid medication, almost certainly as a result of his treatment. Doctors have reported that a patient with a kidney transplant rejected it after taking a checkpoint inhibitor to treat cancer, apparently because the drug spurred his immune system to attack the organ.

检查点抑制剂也会减缓重要腺体的分泌,比如垂体、肾上腺和甲状腺,导致终生需要荷尔蒙治疗。比如卡拉现在就需要使用甲状腺药物,几乎肯定是由于免疫治疗的缘故。医生报告说,有一位接受了肾移植手术的病人在接受检查点抑制剂疗法治疗癌症后,出现了排异反应,貌似是因为这种药刺激他的免疫系统去攻击被移植的肾脏。

Another of Hellmann’s lung-cancer patients, Joanne Sabol, 65, had to quit a checkpoint inhibitor because of severe colitis. She had taken it for about two years, and it shrank a large abdominal tumor 78 percent. Patients like her are in uncharted territory, and doctors are trying to decide whether to operate to remove what is left of her tumor.

另一位霍尔曼恩的肺癌患者,65岁的乔安娜·萨伯尔(Joanne Sabol)由于严重的结肠炎,放弃了检查点抑制剂疗法。她使用这种药物已经两年,巨大的腹部肿瘤缩减了78%。像她这样的患者处于一片未知领域,医生们正在研究是否需要手术切除剩余的肿瘤。

“I have aggressive cancer, but I’m not giving in to it,” Sabol said. “It’s going to be a big battle with me.”

“我患了恶性癌症,但我不会向它屈服,”萨伯尔说。“这将是它和我的一场大战役。”

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