免疫療法 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)爲了增加人壽保險，去做了標準體檢。但結果令人震驚。53歲的他患上了肺癌，已經開始擴散，醫生說他不適宜動手術。
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.
幾年前，醫生會建議他做化療。但如今，他的主治醫生、紐約市紀念斯隆·凱特琳癌症中心(Memorial Sloan Kettering Cancer Center)的腫瘤學醫師馬修·D·霍爾曼博士(Dr. Matthew D. Hellmann)推薦了尚在實驗中的免疫療法。這種療法並不是像化療那樣直接攻擊癌細胞，而是試圖讓患者自身的免疫系統來抗擊疾病。
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.'”
卡拉對此並不確定，他想聽聽其他的意見。另一家大醫院的醫生看了他的掃描片和病理報告後，問他霍爾曼是怎麼建議的。卡拉回憶，那位醫生聽完，“他關上文件夾遞給我，說‘趕快回去吧，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條道路上奔跑。利用免疫系統來抗擊癌症是醫學界長久以來的夢想，如今它正在變爲現實。近年來，腫瘤消失、末期疾病得到緩解的驚人故事不斷傳來——都有可靠數據作爲支持——迅速成長中的免疫療法吸引了人們的極大興趣，以及數十億美元的投資。製藥公司、慈善家和美國政府的“癌症登月計劃”項目都在這項療法的研發上大舉投資。關於這個主題的醫學研討會也層出不窮。
“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.
“這從根本上改變了我們對癌症療法的認識，” 紀念斯隆·凱特琳癌症中心的黑色素瘤與免疫療法學主任傑德·沃爾柯克(Jedd Wolchok)醫生說。
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，有幾百起和免疫療法有關的臨牀試驗正在進行中，有的患者單獨接受免疫療法，有的患者還同時接受其他療法，範圍幾乎涉及了癌症的所有種類。“人們都在詢問和等待，請求接受這些這些實驗，”休斯敦德克薩斯大學MD安德森癌症中心(University of Texas MD Anderson Cancer Center)的腫瘤學醫師、主攻膀胱癌的阿琳·西弗克-拉特克博士(Dr. Arlene Siefker-Radtke)說道。
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.
免疫系統由免疫細胞、免疫組織和它們所分泌的生化物質構成，它保護着身體不受病毒、細菌和其他入侵者的干擾。但是癌症經常能找到辦法躲開免疫系統，或是令其失去戰鬥能力。免疫療法能幫助免疫系統把癌症視爲一種威脅，並對它展開攻擊。
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.
一種被廣泛使用的免疫療法是通過藥物屏蔽一種名爲“檢查點”的機制，令免疫細胞恢復抗擊癌症的能力；癌細胞正是利用檢查點機制來關閉免疫系統的。
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.
這類藥物名叫檢查點抑制劑，已經被食品與藥物管理局批准，用於治療晚期黑色素瘤、霍奇金淋巴瘤，以及肺癌、腎癌和膀胱癌。更多此類藥物也在研製過程中。患者迫切希望得到檢查點藥物，其中包括一種名爲Keytruda的藥，很多人都稱之爲“那種吉米·卡特(Jimmy Carter)的藥”——前總統卡特使用這種藥，配合外科手術和放射療法，目前沒有出現復發跡象，儘管黑色素瘤已經擴散到他的肝部和腦部。
Checkpoint inhibitors have become an important option for people like Cara, with advanced lung cancer.
檢查點抑制劑對於卡拉這樣的晚期肺癌患者來說是一種非常重要的選項。
“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.
“我們可以誠實地對患者說，雖然我們不能保證可以馬上治癒轉移性肺癌，但我們可以告訴他們：他們有希望再活若干年，許多患者可以活很多年，這真的是一大突破，”肺癌專家和MD安德森癌症中心(MD Anderson)胸部/頭頸部醫藥腫瘤科主任約翰·V·海馬克博士(Dr. John V. Heymach)說。
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，儘管有如此前景，也令人興奮，但現實是，免疫療法目前只對一小部分病人生效。爲什麼會這樣，研究者還在努力尋找答案。他們知道，他們找到了一種非常強大的工具，但他們尚不能充分理解和掌握它。
One Patient’s Story
一個病人的故事
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.
卡拉是新澤西州布里奇沃特一個服裝公司的行政管理人員，他患上的是非小細胞肺癌，是肺癌中最常見的一種。他原本過着田園詩般的生活：婚姻幸福，兒子們已經進入大學、事業有成、漂亮的家、定期度假，經常打高爾夫。這一切都被這個診斷打碎了。
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，他開始使用兩種檢查點抑制劑。這些藥一年要花15萬美元，但他是研究對象，所以無需付費。
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.
這些藥物作用於免疫T細胞，這種白細胞經常被描述爲免疫系統的士兵。T細胞非常兇猛，因此它們有內置的“剎車”——就是所謂檢查點——以便在必要時關閉它們，以免它們攻擊正常組織。一旦T細胞攻擊正常組織，就會引發自體免疫性疾病，比如克羅恩病、狼瘡或類風溼性關節炎。一種檢查點用來阻止T細胞成倍增長，另一種檢查點用來削弱它們的力量，縮短它們的生命週期。
As the name suggests, checkpoint inhibitors block the checkpoints, so cancer cannot use them to turn off the immune system.
顧名思義，檢查點抑制劑可以解除檢查點的作用，這樣癌細胞就不能利用它們來關閉免疫系統。
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.
卡拉使用的藥物能抑制這兩種檢查點。每兩週，他接受一次靜脈Yervoy和Opdivo注射，兩種藥都是由百時美施貴寶公司(Bristol-Myers Squibb)製造的。一開始他沒什麼問題，只是在注射後的第二天覺得有點疲憊。工作也基本不受影響。
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.
但是激發免疫系統的強大力量去抗擊癌症可能是很危險的：有時候，患者的身體也會在激烈交鋒中受到傷害。治療進行了兩個月後，卡拉的胳膊、後背和胸前長出了大片皮疹。皮疹十分嚴重，他不得不停藥。用類固醇藥膏治好皮疹後，他恢復了免疫治療，但是隻使用Opdivo。醫生停掉了另一種抑制劑，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.
檢查點抑制劑可能要幾個月才能生效，有時候還會造成炎症，在治療初期，從掃描結果上看，這可能會造成癌細胞在增長的假象。但是2015年3月，卡拉的初次掃描結果很驚人。
His tumor had shrunk by a third.
他的腫瘤縮小了三分之一。
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，一多半的腫瘤都消失了，但皮疹又復發，並且惡化了。類固醇藥膏再次生效，但是到了10月，又發生了另一種更讓人擔憂的副作用：呼吸困難。
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.
醫生診出了肺炎，這是一種由免疫系統攻擊肌體造成的感染——也是檢查點藥物的一種已知風險。繼續治療的風險太大。
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，但是這幾個月的治療令他的癌症從四期變成了二期，也就是說可以手術治療了。今年春天，他通過手術切除了三分之一的右肺，並且發現癌細胞完全消失了。
“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.”
“切除的組織中沒有發現癌細胞，”霍爾曼恩說。“完全是免疫療法的功效，”他讀着病理報告。“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，他不再需要進一步治療了，但還是需要定期觀察。他又開始工作，也恢復了打高爾夫球。
“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.”
“他的療效是最好的，”霍爾曼恩說。“我希望能持久。這還需要時間檢驗，我覺得他清楚這一點。”
Helping Some, but Not Others
對一些人奏效，對另一些人無效
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.
檢查點抑制劑生效時，效果會非常好，帶來很長的緩解期，看上去很像得到了治癒，甚至在治療停止後，也會維持下去。20%到40%的患者，有時候甚至更多患者，能夠收到很好的療效。但是對於很多患者來說，這類藥物卻根本不起作用。對於另一些患者來說，它們會生效一段時間，之後就不起作用了。
The vexing question, and the focus of research, is, why?
爲什麼？這個問題讓人惱火，同時也是研究的焦點。
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.
一種解釋認爲，還有目前尚未發現的檢查點在起作用。研究者在努力尋找它們，然後開發針對它們的新藥物。
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.
儘管人們的認識還存在不足，但檢查點抑制劑正在被廣泛應用，試用於各種常規化療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.
這種藥最初只在晚期患者身上使用，特別是那些化療已經不起作用，只能背水一戰的患者；但MD安德森中心的海馬克醫生預言，不久後，有些患者（包括較早期的肺癌患者）會在一開始就接受檢查點抑制劑治療。
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，醫生們說，潛在的危險副作用不可輕視。一篇2010年的醫學期刊文獻報告，幾名黑色素瘤患者死於Yervoy帶來的副作用。
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.
除了導致肺部炎症，檢查點抑制劑還可能導致類風溼關節炎和結腸炎——一種嚴重的腸道系統感染；這些由活躍的免疫系統攻擊所導致的疾病是非處方藥無法治療的。患者需要強的鬆等類固醇藥物來抵禦這些攻擊。沃爾科克說，幸運而且神祕的是，類固醇可以治療腸道問題，同時又不會停止免疫系統攻擊癌細胞。但是，沃爾科克警告，如果患者沒有及時把腹瀉的情況告知醫生，“他們可能會死於結腸炎”。
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.
檢查點抑制劑也會減緩重要腺體的分泌，比如垂體、腎上腺和甲狀腺，導致終生需要荷爾蒙治療。比如卡拉現在就需要使用甲狀腺藥物，幾乎肯定是由於免疫治療的緣故。醫生報告說，有一位接受了腎移植手術的病人在接受檢查點抑制劑療法治療癌症後，出現了排異反應，貌似是因爲這種藥刺激他的免疫系統去攻擊被移植的腎臟。
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.
另一位霍爾曼恩的肺癌患者，65歲的喬安娜·薩伯爾(Joanne Sabol)由於嚴重的結腸炎，放棄了檢查點抑制劑療法。她使用這種藥物已經兩年，巨大的腹部腫瘤縮減了78%。像她這樣的患者處於一片未知領域，醫生們正在研究是否需要手術切除剩餘的腫瘤。
“I have aggressive cancer, but I’m not giving in to it,” Sabol said. “It’s going to be a big battle with me.”
“我患了惡性癌症，但我不會向它屈服，”薩伯爾說。“這將是它和我的一場大戰役。”
