Harnessing the Immune System to Fight Cancer
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.
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.'”
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.
“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.
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.
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.
Checkpoint inhibitors have become an important option for people like Cara, with advanced lung cancer.
“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.
One Patient’s Story
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.
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.
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.
As the name suggests, checkpoint inhibitors block the checkpoints, so cancer cannot use them to turn off the immune system.
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.
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.
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.
His tumor had shrunk by a third.
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.
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.
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.
“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.”
As of now, he needs no further treatment, but he will be monitored regularly. He is back to work, and golf.
“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.”
Helping Some, but Not Others
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.
The vexing question, and the focus of research, is, why?
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.
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.
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.
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.
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.
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.
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.
“I have aggressive cancer, but I’m not giving in to it,” Sabol said. “It’s going to be a big battle with me.”