An unleashed immune system can attack healthy, vital organs, notably the bowel, the liver and the lungs, but also the kidneys, the adrenal and pituitary glands, the pancreas and, in rare cases, the heart.
As Chuck Peal lay in a Waterbury, Conn., emergency room one Sunday in early September, doctors tried to make sense of his symptoms. Peal, 61, appeared to be dying and they were not sure why.
A doctor suspected a heart attack, but uncertainty left him researching the situation on his phone. It was not a heart attack. Peal’s body was attacking itself, a severe reaction by his immune system that was a side effect of a seemingly miraculous cancer treatment.
In the previous seven weeks, doctors at Yale University had combated Peal’s melanoma with two of the most promising drugs in cancer treatment. These medicines work by stimulating the immune system to attack cancer as ferociously as it kills other threats, such as viruses and bacteria.
Immunotherapy drugs have been hailed as a breakthrough in cancer treatment, attracting billions of research dollars and offering new hope to patients. But as their use grows, doctors are finding that these therapies pose serious risks that stem from the very thing that makes them effective: An unleashed immune system can attack healthy, vital organs, notably the bowel, the liver and the lungs, but also the kidneys, the adrenal and pituitary glands, the pancreas and, in rare cases, the heart.
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Doctors at Yale believe immunotherapy is causing a new type of acute-onset diabetes, with at least 17 cases there, Peal among them. In cancer clinics around the world, and in drug trials, myriad other side effects are showing up. Studies are finding some drugs cause severe reactions nearly 20 percent of the time, and in more than half of cases when some drugs are used in combination.
Another recent paper found that 30 percent of patients experienced “interesting, rare or unexpected side effects,” with a quarter of reactions described as severe, life-threatening or requiring hospitalization. Some patients have died, including five in recent months in clinical trials with a new immunotherapy drug being tested by Juno Therapeutics.
The upshot, oncologists and immunologists say, is that the medical field must be more vigilant as these drugs soar in popularity.
“We are playing with fire,” said Dr. John Timmerman, an oncologist and immunotherapy researcher at UCLA, who recently lost a patient to side effects. The woman’s immunotherapy drugs had successfully “melted away” her cancer, he said, but some weeks later, she got cold and flulike symptoms, and died in the emergency room from an inflammatory response that Timmerman described as “a mass riot, an uprising” of her immune system.
“We’ve heard about immunotherapy as God’s gift, the chosen elixir, the cure for cancer,” he said. “We haven’t heard much about the collateral damage.”
Despite the warnings, doctors like Timmerman remain hugely supportive of drugs that are saving the lives of people who otherwise would die. Far better to cope with diabetes, hepatitis or arthritis, the thinking goes, than to die. Most reactions are not nearly so bad and are treatable.
With lives to be saved and billions of dollars to be made — $250,000 or more is the list price for a year of some regimens — not enough research has been done into the risks of the new therapies, said William Murphy, a professor of dermatology at the University of California, Davis. “The number-one priority is anti-tumor effects. Everything else, however severe, is considered the price worth paying.”
Caught in the middle are patients like Peal.
Peal was dealing with melanoma that had spread to tumors in his lungs in June 2015, when he saw a Yale oncologist, Dr. Harriet Kluger. In the past, a patient like him would have been given little chance.
“We’d sit the patient down and say, ‘I’m really sorry, the median life expectancy is nine months. Get your affairs in order,’ ” said Kluger, who runs immunotherapy clinical trials, focusing on skin and kidney cancer.
Now she could offer Peal hope. Consider: One study co-authored by Kluger found positive responses in more than 40 percent of advanced melanoma patients when they used a combination of two immunotherapy drugs, Nivolumab and Ipilimumab.
Peal started taking Nivolumab and Ipilimumab on July 8. Kluger told him he might feel drowsy or nauseated, or he could get a rash. A rash struck with a vengeance on Aug. 30, red welts from his knees to his waist; on Sept. 1, a Thursday, he visited Kluger’s office, where he was given a steroid.
The next day, he had a fever, nausea and was “dying of thirst — like beyond being in the desert,” he said. His girlfriend, Jo-ann Keating, called Kluger’s office, and an on-call doctor prescribed an anti-nausea drug. Keating called back to say it was not working and was prescribed a second anti-nausea drug. By Sunday, Peal, unable to move, took an ambulance to the emergency room.
Peal’s family told the emergency-room doctor about the treatment, recalled Keating.
“The doctor kept on saying he was on chemotherapy,” she recalled. “I said, ‘They’re calling it immunotherapy.’ He went on his phone and started looking for information.”
But even Kluger’s experienced team, which answered the distressed phone calls that weekend, did not react immediately to the symptoms. “It took us by surprise,” Kluger said.
Peal spent 24 days in the hospital. First his pancreas failed, then his bowels inflamed and his kidneys became dysfunctional, and “to top it off, he has a fever of 103 for which we can’t find a source,” Kluger said in an interview during the crisis.
Peal had gone into diabetic ketoacidosis, a condition in which the body, desperate to compensate for energy it was missing when his pancreas shut down, created a flux of acid that could keep him functioning in the short term, at the risk of gravely harming his organs.
The pancreas problem is particularly noteworthy. It is among a growing number of such cases that have led a Yale endocrinologist, Dr. Kevan Herold, an authority on autoimmunity, to conclude he is seeing a new form of Type 1 diabetes. Typically, the peak age of onset is between 6 and 12, and it involves the immune system destroying, bit by bit, the cells in the pancreas that make the insulin needed to metabolize sugar into energy.
But this is different: Patients are 50 or older and losing insulin production all at onceHerold said he was hearing similar stories from peers around the country. “A single case like this is uncommon,” he said. “As an aggregate, it’s unheard-of.”
Peal now takes multiple insulin shots each day but feels the trade-off is well worth it. “I can deal with diabetes,” he said, “if I can beat melanoma.”
In the mid-1990s, Matthew Krummel, an immunology graduate student, worked at a lab at the University of California, Berkeley, that would become one of the most influential in the development of immunotherapy. The lab was run by Dr. James Allison, who, along with Krummel, published a seminal paper in 1995 showing they could eliminate tumors in mice by turning off a brake on the immune system.
The lab got less attention for a related experiment: The skin of some mice treated this way would turn from black to white. They had lost their pigmentation, the result of the immune system attacking the cells that make melanin. The change was not life-threatening but indicated the power of tinkering with the immune system.
It was novel but not particularly celebrated compared with the promise of curing cancer.
Then came the TeGenero tragedy in 2006.
TeGenero Immuno Therapeutics designed a drug to stimulate the immune system to fight leukemia. At Northwick Park Hospital in London, a Phase 1 trial took place, with six healthy patients getting the drug. Within hours, all suffered multiorgan failure.
The results suggested more work needed to be done, but enthusiasm came roaring back.
“It’s the nature of the beast,” said Martin Bachmann, a professor and immunologist at the Jenner Institute, which is affiliated with Oxford University. “I’m not sure you can get rid of the side effects; it’s really what you want.”
Chemotherapy, too, has side effects, but Kluger prefers immunotherapy’s trade-offs because the drugs may offer enduring control of cancer without the need for continued treatment.