An unleashed immune system can attack healthy organs as well as cancer

"We are playing with fire," said Dr John Timmerman, an oncologist and immunotherapy researcher at the University of California, Los Angeles, 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 flu-like 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, physicians like Timmerman remain hugely supportive of drugs that are saving the lives of people who would otherwise 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.

The rub, doctors and researchers say, is that the medical system – from front-line nurses to oncologists to emergency rooms – is too often caught off guard. This is happening for a number of reasons: The drugs are new so many side effects just have not been seen. Symptoms appear at random, sometimes months after treatment, and can initially seem innocuous. Finally, oncologists are trying to treat patients with a combination of two or more immunotherapy drugs, hoping for more effective treatment but sometimes getting amplified risks.

In the meantime, these drugs are moving from the academic centres into cancer clinics across the country, where oncologists in smaller cities most likely have less experience with the side effects.

And with lives to be saved and billions of dollars to be made – $US250,000 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, who reviews immunotherapy-related grants for the government.

It's "a massively understudied area," Murphy said, adding: "The number one priority is anti-tumour effects. Everything else, however severe, is considered the price worth paying."

Caught in the middle are patients like Peal, whose stories show the delicacy of tinkering with the immune system. It may hold the keys to curing cancer if it can be at once stoked and tamed.

Real Promise, and Real Risks

Peal, bespectacled and lean, was dealing with melanoma that had spread to 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-written by Kluger found positive responses in more than 40 per cent of advanced melanoma patients when they used a combination of two major immunotherapy drugs, nivolumab and ipilimumab.

Other research, however, shows that the promise comes with real risks. A 2015 paper in The New England Journal of Medicine showed that use of these drugs carried a risk of side effects that were severe, required hospitalisation or were life-threatening 54 per cent of the time.

"It's at least that high, at least," Kluger said. But, she noted, most of the side effects are manageable through immune suppression, such as with steroids.

The effectiveness of immunotherapy drugs and their side effects are intimately bound by the same biological mechanisms.

Called "checkpoint inhibitors," the drugs work by essentially reversing a trick that cancer plays on the immune system: The cancer cells send nefarious signals to immune-system cells that cause them to stand down. Cancer is turning on the immune system's brake.

There is a valuable reason the brake exists: It can shut down the body's powerful defenders so that they do not inadvertently attack the body itself. Cancer is taking advantage of this key survival mechanism.

When an immunotherapy drug turns the brake off, the immune system can sometimes shrink tumours in mere days.

Peal, an engineering technician who tests the performance of helicopter parts, 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 indeed struck with a vengeance on August 30: red welts from his knees to his waist. On September 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. He threw up everything. His girlfriend, Jo-ann Keating, called Kluger's office, and an on-call doctor prescribed an anti-nausea drug. Later, Keating called back to say it was not working and was prescribed a second, anti-nausea drug. By Sunday morning, Peal, unable to move, took an ambulance to the emergency room.

In his wallet, he kept an information card published by Bristol Myers Squibb. It lists dozens of risks, including that the therapy "can cause serious side effects in many parts of your body, which can lead to death." Peal's family told the emergency room doctor about the treatment, recalled Keating.

"The doctor kept on saying he was on chemotherapy," she said. "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, was caught off guard and did not react immediately to the symptoms.

"It took us by surprise. He looked absolutely fine on Friday," Kluger said. Part of the problem, she thinks, is that Peal was relatively new to the clinic and so she and her staff members did not have the experience with him to accurately assess his symptoms. "It also happened very quickly. It spiralled within hours."

Ultimately, Peal spent 24 days in the hospital, where trouble mounted. 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. She was trying to figure it out and had emailed other experts around the country to see if they had ever had a patient with this combination of acute immune reactions. No one had seen it before.

The pancreas problem was particularly noteworthy. Peal's is among a growing number of such cases that have led a Yale endocrinologist, Dr Kevan Herold, an authority on autoimmunity, to conclude that he is seeing a new form of Type 1 diabetes. Typically, the peak age of onset of Type 1 diabetes is 6 to 12, and it involves the immune system's destroying, bit by bit, the cells in the pancreas that make the insulin needed to metabolise sugar into energy.

But this is different: Patients are 50 or older and are losing insulin production all at once, including in one case of an 83-year-old. Herold 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."

Another case at Yale involved Colleen Platt, 65, a real estate agent from Torrington, Connecticut, who was being treated by Kluger for late-stage kidney cancer. Platt opted for a clinical trial involving two immunotherapy drugs, atezolizumab and a second drug that Kluger declined to name because the trial is continuing.

Days after the second treatment in November 2014, Platt started feeling dizzy and numb and was vomiting water. She went to Kluger's office, where lab tests were done that "were so profoundly abnormal, we thought this was lab error," Kluger recalled. "We thought the machine was messed up."

The tests were right. Like Peal, Platt had gone into diabetic ketoacidosis, a condition in which her body, desperate to compensate for energy it was missing when her pancreas shut down, created a flux of acid that could keep her functioning in the short term, at the risk of gravely harming organs throughout her body. Outside the emergency room, while a chaplain visited Platt to comfort her, Kluger called the drug company to report the extraordinary reaction.

Today, like Peal, Platt takes multiple insulin shots each day, and still her sugar level fluctuates wildly. On the other hand, immunotherapy has largely beaten her cancer. In fact, after consulting with other doctors and one of the drug companies, Kluger recommended Platt continue with treatment, which she did.

"Her pancreas isn't coming back," Kluger said, referring to the diabetic effects of immunotherapy. "She has her life."

Peal – who, like Platt, agreed to let Kluger and Herold discuss his case – feels the trade-off will be well worth it. In fact, on Friday, he got the results from a scan taken the day before and learned immunotherapy had eliminated two of his cancer lesions and shrunk two others. "I can deal with diabetes," he said, "if I can beat melanoma."

'Nature of the Beast'

Evidence of these challenges is decades old.

In the mid-1990s, Matthew Krummel, a young immunology graduate student known as Max, 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 tumours in mice by turning off a brake on the immune system.

But the lab got less attention for a related experiment: The skin of some mice treated this way turned from black to white. They had lost their pigmentation, a result of the immune system attacking the cells that make melanin. The startling change was not life-threatening but indicated the power of tinkering with the immune system.

This discovery was novel but not particularly celebrated compared with the promise of curing cancer, Krummel recalled. The skin study "was kind of a footnote," he said.

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 devastating results tempered the enthusiasm and suggested more work needed to be done in advance of human trials. But enthusiasm came roaring back. Part of the reason was that, ultimately, the autoimmune reactions were seen not only as an acceptable cost of these drugs but as evidence they were working.

"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. So she is joining others looking to address largely unanswered questions: Who is likely to be at risk, can the side effects be recognised before turning dangerous and how should they be treated?

In June, Kluger and Herold submitted a grant proposal to the National Institutes of Health to study whether they could predict which patients would develop these symptoms. They based the proposal on a hypothesis that some patients have a biology or a genetic background that might make them more likely to have side effects. The proposal has not yet been funded.

Only a modicum of work has been done on these questions. Several studies found that older mice were more susceptible than younger mice to autoimmune reactions; another study, also in mice, found that obese subjects were more likely to have adverse effects.

"Old or fat mice were literally dead within hours," said Murphy, the professor at Davis who believes too little is being done. He is well positioned to see the trends: In the past year, he sat on eight government grant review committees focused on immunotherapy, and he said only three out of 500 research proposals he reviewed focused on the toxicity side of immunotherapy.

Part of the problem, he said, is that the drug companies that are driving research prefer working with labs that support trials moving quickly. As a result, Murphy said, human trials are advancing faster than the background research can be done.

Hoping to push access to lifesaving drugs, the US Food and Drug Administration has a "breakthrough therapy designation" that allows faster approval. Since 2012, the agency has granted breakthrough designation about 110 times, almost a quarter of them for immunotherapy.

"When people talk about moonshots, they're talking about curing cancer, but it has to look at the whole picture," Murphy said.

With so much momentum pushing for a cure, the emphasis from researchers and front-line oncologists is on more vigilance about the side effects. Timmerman, from UCLA, said he wished he had seen the signs of trouble in his patient, who survived cancer only to die in the emergency room after exhibiting seemingly modest flu-like symptoms.

"If we had only known the power we had unleashed that was causing such a toll on her organ system, we might have saved her."

"You have to manage this hour by hour," he said. "Minute by minute."

The New York Times