Immunotherapy kills cancer, and organs too

As Chuck Peal lay in a Waterbury, Connecticut, emergency room one Sunday in early September, doctors furiously tried to make sense of his symptoms. Peal, 61, appeared to be dying and they were not sure why. He slipped in and out of consciousness, his blood pressure plummeted, his potassium levels soared and his blood sugar spiked to 10 times the normal level. A doctor suspected a heart attack, but uncertainty left him urgently researching the situation on his phone.

This 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 aimed at saving his life. In the seven weeks prior, doctors at Yale University had combated Peal’s melanoma with two of the most promising drugs in cancer treatment today. These medicines work by stimulating the immune system to attack cancer as ferociously as it does other threats.

Immunotherapy drugs have been hailed as a breakthrough in cancer treatment, attracting billions of research dollars and offering new hope to patients out of options. But as their use grows, doctors are finding that they pose serious risks that stem from the very thing that makes them effective. An unleashed immune system can attack healthy, vital organs.

Doctors at Yale believe immunotherapy is causing a new type of acute-onset diabetes, with at least 17 cases there so far, Peal’s among them. In cancer clinics around the world, and in drug trials, myriad other side effects are showing up. Studies are finding that severe reactions occur nearly 20% of the time with certain drugs, and in more than half of patients when some drugs are used in combination.

Another paper found that 30% of patients experienced “interesting, rare or unexpected side effects,” with a quarter of reactions described as severe, life-threatening or requiring hospitalisation. Some patients have died, including five in recent months in clinical trials of a new immunotherapy drug being tested by Juno Therapeutics Inc. The upshot, oncologists and immunologists say, is that the medical field must be vigilant as these drugs soar in popularity. They say research is needed into who is likely to have reactions and how to treat them.

“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.

The rub, doctors and researchers say, is that the medical system is too often caught off guard. 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.

Meanwhile, these drugs are moving from the academic centres into cancer clinics, 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 — $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, who reviews immunotherapy-related grants for the US government.

It is “a massively understudied area,” Murphy said, adding, “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, 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. Peal 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.

Illusion of hope
Now she could offer Peal hope. Consider: One study co-authored by Kluger found positive responses in more than 40% of advanced melanoma patients when they used a combination of two major immunotherapy drugs, nivolumab and ipilimumab.

Peal, an engineering technician, 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. He visited Kluger’s office, where he was given a steroid. The next day, he had a fever, nausea and was “dying of thirst ,” he said. He threw up everything. In four days, 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, Keating, his girl friend recalled.

But even Kluger’s experienced team, which answered the distressed phone calls, 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 spiraled 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. 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.

Murphy, the professor at Davis who believes too little is being done, said, part of the problem, 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.