Immunotherapy treatment carries risks

Drugs used to fight cancer can leave many vital organs vulnerable to attack

As Chuck Peal lay in a Waterbury, Conn., emergency room 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 sav- ing 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 stimulate the immune system to attack cancer as ferociously as it kills other threats, like viruses and bacteria.

‘Playing with fire’

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 these therapies pose serious risks that stem from the very thing that makes them effective: An unleashed immune system can attack healthy, vital or- gans, 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.

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 and in drug trials, myriad other side effects are showing up. Studies are finding that 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 Inc.

The upshot, oncologists and immunologists say, is that the medical field must be more vigilant as these drugs soar in popularity. And they say more research is needed into who is likely to get 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 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.”

Caught off guard

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.

The rub, doctors and researchers say, is that the medical system 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 centers 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, 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-tumor effects. Everything else, however severe, is considered the price worth paying.”