03 March 2017

Complications of immunotherapy

The immune system, which is stimulated during cancer treatment, can attack healthy organs

Immune System, Unleashed by Cancer Therapies, Can Attack Organs Matt Richtel, The New York Times, Dec. 3, 2016

Translation: Alexander Gorlov, XX2 century

Waterbury, Connecticut, early September, Sunday. While Chuck Peel was in the emergency room, doctors struggled to make sense of his symptoms. The 61-year-old Saw seemed to be dying, and why, it was not very clear.

Peel's consciousness kept coming back to him, then going away, his blood pressure dropped sharply, his potassium level soared, and his blood sugar level was 10 times higher than normal. The doctor suspected a heart attack, but uncertainty forced him to continue urgently investigating the situation over the phone.

It wasn't a heart attack. Peel's body was tormenting itself–a cruel reaction of his immune system, a side effect of what seemed to be a miraculous cancer treatment that was supposed to save the patient's life.

For the past seven weeks, doctors at Yale University have been battling Peel's melanoma using two drugs that are currently among the most promising in the treatment of cancer. These drugs stimulate the immune system to attack a cancerous tumor, and with the ferocity characteristic of such masters of attack as viruses and bacteria.

The use of these so-called immunotherapy drugs has been declared a breakthrough in the treatment of cancer. Such advertising raises billions of dollars for further research and gives new hope to patients who have no other options. But with the increasing use of immunotherapy drugs, it is becoming increasingly clear that they carry serious risks with them. The root of these risks lies in the very reason that makes the drugs effective. A stimulated immune system can attack healthy, vital organs, especially the intestines, liver and lungs, but also the kidneys, adrenal glands, pituitary gland, pancreas and, in rare cases, the heart.

Doctors at Yale University believe that immunotherapy causes a new type of rapidly progressing diabetes, they had at least 17 such patients, and Peel was among them. A myriad of other side effects have been identified in cancer clinics around the world and during drug testing. Studies show that serious complications are observed in almost 20 percent of cases of using a certain drug and in more than half of those cases when some drugs are used in combination.

Another recent study found that 30 percent of patients had "interesting, rare or unexpected side effects." A quarter of these reactions are classified as serious, life-threatening or requiring hospitalization. Some patients died, five of them during clinical trials conducted in recent months of a new immunotherapy drug developed by Juno Therapeutics Inc.

As a result, oncologists and immunologists say, medicine should become more vigilant towards immunotherapy drugs, despite their rapidly growing popularity. And, in addition, they believe, additional research is needed to find out who is most likely to have unwanted side effects and how to treat them.

"We're playing with fire," said Dr. John Timmerman, an oncologist and immunotherapy researcher at the University of California, Los Angeles, who recently lost a patient due to side effects. According to the doctor, immunotherapy drugs successfully "dissolved" her cancer, but a few weeks later she caught a cold and the symptoms of her illness resembled the flu. The woman died in the intensive care unit from an inflammatory process that Dr. Timmerman described as a "mass riot, an uprising" of her immune system.

"We were told about immunotherapy as a gift from God, a unique elixir, a cure for cancer," he said. "We were told almost nothing about collateral damage."

Despite the warnings, doctors like Dr. Timmerman remain extremely supportive of drugs that save from death those who cannot survive without them. The logic is this: it is much better to fight diabetes, hepatitis or arthritis than to die. Most of the side effects are not so harmful and treatable.

The main obstacle, according to doctors and researchers, is that the main links of the oncological care system (emergency room nurses – oncologists – intensive care units) too often get into unexpected situations. This happens for a number of reasons. Firstly, since the drugs are new, many of the side effects they cause simply did not have time to identify. Secondly, these effects occur unpredictably, sometimes months after treatment, and at first may seem harmless. Finally, currently, in order to treat patients more effectively, oncologists are trying to use a combination of two or more immunotherapy drugs. At the same time, the risks sometimes increase.

Meanwhile, immunotherapy drugs from research centers end up in urban cancer clinics across the country, and the smaller the city, the less likely local oncologists know about side effects.

As for the lives that will be saved and the billions of dollars that will be spent on it – some treatments cost $250,000 a year or more at the price list – the risks of new forms of therapy have not been sufficiently investigated, says William Murphy, professor of dermatology at the University of California at Davis (University of California, Davis), which oversees subsidies allocated to local authorities for the development of immunotherapy.

According to Dr. Murphy, "almost nothing is known about the risks associated with immunotherapy." "First of all, anti-cancer effects should be studied. The remaining effects, albeit very serious, are considered a price worth paying," he added.

Patients like Peel were caught between two fires. Their stories demonstrate the sensitivity of reshaping the immune system. It can be the key to cancer treatment if it is both inciting and taming at once.

Real prospects and real risks

In June 2015, when Mr. Peel, skinny, wearing glasses, was struggling with melanoma that had reached his lungs, he met with Yale oncologist Dr. Harriet Kluger (Harriet Kluger). In the past, patients like him had almost no chance of getting better.

"We would sit the patient down and address him like this: "We are sincerely sorry, but you have about nine months left. Get your affairs in order," said Dr. Kluger, who directs clinical research in the field of immunotherapy focused on the treatment of skin and kidney cancer.

Now she could give Mr. Peel hope. Judge for yourself: one of the studies conducted in collaboration with Dr. Kluger gave positive results for more than 40 percent of patients with advanced melanoma who took two main immunotherapy drugs in combination – nivolumab (nivolumab) and ipilimumab (ipilimumab).

Another study, however, suggests that the expected therapeutic effect comes with real risks. According to a 2015 article published in The New England Journal of Medicine, the use of these drugs carried a risk of serious, hospitalization-requiring or life-threatening side effects in 54 percent of cases.

"That's a lot, to say the least," Dr. Kluger said. But, she noted, most of the side effects can be managed using suppression of the immune system, for example, with steroids.

The effectiveness of immunotherapy drugs and their side effects are closely related, since the same biological mechanisms work here and there.

Cancer turns on the brakes of the immune system, sending its cells vile signals that neutralize the immune defense. The same trick, in essence, but directed against cancer, is performed by immunotherapy drugs. For this, they are called immune checkpoint inhibitors.

Inhibition of the immune system can be useful: it can stop powerful defenders of the body, so that the body itself does not accidentally suffer from their attack. Cancer uses this extremely important survival mechanism for the body to its advantage.

When an immunotherapy drug turns off the brake of the immune system, immune cells in some cases can significantly reduce the tumor in a matter of days.


Mr. Peel, a technical engineer who tests the operation of helicopter nodes, began taking nivolumab and ipilimumab on July 8. Dr. Kluger told him that drowsiness or nausea, the appearance of a rash, were possible. On August 30, a rash really appeared profusely: red blisters from the knees to the waist. On Thursday, September 1, Dr. Kluger, after examining the Saw in his office, prescribed him a steroid.

The next day, Peel experienced bouts of fever, nausea and, according to him, "was dying of thirst – worse than in the desert." He was sick of everything. Peel's friend Joanne Keating called Dr. Kluger's office, and the doctor on duty prescribed pills for nausea. A little later, Mrs. Keating called again to say that the medicine was not working, and the doctor prescribed other pills. On Sunday, in the early morning, Drinking, unable to move independently, called an ambulance, and he was taken to the emergency department.
In Peel's wallet was an information card of the pharmaceutical company "Bristol-Myers Squibb" (Bristol-Myers Squibb) with a long list of risks that the cardholder should keep in mind. In particular, she informs Peel that therapy "can cause serious side effects in many organs of your body that can lead to death." The Peel family, Mrs. Keating recalls, notified the doctor from the emergency department about the treatment that Peel was undergoing.

"The doctor kept saying that Peel had chemotherapy," she says. – I corrected him: "It's called immunotherapy." He took out his phone and started looking for information."

But even the experienced team of Dr. Kluger, who responded to the calls of a concerned doctor from the emergency department that Sunday, was caught off guard and did not immediately determine how to respond correctly to the symptoms that appeared in Peel.

"We were terribly surprised. He looked great on Friday," Dr. Kluger said. In her opinion, part of the problem arose due to the fact that Peel became a patient of the clinic relatively recently. So she and her staff did not have the opportunity to accurately assess his condition. "Besides, everything happened very quickly. The patient's health deteriorated dramatically in a matter of hours."

As a result, Peel spent 24 days in the hospital, and he was getting worse and worse. First, his pancreas failed, then his intestines became inflamed and his kidneys failed. "To top it all off, he keeps regaining consciousness, then losing it, and why is unclear," Dr. Kluger said in an interview she gave during this crisis. She tried to sort out the situation and contacted other experts from all over the country by email to find out if they had ever had a patient with a similar set of acute immune reactions. It turned out that there wasn't.

Of particular note is the failure of the pancreas. The number of cases when such a problem arises is growing, and this has led Yale endocrinologist Dr. Kevan Herold, a major expert in the field of autoimmune processes, to the conclusion that there is a new form of type one diabetes. As a rule, this disease manifests itself in children aged 6 to 12 years. The immune system gradually destroys the cells of the pancreas, which produce insulin, which is necessary for the metabolic conversion of sugar into energy.

And now the picture of the disease has become different: the age of patients is 50 years or more (in one case, 83 years), while the production of insulin by cells stops abruptly. Similar stories, says Dr. Herold, were told to him by colleagues from different parts of the country. "Every such case is unusual," he said. "As a whole, this is unheard of."

And here's another Yale case: the patient is 65–year-old Colleen Platt, a real estate agent from Torrington, Connecticut. Dr. Kluger treated her for end-stage kidney cancer. Mrs. Platt chose a clinical trial using two immunotherapy drugs: atezolizumab and a second drug, the name of which Dr. Kluger preferred to keep secret, since the study is still ongoing.

A few days after the second course of treatment in November 2014, Mrs. Platt began to experience dizziness and numbness of her limbs. She was vomiting watery liquid. She underwent laboratory testing at Dr. Kluger's office. The results, says Dr. Kluger, "were so abnormal that we thought there was a mistake. It seemed to us that it was a malfunction of laboratory equipment."

But the testing was done correctly. Like Mr. Peel, Mrs. Platt has entered a state of diabetic ketoacytosis, in which her body, desperate to compensate for the loss of energy due to the failure of the pancreas, creates an acid flow that can maintain the functioning of the body for a short time, but creates a serious threat to all organs. After leaving the emergency room, when the priest came there to calm Mrs. Platt, Dr. Kluger contacted the pharmaceutical company and reported an extraordinary reaction to immunotherapy drugs.

Now, like Mr. Peel, Mrs. Platt takes insulin several times a day, and yet her blood sugar level is dancing wildly. On the other hand, immunotherapy has significantly displaced her cancer. As a result, after consulting with other doctors and with representatives of one of the pharmaceutical companies, Dr. Kluger recommended that Mrs. Platt continue the course of treatment she had begun.

"Her pancreas cannot be cured," Dr. Kluger said, commenting on the diabetic effects of immunotherapy that Mrs. Platt showed. "That's her life."

Mr. Peel, who, like Mrs. Platt, has allowed Dr. Kluger and Dr. Herold to deal with his illness, feels that the deal has turned out well. And indeed: on Friday, Peel received the results of a scan performed the day before, and learned that immunotherapy had rid his body of two foci of cancer, and made two less. "I can deal with diabetes," he said, "if I can beat melanoma."

"Animal Nature"

Decades have been talking about these problems.

In the mid-1990s, Matthew Krummel, a young graduate immunologist known as Max, worked in the laboratory of the University of California, Berkeley, which later became one of the most influential centers for the development of immunotherapy. The laboratory was led by Dr. James Allison. In 1995, he and Krummel published the results of a fundamental study according to which tumors can be eliminated in mice by turning off the brake of the immune system.

Less interest was aroused by a side effect of an experiment conducted in the laboratory: the skin of some mice subjected to immunotherapy changed its color from black to white. As a result of the immune system's attack on the cells that produce melanin, the fur has lost pigmentation. This amazing effect was not life-threatening for mice, but it showed how serious the consequences of the amendments made to the immune system can be.

This discovery was extraordinary, but it was overshadowed by something else – something that promised to cure cancer, recalls Dr. Krummel. The results of the mouse fur study "were text for a footnote," he added.

Then, in 2006, the tragedy of TeGenero occurred.

TeGenero Immuno Therapeutics has created a drug that stimulates the immune system to fight leukemia. A phase one clinical trial was conducted at Northwick Park Hospital in London, during which six healthy volunteers took a new drug. In a matter of hours, all the test participants earned multiple insufficiency of internal organs.

This devastating result dampened enthusiasm and made us see that the work that preceded the testing of the new drug on humans was insufficient. But soon the enthusiasm was revived violently. Partly because, in the end, experts regarded undesirable autoimmune reactions arising from the use of new drugs not only as acceptable side effects, but also as evidence that these drugs work.

"This is the nature of the animal,– said Martin Bachmann, professor of immunology at the Edward Jenner Institute for Vaccine Research, which is affiliated with the University of Oxford. – I'm not sure that it is possible to get rid of side effects – in fact, this is what is needed."

Chemotherapy also has side effects, but Dr. Kluger prefers the compromise that immunotherapy offers, because immunotherapy drugs can sustainably control cancer without a long course of treatment. Thus, she joins those who want to answer questions that have largely remained unanswered: which of the patients is in danger, is it possible to identify dangerous side effects in advance and how to eliminate them?

In June, Dr. Kluger and Dr. Herold submitted a grant application to the National Institutes of Health to receive funds to conduct a study on the ability to predict which patients will have dangerous side effects. This study is based on the hypothesis that some patients have biological features or genetic predisposition that make the probability of side effects high. The application is still being considered.

To date, very little has been done to answer the above questions. A number of studies have found that older mice are more sensitive to autoimmune reactions; another study, which also involved mice, found that fullness increases the risk of adverse effects.

"Old or fat mice died literally in a matter of hours," says Dr. Murphy, a professor from Davis, according to whom there is too little research on this topic. It is very convenient for him to follow the development of immunotherapy: last year he participated in the work of eight state committees that considered applications from immunologists for grants, and, according to him, only three out of 500 applications are related to the study of the toxicity of immunotherapy.

Part of the problem, Murphy says, is that pharmaceutical companies that develop immunotherapy drugs prefer to deal with laboratories that move quickly from one trial to another. As a result, Dr. Murphy notes, human trials are moving too fast, and basic research is lagging behind.

Hoping to speed up access to life-saving drugs, the FDA has introduced a "breakthrough therapy status" that allows the drug to get approval faster. Since 2012, the agency has granted this status to approximately 110 drugs, and almost a quarter of them are immunotherapy drugs.

"When people talk about 'going to the moon,' they mean cancer treatment, but you need to see the big picture," Dr. Murphy said.

By making great efforts to treat cancer, oncologists – both researchers and attending physicians – are trying to pay more attention to side effects. Dr. Timmerman from the University of California at Los Angeles regrets that behind the rather modest symptoms resembling the flu, he did not see the deadly danger that crept up on his patient, and she survived cancer only to die in the emergency department.

"If we only knew that the force we released could cause fatal damage to her body, we could have saved her," the doctor said.

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

Portal "Eternal youth" http://vechnayamolodost.ru  03.03.2017

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