Immune System, Unleashed by Cancer Therapies, Can Attack Organs

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As Chuck Peal lay in a Waterbury, Conn., emergency room one Sunday in early September, doctors furiously tried to make sense of his symptoms. Mr. 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.

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This was not a heart attack. Mr. 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 had combated Mr. 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, like viruses and bacteria.

These so-called 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: 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 so far, Mr. 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 percent of the time with certain drugs, and in more than half of patients 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 the reactions described as severe, life-threatening or requiring hospitalization. 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 more vigilant as these drugs soar in popularity. And they say more research is needed into who is likely to have reactions and how to treat them.
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“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 Dr. 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 Dr. 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 now 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 academic centers 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 — $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, who reviews immunotherapy-related grants for the government.

It is “a massively understudied area,” Dr. Murphy said, adding: “The No. 1 priority is anti-tumor effects. Everything else, however severe, is considered the price worth paying.”

Caught in the middle are patients like Mr. 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

Mr. 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 Dr. Kluger, who runs immunotherapy clinical trials focusing on skin and kidney cancer.

Now she could offer Mr. Peal hope. Consider: One study co-authored by Dr. Kluger found positive responses in more than 40 percent 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 hospitalization or were life-threatening 54 percent of the time.

“It’s at least that high, at least,” Dr. 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 tumors in mere days.

Mr. Peal, an engineering technician who tests the performance of helicopter parts, started taking nivolumab and ipilimumab on July 8. Dr. Kluger told him he might feel drowsy or nauseated, or he could get a rash. A rash indeed struck with a vengeance on Aug. 30: red welts from his knees to his waist. On Sept. 1, a Thursday, he visited Dr. 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 Dr. Kluger’s office, and an on-call doctor prescribed an antinausea drug. Later, Ms. Keating called back to say it was not working, and he was prescribed a second antinausea drug. By Sunday morning, Mr. Peal, unable to move, took an ambulance to the emergency room.
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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.” Mr. Peal’s family told the emergency room doctor about the treatment, Ms. Keating recalled.

“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 Dr. 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,” Dr. Kluger said. Part of the problem, she thinks, is that Mr. 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, Mr. 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,” Dr. 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. Mr. 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 metabolize 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. Dr. 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, Conn., who was being treated by Dr. Kluger for late-stage kidney cancer. Ms. Platt opted for a clinical trial involving two immunotherapy drugs, atezolizumab and a second drug that Dr. Kluger declined to name because the trial is continuing.

Days after the second treatment in November 2014, Ms. Platt started feeling dizzy and numb and was vomiting water. She went to Dr. Kluger’s office, where they did lab tests that “were so profoundly abnormal, we thought this was lab error,” Dr. Kluger recounted. “We thought the machine was messed up.”

The tests were right. Like Mr. Peal, Ms. 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 Ms. Platt to comfort her, Dr. Kluger called the drug company to report the extraordinary reaction.

Today, like Mr. Peal, Ms. 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, Dr. Kluger recommended Ms. Platt continue with treatment, which she did.

“Her pancreas isn’t coming back,” Dr. Kluger said, referring to the diabetic effects of immunotherapy. “She has her life.”

Mr. Peal — who, like Ms. Platt, agreed to let Dr. Kluger and Dr. 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 that 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 Dr. Krummel, published a seminal paper in 1995 showing that they could eliminate tumors 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’s 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, Dr. 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 that 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 Dr. 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 recognized before turning dangerous, and how should they be treated?

In June, Dr. Kluger and Dr. 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.

Thus far, 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 Dr. 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, Dr. Murphy said, human trials are advancing faster than the background research can be done.

Hoping to push access to lifesaving drugs, the 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,” Dr. 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. Dr. Timmerman, from U.C.L.A., 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 flulike 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,” he said.

“You have to manage this hour by hour,” he added. “Minute by minute.”

Chemists officially add new elements to the periodic table

Jav hdKids have to memorize four new elements, now that the powers that be in the world of chemistry have expanded the periodic table. The International Union of Pure and Applied Chemistry has accepted the official names for elements 113, 115, 117 and 118, which it recognized in late December 2015. Previously known by their unappealing placeholder names ununtrium, ununpentium, ununseptium and ununoctium, the elements have been christened Nihonium (Nh), Moscovium (Mc), Tennessine (Ts) and Oganesson (Og), respectively.

These four superheavy elements -- they break down into lighter elements quickly -- were synthesized between 2002 and 2010 by Japanese, Russian and American teams. The scientists sent in their name proposals in June but had to go through a five-month waiting period.

Wondering how the teams came up with those names? The Japanese researchers who created element 113 based Nihonium from the word "Nihon," which means Japan in the country's language. Element 115's Russian creators named it Moscovium after Moscow, while their countrymen who made element 118 (with the help of American scientists) named theirs Oganesson after Yuri Oganessian. He's a Russian nuclear physicist who helped discover the heaviest elements in the periodic table. Finally, the Oak Ridge National Laboratory scientists, who also helped create element 115, named element 117 Tennessine after their home state of Tennessee.

It appears machines may already be catching up to humans, at least in the world of computational biology. A team of researcher's at the MIT-based Center for Brains, Minds and Machines (CBMM) found that the system they designed to recognize faces had spontaneously come up with a step that can identify portraits regardless of the rotation of the face. This adds credence to a previous theory about how humans recognize faces that was based on studies of MRIs of primate brains.
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The as-yet-unnamed system is a computational model of how the human brain recognizes faces, and was trained to identify particular visages from a battery of sample images it was fed. In the process of learning to spot faces, the program created an intermediate processing step that looked at "a face's degree of rotation - say 45 degrees from center - but not the direction."

In layman's terms, this means the system, which was looking for invariance (or non-difference) between faces, was able to do so regardless of whether a face was flipped, as long as it was rotated in the same angle. That property is known as "mirror symmetry."

This discovery excites scientists because it duplicates a previously observed feature of how primates process faces, indicating that the system might be doing something similar to the brain. However, it's not for sure. "This is not a proof that we understand what's going on," says Tomaso Poggio, a professor of brain and cognitive sciences at MIT and director of the CBMM.

The researchers' machine-learning system in this case is a neural network, which has been employed by tech giants such as Microsoft, Google and Facebook. These companies all have their own facial recognition systems in place, and have been investing in machine-learning to enhance their tools.
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Understanding how we recognize people could help facial recognition systems get significantly better and more accurate, which has vast applications in tech. Face unlock is an increasingly popular feature of phones and laptops, and identifying people in photos lets companies like Facebook, Apple and Google better sort your photos. The downside, if you choose to see it that way, is that surveillance systems could also get pictures accurate at finding the exact individuals they wish to seek from the endless amount of security camera footage and DMV photos they have. While this is clearly in early stages, and a tiny step towards implementing human-level facial recognition in machines, it certainly is a sign that artificial intelligence is capable of replicating specific functions of the human brain.

Unmanned ISS cargo ship burns up on way to ISS: Russia

Jav onlineAn unmanned cargo ship travelling to the International Space Station burned up in the atmosphere shortly after lauching Thursday, the Russian space agency said, raising concerns over space travel safety.

"According to preliminary information, as a result of an abnormal situation, the cargo ship's loss occurred some 190 kilometres above the remote, unpopulated mountainous territory of (Russia's) Tuva region, and most fragments burned up in dense layers of the atmosphere," Roscosmos said in a statement.

Roscosmos said earlier Thursday that it had lost contact with the Progress MS-04 ship 383 seconds after it launched from the Baikonur cosmodrome in Kazakhstan, and that its specialists were looking into the problem.

The space agency said the loss of the cargo ship will "not affect the normal operations of the ISS systems and the subsistence of the station's crew".

NASA meanwhile said on its website that supplies at the space laboratory are "at good levels".

The cargo ship, which had been scheduled to arrive at the ISS on Saturday, was carrying 2.4 tonnes of fuel, food and equipment when it took off from Baikonur, Roscosmos said.

- Second failed launch -

The Russian agency said a state commission would probe the incident but did not say whether it would affect future launches.

This latest incident represents the second failed launch of a Progress cargo ship in less than two years.
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In April 2015 a Progress ship disintegrated as it plummeted to Earth, a failure Russia blamed on a problem with a Soyuz rocket.

The incident saw Russia put all space travel on hold for nearly three months and forced a group of astronauts to spend an extra month on the ISS.

Russia said at the time that because the same type of rocket is used for manned ships, all issues with Progress resupply missions needed to be thoroughly investigated before any manned vessels could be launched.

Russia sends three or four such spacecraft per year to supply the ISS. After making their delivery, they plummet back to Earth, burning up in the atmosphere above the Pacific Ocean.

Last month Frenchman Thomas Pesquet, Russian cosmonaut Oleg Novitsky and American astronaut Peggy Whitson launched to the ISS for a six-month mission.

The launch followed that of Russians Andrei Borisenko and Sergei Ryzhikov and American Shane Kimbrough in October, which was pushed back by nearly a month due to technical issues.

Technical mishaps have complicated plans to extend the periods during which the ISS is fully staffed with six astronauts.
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Russia's Soyuz capsules offer the only way for global astronauts to reach the space station since the American space shuttle programme was retired in 2011.

The space laboratory, where a range of research is carried out, has been orbiting Earth at about 28,000 kilometres per hour (17,000 miles per hour) since 1998.