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PD-1 New Cancer immunotherapy Drugs Success - Adverse Events, HIV
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Download the PDF here
Download the PDF here
Download the PDF here
Download the PDF here
June 5, 2016
AASLD: Nivolumab in Patients With Advanced Hepatocellular Carcinoma: the CheckMate 040 Study - (11/16/16)
Nivolumab and Ipilimumab in Treating Patients With HIV Associated Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery
Objective Responses in Anal Carcinoma With PD-1 Inhibitor......There is no standard of care for patients with refractory metastatic squamous cell carcinoma of the anus (SCCA), but the anti PD-1 antibody nivolumab may have a role.......http://journals.lww.com/oncology-times/pages/articleviewer.aspx?year=2016&issue=08250&article=00014&type=Fulltext
Can immunotherapy cure HIV? - meeting at Fred Hutchinson Cancer Research Center last week - (08/10/16)
Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy - (08/10/16)
In the first-ever clinical trial for metastatic patients previously treated for the disease, research led by The University of Texas MD Anderson Cancer Center found that the immune checkpoint blockade nivolumab shows promise for the majority of patients with squamous cell carcinoma of the anal canal (SCCA)......Also of note, this is the first completed anti-PD1 study to include HIV-positive patients as well as patients with Hepatitis B or C. Two HIV-positive patients were enrolled in the trial........http://www.natap.org/2016/newsUpdates/060816_01.htm
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Immune System, Unleashed by Cancer Therapies, Can Attack Organs
NY times - Dec 3 2016 - see below fill text/link
"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.....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.
.....You have to manage this hour by hour," he added. "Minute by minute."......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?.....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."
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Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma......NEJM July 2016.....Conclusions: Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipilimumab alone. In patients with PD-L1-negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone. (Funded by Bristol-Myers Squibb; CheckMate 067 ClinicalTrials.gov number, NCT01844505.)....Results: The median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) with nivolumab plus ipilimumab, as compared with 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P<0.001), and 6.9 months (95% CI, 4.3 to 9.5) with nivolumab (hazard ratio for the comparison with ipilimumab, 0.57; 99.5% CI, 0.43 to 0.76; P<0.001). In patients with tumors positive for the PD-1 ligand (PD-L1), the median progression-free survival was 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group, but in patients with PD-L1-negative tumors, progression-free survival was longer with the combination therapy than with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] vs. 5.3 months [95% CI, 2.8 to 7.1]). Treatment-related adverse events of grade 3 or 4 occurred in 16.3% of the patients in the nivolumab group, 55.0% of those in the nivolumab-plus-ipilimumab group, and 27.3% of those in the ipilimumab group.
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Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma.....NEJM May 2015....."In summary, the combination of ipilimumab plus nivolumab resulted in durable responses and a substantially higher objective response rate, longer progression-free survival, and higher rates of complete response than ipilimumab monotherapy among patients with BRAF wild-type advanced melanoma and those with BRAF-mutant advanced melanoma. The incidence of grade 3 or 4 adverse events was higher with combination therapy, but adverse events were generally manageable when established safety guidelines were used. The risk-benefit profile of combined PD-1 and CTLA-4 blockade, as compared with monotherapy, will be further clarified by data from ongoing phase 3 double-blind, randomized trials, such as the CheckMate 067 study....Among patients with BRAF wild-type tumors, the rate of confirmed objective response was 61% (44 of 72 patients) in the group that received both ipilimumab and nivolumab (combination group) versus 11% (4 of 37 patients) in the group that received ipilimumab and placebo (ipilimumab-monotherapy group) (P<0.001), with complete responses reported in 16 patients (22%) in the combination group and no patients in the ipilimumab-monotherapy group. The median duration of response was not reached in either group. The median progression-free survival was not reached with the combination therapy and was 4.4 months with ipilimumab monotherapy (hazard ratio associated with combination therapy as compared with ipilimumab monotherapy for disease progression or death, 0.40; 95% confidence interval, 0.23 to 0.68; P<0.001). Similar results for response rate and progression-free survival were observed in 33 patients with BRAF mutation-positive tumors. Drug-related adverse events of grade 3 or 4 were reported in 54% of the patients who received the combination therapy as compared with 24% of the patients who received ipilimumab monotherapy. Select adverse events with potential immunologic causes were consistent with those in a phase 1 study, and most of these events resolved with immune-modulating medication."
Nivolumab/Ipilimumab Combination Shows Survival Benefit in Advanced Melanoma - April 2016 http://www.onclive.com/conference-coverage/aacr-2016/nivolumab-ipilimumab-combination-shows-survival-benefit-in-advanced-melanoma
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Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy.....June 1016 Eur J Cancer......."Nivolumab and pembrolizumab have been shown to enhance pre-existing immune responses including anti-tumour response by directly blocking programmed cell death receptor-1 (PD-1) which is a checkpoint of the effector stage of the immune system [1, 2]. While the response rate of ipilimumab-treated patients is around 10-15% [3, 4], response rates of pembrolizumab- and nivolumab-treated patients are 33% [5] and 32% [6], respectively."
Highlights
⋅Anti-PD-1 antibodies can induce a plethora of immune-related adverse events (irAEs).
⋅IrAEs of the skin, gastrointestinal tract, liver, endocrine and renal system were analyzed.
⋅Diabetes mellitus, lichen planus and pancreas insufficiency due to pancreatitis were reported.
⋅If symptoms are autoimmune-related, prompt treatment has to be initiated to reduce morbidity.
⋅Since irAEs can start asymptomatic or with minimal symptoms, careful monitoring is essential.
Abstract
Background
Anti-programmed cell death receptor-1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma as well as for other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects affect skin, gastrointestinal tract, liver, endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential.
Methods and findings
In total, 496 patients with metastatic melanoma from 15 skin cancer centers were treated with pembrolizumab or nivolumab; 242 side-effects were described in 138 patients. In 116 of the 138 patients, side-effects affected the skin, gastrointestinal tract, liver, endocrine, and renal system. Rare side-effects included diabetes mellitus, lichen planus, and pancreas insufficiency due to pancreatitis.
Conclusion
Anti-PD1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.
Introduction
Nivolumab and pembrolizumab have been shown to enhance pre-existing immune responses including anti-tumour response by directly blocking programmed cell death receptor-1 (PD-1) which is a checkpoint of the effector stage of the immune system [1, 2]. While the response rate of ipilimumab-treated patients is around 10-15% [3, 4], response rates of pembrolizumab- and nivolumab-treated patients are 33% [5] and 32% [6], respectively.
Grade 3-4 adverse events (AEs) are observed in 22-24% of ipilimumab-treated patients [7, 8], in 5-10% of nivolumab- and pembrolizumab-treated patients [5, 6] and in 54-55% of ipilimumab plus nivolumab-treated patients [8, 9]. A permanent discontinuation of therapy due to side-effects has been reported in 5% of patients treated with anti-PD-1 antibodies [10]. All checkpoint inhibitors can potentially induce immune-related AEs (irAEs) in any organ system. In contrast to ipilimumab, treatment with anti-PD-1 antibodies is continuous with some studies finishing application after 2 years. Thus, irAEs can occur late after initiation of therapy but possibly also after cessation of therapy. To date, cases of rare life-threatening or even fatal side-effects have been reported after anti-PD-1 antibody therapy like severe skin reactions [11], diabetes mellitus type 1 [12], and rhabdomyolysis [13].
Both nivolumab and pembrolizumab are approved for treatment of metastatic melanoma, nivolumab also for squamous non-small-cell lung cancer (NSCLC) after prior chemotherapy. Since they are also effective in various other tumour entities, they are expected to be employed widely. Therefore, physicians should be aware of potential side-effects. To facilitate prompt diagnosis and adequate management, cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects are summarised. Rare and therapeutically challenging side-effects from 15 cancer centers in Germany and Switzerland are described in detail.
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Adjuvant ipilimumab in stage III melanoma: New landscape, new questions....European J of Cancer Dec 2016.....The checkpoint inhibitor ipilimumab was approved for advanced melanoma in 2011, based on improved survival observed in phase III trials [[14], [15]]......Abstract: The recently reported significant prolongation of overall survival with ipilimumab as adjuvant in high-risk stage III melanoma patients represents an important event in the adjuvant treatment landscape. The European Organisation for Research and Treatment of Cancer 18071 trial demonstrated a 28% reduction in risk of death in patients treated with ipilimumab at 10 mg/kg (hazard ratio for death, 0.72; 95.1% CI, 0.58-0.88; P = 0.001) compared with placebo. All end-points-recurrence-free survival (RFS), distant-metastasis-free survival (DMFS) and overall survival (OS)-showed similar benefits. Survival rates at 5 years in ipilimumab-treated patients were OS 11%, DMFS 9% and RFS 11% higher than in placebo-treated patients. Global Health quality-of-life scores were not significantly different between treatment arms, in spite of significant adverse event rates that resulted in only 42% of patients receiving more than four doses of ipilimumab and only 28.9% of patients going beyond 1 year of treatment. Grades 3-4 immune-related adverse events occurred in 41.6% of ipilimumab-treated patients and in 2.7% of placebo-treated patients. One can speculate on dose and duration of treatment, as well as on the requirement for complete lymph-node dissection in sentinel-node-positive patients. The remaining role of interferons will be discussed regarding differences in sensitivity profiles-such as in ulcerated melanoma versus non-ulcerated melanoma-and access to new drugs. Ongoing trials with targeted agents and with anti programmed cell death protein 1 (anti-PD-1) agents may bring significant additional results in the next few years that will redefine how we treat stage III patients. Overall, pricing of new treatments will determine access and whether patients will actually benefit from new treatment options.......Prolonged survival with adjuvant ipilimumab: In the EORTC 18071 trial 951 stage III melanoma patients, after full regional lymph-node dissection, were randomised to receive either an intravenous infusion of ipilimumab 10 mg/kg or placebo every 3 weeks for 4 doses (induction), then every 3 months for up to 3 years (maintenance), or until disease recurrence or unacceptable toxicity occur. The primary end-point was recurrence-free survival (RFS). A significant improvement of RFS by adjuvant ipilimumab (hazard ratio 0.75, P = 0.0013) had already been reported in 2015, leading to the US Food and Drug Administration approval [18]. Now, in 2016, at a median follow up of 5.3 years, ipilimumab (compared with placebo) significantly improved overall survival (OS; hazard ratio for death, 0.72; 95.1% CI, 0.58-0.88; P = 0.001) and distant-metastasis-free survival (DMFS; hazard ratio for death or distant metastasis, 0.76; 95.8% CI, 0.64-0.92; P = 0.002). Five-year OS rates were 65.4% in the ipilimumab arm and 54.4% in the placebo arm. The 5-year DMFS rates were 48.3% in the ipilimumab arm and 38.9% in the placebo arm [19]. The RFS benefit observed previously was maintained (hazard ratio for death or recurrence, 0.76; 95% CI, 0.64-0.89; P < 0.001). Treatment benefits were by and large consistent across subgroups, with stage III apparently deriving more benefit than stage IIIB and more than stage IIIA, which was the only subgroup that did not seem to benefit (HR 0.98). In general, patients with only microscopic nodal involvement seemed to derive a greater benefit than patients with palpable nodes, as did patients with an ulcerated primary compared with patients with a non-ulcerated primary.
Global Health quality-of-life scores were not significantly different between treatment arms [20], despite significant adverse event rates that resulted in only 42% of patients receiving more than 4 doses of ipilimumab and only 28.9% of patients going beyond 1 year of treatment. Grades 3-4 immune-related adverse events (irAEs) occurred in 41.6% of ipilimumab-treated and 2.7% of placebo-treated patients. The most important grades 3-4 irAEs were: diarrhoea/colitis in 17.2%, hepatitis in 15.2% and endocrinopathies in 7.8% with hypophysitis in 4.4%, and neurological events in 1.1%. Five patients died from drug-related causes: three with colitis, one with myocarditis, and one with a Guillain-Barre syndrome leading eventually to multiple organ failure. The great majority of grade 3-4 irAEs occurred during the induction phase. Median time to resolution after stopping ipilimumab and corticosteroid medication was 6 weeks, with the exception of endocrinopathies (31 weeks). In conclusion, one can state that adjuvant ipilimumab therapy provides consistent improvements in terms of RFS, DMFS and OS, but that it comes at a price in terms of irAEs that need expertise and experience for early recognition and handling with established treatment algorithms. This treatment should be handled by centres with sufficient experience.
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Immune System, Unleashed by Cancer Therapies, Can Attack Organs
"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.....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.
.....You have to manage this hour by hour," he added. "Minute by minute."......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?.....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."
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http://www.nytimes.com/2016/12/03/health/immunotherapy-cancer.html?_r=0
By MATT RICHTELDEC. 3, 2016
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.
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.
"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.
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.
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."
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