Toxin or treatment?

Jacob Kingsley was 9 years old when he was handed the poison he’d shunned since before he could walk and told to swallow it as medicine. Obediently, he gulped down a few micrograms of peanut flour—less than 1/1000 of a peanut—diluted in grape Kool-Aid. His mother and a nurse hovered, ready to inject him with epinephrine if an itchy throat and wheezing struck. Jacob’s mother, Jennifer Kingsley, had driven him 2 hours from their home in Columbus to this doctor’s office in Cincinnati, Ohio, for the first of dozens of sessions of peanut immunotherapy. Giving Jacob gradually increasing doses of peanuts, she hoped, would desensitise his immune system. It’s a strategy Kingsley hadn’t pursued until she reached her breaking point. A year earlier, Jacob had swallowed a handful of popcorn that, unbeknownst to him, was laced with peanut product. He suffered a particularly frightening reaction: two bouts of intense symptoms about 6 hours apart. The incident marked his second peanut-related trip to the emergency room, and Kingsley was terrified that the next encounter could be fatal. “I decided, ‘I can’t live like this,’” she says. “I was desperate.” As Jacob sat through the hours-long appointment in Cincinnati, playing video games and swigging increasing doses of peanut-spiked Kool-Aid, he joined legions of children writing food allergy’s next chapter. Today, more than 3000 people worldwide, most of them children, have undergone peanut immunotherapy, with the goal of protecting them if they accidentally encounter the food. Other children are trying immunotherapy for allergies to milk, eggs, and tree nuts. Some, like Jacob, get treatment in allergists’ offices, where doctors share protocols informally and in published papers. Other children have enrolled in clinical trials, including those run by two companies racing to introduce a peanut-based capsule or skin patch. Both plan to apply for approval from the Food and Drug Administration (FDA) this year. The agency’s blessing would dramatically boost immunotherapy’s credibility and reach. In a field that for decades has had nothing to offer patients beyond avoidance, immunotherapy marks a seismic shift. As it edges closer to mainstream, “There’s mixed feelings, with a whole range of enthusiasm,” says Corinne Keet, a paediatric allergist-immunologist at Johns Hopkins Medicine in Baltimore, Maryland. Fear that it might cause harm is mingling with euphoria that children living constrained lives could be set free. Doctors who offer immunotherapy describe families eating in Chinese restaurants for the first time and home-schooled children rejoining their peers. Like many medical firsts, the therapy is not perfect. “This is version 1.0,” says Brian Vickery, a paediatric allergist-immunologist at Emory University in Atlanta. He has conducted peanut immunotherapy trials and worked for 2 years at Aimmune Therapeutics, headquartered in Brisbane, California, one of the companies whose products are nearing approval. Physicians fret about oral immunotherapy’s rigors—treatment must continue indefinitely—and its risks, which include the same allergic reactions it aims to prevent. Last year in Japan, a child suffered brain damage during a trial of immunotherapy for milk allergies. Meanwhile, physicians on the front lines are navigating hazy science. No one knows exactly how immunotherapy works or who’s most likely to be helped or hurt by it. “For me,” Keet says, “it’s really not clear for an average child with peanut allergy whether it will make sense to do oral immunotherapy or not.” Like many who study food allergies, Keet was enticed by their mystery. Animal models are poor. The intensity of allergic reactions varies unpredictably, even in the same person over time. Why one child outgrows an allergy and another doesn’t is unknown. “This was something we didn’t cover much in medical school” in the 1990s, says Matthew Greenhawt, a paediatric allergist-immunologist at Children’s Hospital Colorado in Denver. Greenhawt’s career trajectory tracks with a surge in food allergies, and these days, he can barely keep up with the stream of affected children who visit his hospital. Today, between 1% and 2% of people in the United States, the United Kingdom, and several other countries are allergic to peanuts—a rate that has roughly tripled since the mid-1990s. Other food allergies, such as those to tree nuts, are also on the rise. What’s causing the increase is not well understood. Despite rising caseloads, deaths from food allergies remain rare. Precise numbers are hard to come by, and estimates range from fewer than 10 to more than 150 a year in the United States. But even though an affected child is more likely to be struck by lightning than to die of a food allergy, the risk can feel ever-present. Parents never know when their children will happen upon culprit foods and how they’ll be affected if they do. “We live in a complex world—people move food all over the place,” says David Bunning, a businessman whose two sons, now adults, have multiple food allergies. “The impact on children in terms of their confidence to explore their environment can be extreme.” Bunning’s family almost never travelled or ate out. At their grandparents’ house, the boys were usually confined to one room where food wasn’t allowed.

Bunning now chairs the board of directors at Food Allergy Research & Education (FARE), an advocacy group in McLean, Virginia. Families like his, and the doctors who cared for their children, began to agitate for new treatments about a decade ago. Immunotherapy was the obvious candidate: Injections that desensitize the immune system to pollen, grass, pet dander, and bee venom have been around for decades. Whether for an allergy to cats or pistachios, immunotherapy aims to disrupt the cells that swing out of control when faced with an allergen. When a child who is allergic to a food eats it, food proteins cross from the digestive tract into the bloodstream. An antibody called immunoglobulin E (IgE), which is bound to white blood cells called mast cells in tissues, recognises the culprits. IgE activates the mast cells, which release histamine and other chemicals. In the skin, that response can lead to hives; in the respiratory tract, wheezing; and in the gut, vomiting. The most serious symptoms, such as a swollen throat or a reaction throughout the body, mark anaphylaxis, which is what families fear the most. Allergy shots blunt production of IgE, in part, researchers believe, by boosting levels of certain T cells that prompt a cascade of immune changes. Eating gradually increasing doses of a food allergen seems to desensitise the immune system over time. Thousands of children have tried oral immunotherapy, and a capsule to treat peanut allergies might be approved by regulators next year. But there’s anxiety about the strategy’s risks and unknowns. Brief testing decades ago indicated that shots for food allergies weren’t safe. So, around the mid-2000s, scientists began to feed children the allergen instead. One watershed moment came in 2005, when the National Institutes of Health formed a consortium for food allergy clinical trials. A second was in 2011, when advocates sponsored a symposium at Harvard Medical School in Boston to standardise goals and strategy for the pioneering immunotherapy efforts. About 60 people attended. “The patients were very clear,” says Carla McGuire Davis, a paediatric allergist-immunologist at Texas Children’s Hospital in Houston. They didn’t care about eating a peanut butter sandwich; they wanted protection if they accidentally encountered one. Trialists set their end dose at a couple of peanuts and pressed ahead. The results of early clinical trials were promising, says Hugh Sampson, a paediatric allergist-immunologist at the Icahn School of Medicine at Mount Sinai in New York City, who has studied immunotherapy in food allergies for many years. After 6 to 12 months of treatment, he says, about 70% to 80% of patients could handle higher doses of the food than before. Lab data were encouraging, too: Ingesting allergens over time seems to make mast cells less reactive, inhibiting their release of harmful chemicals. The therapy also produces other immunoglobulins: IgG4, which further inhibits mast cell activity, and IgA, which helps keep food allergens from escaping the gut. The 2011 conference inspired the founding of the company now called Aimmune, fuelled by more than $3.5 million from FARE. A second company, DBV Technologies, based in Montrouge, France, and New York City, expanded a few years later. Aimmune began to develop an oral product, essentially a capsule of powder derived from peanut flour with proteins held to consistent levels. In February, the company announced in a press release the results of a phase III trial involving 496 children and teenagers, with a regimen stepping up every 2 weeks through 11 dose levels. Among the 372 people in the treatment group, about 20% dropped out for various reasons, including side effects. After about a year, 96% of people who completed treatment could consume one peanut with no more than mild symptoms, 84% could tolerate two, and 63% could tolerate at least three. DBV’s skin patch represents a more conservative strategy: It delivers tiny amounts of peanut protein, the equivalent of one peanut over 3 years. Last year, DBV announced that in its phase III trial of almost 400 patients, after a year, those using the patch could, on average, eat three peanuts over the course of several hours before experiencing clinical symptoms such as vomiting or hives; before the trial, the average was just under one peanut. Outcomes varied substantially from person to person. If one or both products are approved by FDA in the coming months, expectations are high that they’ll be welcomed: Aimmune is now worth about $1.5 billion on the U.S. stock exchange. In 2016, FARE sold its share in Aimmune for $47 million.

Meanwhile, some doctors embrace another route: offering peanut immunotherapy in their practices. “I can treat 20 patients with $5.95 of peanut flour,” says Richard L. Wasserman, a pediatric allergist-immunologist in Dallas, Texas. Wasserman ventured into food allergy immunotherapy 11 years ago. He developed a protocol based partly on published case reports and protocols for allergy shots, and he put IVs into his first five peanut allergy patients in case he had only seconds to rescue them from severe anaphylaxis. “When they all sailed through the first day, we stopped doing IVs,” he says. “But that’s a measure of how concerned I was.” Wasserman has since treated more than 300 children with peanut allergies and more than 400 with other food allergies. Other practitioners are joining in, among them the Cincinnati allergist whom the Kingsley family sought out: Justin Greiwe at Bernstein Allergy Group. Greiwe joined the practice in 2014, straight out of medical training. “It was a little nerve-wracking at the beginning,” he says, because no officially sanctioned oral immunotherapy protocol existed. He took precautionary measures, such as lung testing before every treatment, to help ensure patient safety. Some clinicians—and executives at the companies developing products—aren’t happy about the doctor’s office treatments. “That gives a lot of us pause,” says Sampson, who in addition to his academic post is chief scientific officer of DBV. “We’re very afraid that if this goes on enough, somebody is going to have an accident or a fatal reaction, and that’s really going to change the FDA’s viewpoint” about the products in development, he says. Wasserman agrees about the need for caution. “Not every practicing allergist should be doing oral immunotherapy,” he says. Greiwe suggests the treatment requires a dedicated staff, and he gives every immunotherapy family his cellphone number. Jacob was one of Greiwe’s first immunotherapy patients. His mother remembers Jacob’s ears burning—a minor reaction that subsided on its own. “Or he said he hated peanuts and wanted to quit,” she says. Worst was about 6 months in, when Kingsley discovered that for 2 weeks, Jacob had hidden his dose to avoid eating it. That was “the only time we ever felt danger,” she says. Stopping treatment can quickly alter the immune system, says Cecilia Berin, an immunologist at Mount Sinai, because immunotherapy requires constant exposure. When Jacob squirreled away his daily dose, the changes induced in his immune system almost certainly started to fade out, putting him at risk. Greiwe restarted him on a lower dose and, his mother says, “We got through it.” Even children who faithfully follow instructions face risks. The immune system can react to even subtle pressures, and the list of what can provoke a reaction to treatment is long. Exercising within a couple of hours of the dose can do it; so can a cold, a stomach virus, menstruation, or a hot shower. An asthma attack can trigger a reaction—many children with allergies have asthma as well—and so can stress. “We had a patient who had just played the violin on a stage, came down, and about 15 minutes later … took the dose and had a reaction,” Davis says. Berin posits that external pressures such as physical activity or illness make the gut more permeable, pushing more of the immunotherapy dose into the bloodstream. But that remains hypothesis. Regardless, it’s becoming clear that “there are people who react years down the road to a maintenance dose,” Keet says. For Jacob, such a moment came 9 months in. One evening while watching a movie, he downed his peanut M&M’s and later ran outside with his cousins to dance in a rainstorm. He broke out in hives head to toe. Kingsley dialled Greiwe’s number, and Jacob got a double dose of an allergy medication. The most tragic data point to date is the case in Japan. A child had enrolled in a trial of immunotherapy for milk allergies at the Kanagawa Children’s Medical Centre in Yokohama. He’d raised what he could ingest from less than 8 millilitres to 135 millilitres—about half a glass of milk. After 3 months on that maintenance dose, he swallowed it and soon complained of pain. Within minutes, he had stopped breathing. His heartbeat was later restored in the emergency room, but he’d gone too long without it and sustained severe brain damage, according to a statement from the hospital’s president, Sumimasa Yamashita, in November 2017. Kanagawa Children’s Medical Centre declined to comment, saying only that the incident remains under investigation. In its statement, the hospital noted the boy had suffered an asthma attack the day before the catastrophic dose. He also was on a protocol that aimed to rapidly escalate the volume of milk he could drink over less than 3 weeks. But why the child reacted so disastrously to that glass of milk is unknown. “What people don’t understand is this level of protection fluctuates,” says Mimi Tang, a paediatric allergist-immunologist at Murdoch Children’s Research Institute in Melbourne, Australia. “It is not guaranteed, nor is it constant.” One of the few long-term analyses was published in 2013 in The Journal of Allergy and Clinical Immunology. Keet, paediatric allergist-immunologist Robert Wood at Johns Hopkins Medicine, and their colleagues sought out 32 children who’d been in a milk immunotherapy trial. Three to 5 years later, “The results were surprising in a sobering kind of way,” Wood says. Only about a quarter “were doing great … tolerating unlimited quantities of milk without side effects.” Another quarter had abandoned the protocol and returned to strict avoidance. The rest were eating dairy products inconsistently, with intermittent or even frequent allergic reactions. “It’s hard to know which comes first, whether they got complacent” about ingesting it “or backed off because [they were] having too many symptoms,” Wood says.

More and more families are willing to live with those uncertainties because the alternative is greater anxiety. “We were scared senseless,” says Divya Balachandar, whose daughter Leena Wong, now 7 years old, had her first episode of anaphylaxis at age 4 after being touched by a cashew. Testing revealed Leena also was allergic to sesame, eggs, milk, other tree nuts, and peanuts. Balachandar, a paediatric pulmonologist in New York City, and her husband enrolled Leena in a federally funded oral immunotherapy trial for peanut allergy in 2015. “It made me nervous, really nervous, to put something in my daughter’s mouth that she was allergic to,” Balachandar says. She gravitated toward a trial over treatment with a local allergist because, she says, “there were no rules” about how to treat in private practice. By this spring, Leena could eat two spoonfuls of peanut butter—about 25 peanuts—without a problem. She started second grade sitting with her classmates at lunchtime, liberated from a separate nut-free table. Both companies developing peanut-based treatments say they had more volunteers for their trials than they could accommodate. Private practitioners usually have a waiting list; Greiwe’s runs more than 4 months. At Stanford University in Palo Alto, California, which has a large food allergy research program, more than 2000 patients are waitlisted to enrol in the university’s clinical trials, says Sharon Chinthrajah, an allergist-immunologist there. More treatments are on the horizon. In Australia, Tang is working with a company that’s testing an approach she pioneered, a combination of a probiotic and oral peanut immunotherapy. The probiotic should tilt the body toward producing the subset of T cells that tolerate the allergen and away from making cells that attack it, she says. Chinthrajah and others are enthusiastic about combining oral immunotherapy with a monoclonal antibody called omalizumab, which is FDA approved to treat allergic asthma. Clinical trials are also gearing up to test other monoclonal antibodies that target molecules involved in allergic inflammation. Jacob’s and Leena’s families are eager to see what comes next. Jacob is also allergic to pistachios and cashews, but because he finds those foods easier to avoid than peanuts, the family has rejected immunotherapy that targets them. Leena’s family is the opposite. With her older sister and her parents, Leena attends Indian functions regularly, where tree nuts are a common ingredient in sauces. In August, another episode of anaphylaxis landed her in the emergency room: She began to vomit and suffered chest tightness and eye swelling after eating Indian food her parents suspect contained cashews—despite having triple-checked with the restaurant that it did not. “I would love to do tree nuts,” Balachandar says, once immunotherapy “becomes more available and better understood.” Physicians with deep roots in food allergy immunotherapy hope those new to it tread carefully. Doctors who offer such treatments “have to know the data cold,” including published results and side effects that may crop up, Greenhawt says. Still, he’s thrilled that peanut immunotherapy treatments may soon be approved. The other day, talking with a peanut-allergic 4-year-old and his mother, Greenhawt shared what the next year might bring. “I said, ‘I’m going to see you a year from now; hopefully, we will have two products that are approved, and we can talk about which one might be best for you.’” The mother looked startled and delighted, Greenhawt says. “I’ve never seen somebody smile as brightly as that.”

Science, 19 October 2018 ;