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The Hunt for a Food Allergy Cure: Where Is It Heading?
Posted By Allergic Living On 2013/10/10 @ 10:00 am In Food Allergy | No Comments
Originally published in Allergic Living ‘s Summer 2013 edition.
FOR four years in a row, there were upbeat reports at the annual meeting of the American Academy of Allergy Asthma & Immunology about the progress with oral immunotherapy – the most basic type of desensitizing treatment imaginable for food allergy.
Called OIT for short, it involves feeding a food like milk or peanut to allergic children. The children start by swallowing microscopic specks of their allergen on a daily basis. If they can manage that, they progress to a tiny bit larger daily dose, then a bit bigger again, and on it goes until they reach their maintenance dose – an amount of the food that they’ll need to eat every day at home for months or even years.
Some lucky kids even finished their clinical trials able to eat full servings as their daily “dose” – perhaps a glass of milk, an ice cream cone or a handful of peanuts. When you consider that scant years before, there were precisely zero food allergy treatments in the pipeline, the news of these studies was phenomenal.
Yes, there was a high rate of reaction – mostly stomach aches and itchy mouths – accompanying the treatment, and some children had stronger reactions and could not proceed. But something remarkable was also happening: a majority of the allergic kids were able finish their trial eating some amount of their allergen every day – a food that had long been viewed as their personal poison, one that could be life-threatening. The presenting researchers were optimistic; the mainstream media began using the “cure” word.
Then came the March 2013 meeting of the AAAAI. Dr. Wesley Burks, the organization’s outgoing president and a pioneer of OIT research, quickly signaled times had changed. He told the assembled allergists that it was not at all clear that long-term tolerance – in which a person on oral immunotherapy could stop taking daily doses of their allergen and still be protected – was achievable.
Burks spoke of encouraging OIT results, like the significant gains in patients’ peanut consumption in one of his studies, but also of instances of patients quite abruptly losing the ability to eat the food without reacting. His message was: “The treatment is promising, but it’s not ready yet.”
Burks raised eyebrows, but a later presentation from Johns Hopkins University  became the talk of the conference. The preliminary findings of a long-term follow-up on two milk OIT studies were both surprising – and disappointing.
The Hopkins researchers surveyed 32 children and teens who had completed the two OIT studies, and had been given clear instructions on what milk products to consume daily. Three to five years after graduating from their trials, only 25 percent were consuming milk without ever getting symptoms, while 16 percent had stopped their daily doses because of symptoms. The rest were reacting (to varying degrees), either frequently or occasionally. Among those reacting, almost a third reported a “systemic” or more serious reaction.
Pulling no punches, Dr. Robert Wood, director of pediatric allergy and immunology at Johns Hopkins said: “Some of the more dramatic failures had looked like absolute successes in the study. They were about as close to ‘cured’ as we could imagine.”
Although it wasn’t completely clear, Wood says the loss of protection in these kids is likely tied to reducing the daily milk dose. “A lot of them just ratcheted down their milk exposure because they were having reactions,” he said. “And as they ratcheted down exposure, they lost some, most or all protection that the study had given them.”
Was this small investigation the beginning of the end for OIT? Definitely not, say several leading allergists, including Wood and Burks, who is the chair of pediatrics at the University of North Carolina’s school of medicine.
It’s more that the long-term results are a flag on the play, an indicator that scientists can’t presume the level of protection reached in a one- or two-year OIT trial will not change over time. The same goes for its cousin the sublingual immunotherapy trial (which involves giving the allergen doses in tiny amounts in under-the-tongue drops or tablets).
“We need long-term followup,” stresses Wood. “Letting kids go at the end of the study is not the end of the story.”
He and Burks both view the bigger picture as far more positive. “To go from where we were 10 years ago, which was to say that ‘we probably can’t give food to a highly allergic patient safely at all,’ to say now that some patients are having extremely good outcomes, is big progress,” said Wood. “The long-term potential is very real.”
But he does see a need to temper expectations of just how quickly an OIT-style of treatment will be available at the allergist’s office.
What several allergists tell this magazine is that OIT in and of itself may not be the solution, nor the only treatment option. The therapy may simply be a first stage, which needs to evolve. In fact, it appears that’s already happening.
Next: Great hopes for combination therapies
Dr. Hugh Sampson is one of the leaders in the food allergy field, and a student of history. He can cite that the first paper on on oral immunotherapy for food allergy was published in 1908, and that the strategy was largely abandoned until Italian researchers began working with it in the 1990s.
“One of my concerns has always been, why did people stop doing it?” says the director of the Jaffe Food Allergy Institute  at New York’s Icahn School of Medicine at Mount Sinai. He knows of one potential answer: reactions.
The work on stinging insect allergy also looms large in Sampson’s thinking: For years, the extract for allergy shots to protect against wasp, hornet and other stingers was made by grinding up whole insects. “There was one lone voice who said: ‘But people are allergic to the venom, that’s what we ought to be using,’” he notes.
This led to a study that found, eureka, using venom extract prevented reactions in 96 percent of allergic patients. Meantime, the “whole body” extract proved no more effective than a placebo.
“They were giving something that was no better than injecting water,” says Sampson, who published an academic article in January 2013 warning the community of allergists not to rush OIT into their practices before it’s ready. “I just don’t want us to make a similar mistake with oral immunotherapy [for food].
We’ve got to do the studies right, we’ve got to make sure we’ve got the data right,” he told Allergic Living.
Since 2005, Sampson has been trying to get a different approach to food OIT off the ground. His idea was to combine the desensitization process with the injectable drug omalizumab – better known by the Xolair brand name. Xolair prevents or reduces reactions by neutralizing free-roaming IgE antibodies, the type of antibodies that set off allergic symptoms. In persistent asthma, the drug has shown largely favorable results.
For years, regulatory issues delayed Sampson’s use of this combined approach. Today, it is back on the drawing board, and Mount Sinai, Johns Hopkins and Stanford University researchers have 56 milk-allergic children enrolled in a significant study. Sampson says: “This is a placebo-controlled trial that should answer the question: ‘Does Xolair make a significant difference in the number of adverse reactions?’”
He explains that the drug doesn’t just reduce the IgE antibodies that attach to the mast cells involved in allergic reactions. It also should change the immune system’s overall response to the allergen. “Our hope is that we’ll be able to block the allergic reaction in favor of a more natural reaction seen in patients who aren’t allergic. This may possibly lead to tolerance.”
That, of course, is the big and complex issue. But Sampson’s team hopes to be able to soon answer the first question about reducing reactions. In safety trials with a few patients, conducted at Harvard and Stanford universities, there are already encouraging signs.
From his lab at Harvard, immunologist Dr. Dale Umetsu has become intrigued by the idea of a combination therapy with Xolair – both to decrease symptoms in patients as they go through desensitization, and also as a “rush” method for OIT, which is normally a long process with a high dropout rate.
“We think if you use Xolair with oral immunotherapy you can get to the high doses of the food allergen pretty quickly and minimize allergic reactions. Half of our patients have no reaction at all over the course of the desensitization,” he says of his team’s OIT trials that include Xolair injections at Boston Children’s Hospital , where he directs the asthma center.
Following three months of pre-treatment with Xolair, that’s just six weeks into combination oral immunotherapy for milk and eight weeks for peanut. (By comparison, the non-Xolair immunotherapy trials can run from six months to two years.)
“It just hastens the process,” agrees Dr. Kari Nadeau, an associate professor at the Stanford University School of Medicine who has collaborated on some of these small studies with Umetsu, whom she describes as a mentor. This spring, The New York Times Magazine  featured the impressive results she has also been seeing with the combination therapy in children with multiple food allergies, setting the allergy world – both patients and professionals – abuzz.
“There’s so much excitement,” notes Nadeau, the director of the Stanford Alliance  for Food Allergy Research. “People want something they can feel good about. They really want a cure.”
Next: More ideas – Chinese herbs and the peanut patch
For some young study subjects, her multiple allergy desensitization work has been life-changing. They use words like “magic” and “miracle” to describe what life is like now that they don’t have to worry about accidental exposures at birthday parties or restaurants.
But their allergist is at pains to temper expectations. “These studies are at the neonatal stage. OIT is experimental and I don’t want to give people the wrong feeling that there is a perfect cure out there,” she says. “There is not.”
There are some drawbacks to Xolair: it’s very expensive, not every allergic person tolerates the injections well, and some people may have too high a level of IgE antibodies to qualify for trials. Plus, Nadeau echoes Wood and Burks when she notes: “We don’t know the long-term effects.”
Still, back in New York at Mount Sinai, Sampson and his colleagues are cautiously optimistic about the combination therapy. Dr. Scott Sicherer, chief of the school of medicine’s division of allergy and immunology, is also quick to point out other promising food allergy therapies on the drawing board. For instance, there’s the research of Mount Sinai’s Dr. Xiu-Min Li.
She has been working for several years with the Chinese herbal remedy called FAHF-2 , which is meant to raise an allergic person’s threshold for allergenic foods. The formula, a highly specific blend of herbs, has worked extremely well in experiments with mice – and is now being studied in humans at Mount Sinai, Arkansas Children’s Hospital and Northwestern University. The researchers hope to have results in late 2013.
The downside of this approach is a practical one: a person needs to take 30 tablets a day to consume enough of the remedy to prevent reactions. “We’re working on getting the pills more concentrated, and getting that number down,” Sicherer says.
There are also high hopes for the allergy “patch,” where the strategy is to expose the patient to the allergenic food by putting it on the skin, like a nicotine patch in smoking cessation. While it’s early days for this research, Sicherer says “the thing that’s nice about that one is we anticipate fewer side effects because you’re not swallowing increasingly larger amounts of the food. Instead, you’re putting the food on the skin.”
He says other emerging lab work will attempt to answer: “Can you combine an allergen with an immune stimulator that tells the immune system to ‘see’ the food in a better way and have non-allergic responses to it?” OIT therapy of itself may also hold promise if approached differently.
Perhaps, says Sicherer, the dosing needs to continue for prolonged periods of time. “We may be expecting too much of a one-year or two-year therapy,” he says. “It may turn out that if you’re on this daily treatment for three or five years, maybe that is a cure.”
Among these top researchers, there is little sense of any academic race to be the scientist with the big answer, instead the approach is refreshingly collaborative. The day Allergic Living spoke to Sicherer, Nadeau was arriving from California – both to speak to a luncheon for FARE, the food allergy organization that contributes significant funding to research, and to visit the Mount Sinai team.
In that visit, she and Dr. Xiu-Min Li roughed out a unique new OIT study, one that would combine the FAHF-2 formula with OIT desensitization. “We hope, if possible and if safe, to use the herbal medicine in combination with multi-OIT to see if these are safe and efficacious together,” confirmed Nadeau. Quickly she added that “we have barely mapped out a study on a napkin, so I don’t want to say more until we have the regulatory approval and the right protocol.”
Yet it’s another example of leaders from different branches of food allergy research coming together with creative approaches. “Everybody just wants to solve this problem and work together to do it,” says Sicherer. “We are in this together. As a physician, it kills me to see the impact of food allergy on quality of life. You just want to make it better.”
Next: Change seen in immune systems
But how better can it be made? Back at the AAAAI meeting, Burks was raising one of the key issues in food allergy therapy. Can you ever find true, lasting tolerance – that elusive cure? In fact, he even described the term ‘tolerance’ as “extremely controversial” to define, preferring to speak of allergic patients attaining “sustained unresponsiveness”.
It helps to understand the terminology. Sicherer notes that “desensitization” simply means that the food-allergic patient, through a therapy, is able to gain some level of protection to an allergenic food, such as peanut. That person has to keep taking an assigned amount of peanut “dose” every day or the protection will diminish or even disappear. “If you stop taking it as a daily treatment, you go back to being perhaps as sensitive as you were before,” he says.
In some studies, patients are taken off their doses for a few weeks and then tested to see if they sustain their threshold of “unresponsiveness”. But that wasn’t the case in the Johns Hopkins follow-up study of the 32 who had undergone milk oral immunotherapy. Umetsu and Nadeau say those findings serve as a reality check, that the long term remains the big question mark.
They note that the study is preliminary [Ed.’s Note: It is now published in JACI, Sept. 2013 ] and one vital point remains unclear: after the trial, only about half of the patients had stuck to their full daily serving of milk. What happened to the rest?
Dr. Corinne Keet of Johns Hopkins led that follow-up. She says in the case of 16 percent who stopped taking their milk doses outright, they quit because of reactions. When it came to the others who were having varying degrees of reactions, the picture is less clear.
But Wood, the Johns Hopkins director, says: “The main thing I’ve come to believe is that they were not as protected as we believed and that they self-restricted [consumption] because they didn’t like the side effects the milk was putting them through.”
Past OIT studies have shown that factors such as catching a cold, exercise and menstruation can have an impact on the threshold at which an allergic study participant will react. If a person pulls back allergen consumption because of symptoms, he or she needs to gradually work back to the full dosing. It’s not yet known if any of these factors were issues in the Johns Hopkins study.
The big picture discussion raises this intriguing question: in the quest for a food allergy cure, might this be a two-stage process, one in which an allergic patient’s threshold of protection to an allergen is first significantly raised through oral immunotherapy, or OIT plus Xolair – or perhaps via Chinese herbs or another therapy?
That’s desensitization, which offers a safety net against an accidental exposure. The second stage would be the continuing hunt for the cure.
At the AAAAI conference, some researchers felt that first goal was less than adequate, even in the short term. “But that is personal opinion,” says Sicherer. “If you’re the parent of a child, who has had multiple allergic reactions despite your best efforts, you might say, ‘This sounds good to me.’”
Burks also views that as a huge step for the average patient. “If a patient can tolerate the procedure, they’re likely after a year of therapy to tolerate a whole lot more food [allergen] than when they started, and that change stays as long as they’re on the therapy.”
When it comes to the longer term, the moving target of finding a true cure for food allergy, Californian Nadeau can hold out this ray of optimism: in her small studies with the combination of Xolair and oral immunotherapy, patients’ immune systems are actually changing.
“It’s only in a few patients, but we’ve shown that indeed their immune systems became more like those people who have naturally lost their food allergy. We’re not yet able to offer what we think is a cure,” she says. But here’s what she, and the other experts, can offer: “There is a lot of promise and hope.”
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Next: How to join a study
See also: Brave Girl’s New Food Freedom 
JOINING A STUDY
Food allergy researchers all mention the great need for study participants. “We call them the heroes,” says Dr. Hugh Sampson. “They’re the ones willing to go into these trials and help us to figure out whether an approach is going to work. Without them, we’re not going to get there.”
Visit Clinicaltrials.gov  to see if there are studies in your area.
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URLs in this post:
 Image: http://allergicliving.com/wp-content/uploads/2013/10/wood.png
 Allergic Living: http://allergicliving.com/get-allergic-living/?mod=home&act=US
 Johns Hopkins University: http://www.hopkinschildrens.org/allergy/
 Image: http://allergicliving.com/wp-content/uploads/2013/10/sampson3.png
 Jaffe Food Allergy Institute: http://icahn.mssm.edu/research/programs/jaffe-food-allergy-institute
 Boston Children’s Hospital: http://www.childrenshospital.org/centers-and-services/allergy-and-asthma-program
 The New York Times Magazine: http://www.nytimes.com/2013/03/10/magazine/can-a-radical-new-treatment-save-children-with-severe-allergies.html?pagewanted=all&_r=0
 Stanford Alliance: http://foodallergies.stanford.edu/
 Image: http://allergicliving.com/wp-content/uploads/2013/10/nadeau-li.jpeg
 FAHF-2: http://www.asthmaallergieschildren.com/2010/08/16/traditional-chinese-medicine-and-allergy/
 Image: http://allergicliving.com/wp-content/uploads/2013/10/umetsu3.png
 JACI, Sept. 2013: http://www.jacionline.org/article/S0091-6749%2813%2900768-9/fulltext
 Brave Girl’s New Food Freedom: http://allergicliving.com/index.php/2013/10/10/brave-girls-new-food-freedom/
 Clinicaltrials.gov: http://clinicaltrials.gov
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