Food allergy is estimated to affect 7-8% of individuals of all ages in Canada and has become increasingly prevalent over the last two decades. For those with severe anaphylaxis, ingestion of a food allergen can trigger life-threatening consequences, yet there is still no approved cure or therapy for food allergy.

Until now, the standard of care has been food avoidance and emergency management, consisting of rescue medications in the form of auto-epinephrine injectors administered during accidental exposures. But for many allergic individuals, this careful avoidance must extend beyond what is clearly visible to the eye, since trace amounts of cross-contaminating allergens can be hidden in processed foods and on the pots and pans of restaurant kitchens. These invisible, yet ubiquitous, sources of allergen often become the primary source of anxiety in the daily life of patients and their families. Fortunately, allergen-specific immunotherapy (AIT) for food allergy has been an active area of investigation, which aims to relieve these small but significant day-to-day risks that allergic patients face. As a result, AIT therapies will soon be emerging on the market for peanut allergy, which may mark the beginning of a new paradigm for the way we approach food allergy management.

There are three major types of AIT that are being investigated, all of which share the same underlying strategy – to re-educate the immune system by exposing patients to tiny but slowly increasing and regular allergen doses with medical supervision. AIT research has been focused on 3 different routes of allergen administration: (1) oral immunotherapy (OIT), (2) epicutaneous immunotherapy (EPIT), and (3) sublingual immunotherapy (SLIT). In each case, the goal is to help patients tolerate larger amounts of allergen by increasing the threshold of activation for the cells responsible for the allergic reaction and by inducing changes in the regulatory mechanisms of the immune system. If successful, these patients will be considered to have achieved a state of either “desensitization” or “sustained unresponsiveness”. In other words, patients on AIT may benefit from treatment by gaining protection from the “may contains” – the trace amounts of allergens that are most difficult to control – and in some cases, they may even be able to consume larger amounts of allergen.

While desensitization and sustained unresponsiveness are similar concepts that involve a dampened immune response to a food allergen, it is important to note some of the differences between these two phenomena. Desensitization is a state that persists only while remaining on continuous AIT therapy, whereas sustained unresponsiveness is a state that can persist for a prolonged period without ongoing therapy, somewhere between weeks to months. However, current studies show that only a small subset of participants develop sustained unresponsiveness and that the length of this period is not yet easily predicted. Therefore, the current recommendations indicate that all patients undergoing AIT continue consuming a small maintenance dose consistently throughout their lifetime to help maintain the benefits of AIT. Additionally, there are external factors that can alter a patient’s day-to-day threshold, like acute illness, intense exercise, or alcohol consumption – all activities that may lower one’s threshold and could cause a reaction.

Additional strategies like OIT treatment and EPIT treatment for peanut allergy are at the forefront of the food allergy field. Results from the PALISADE trial, which marked the first phase 3 clinical trial completed for peanut OIT, were published in November 2018. This placebo-controlled study recruited approximately 500 peanut allergic children between the ages of 4 to 17. Those in the treatment group were administered increasing oral doses up to 300mg of a peanut-derived product, which is equivalent to roughly one peanut. After one year on the treatment protocol, 67.2% of the children in the treatment group were able to tolerate 600mg of peanut in a single serving and 50.3% tolerated 1000mg, compared to 4% and 2.4% of children in the placebo group. These results yielded a significant difference between the groups, which has led Aimmune Therapeutics, the manufacturer and sponsor of this trial, to file for FDA approval in December 2018. Aimmune is now extending their research scope to determine the efficacy and safety of their product within an even younger age group – peanut allergic children between 1-3 years old. Results from previous AIT clinical trials tend to observe greater rates of success in younger children than in adults, and this age-dependent treatment response was also observed in PALISADE, where the adult treatment group failed to demonstrate significant differences compared to the placebo group. Thus, the current evidence suggests that there may be window of opportunity for AIT effectiveness in younger children.

This window of opportunity for AIT is also evident within EPIT therapy, an alternative to OIT that is also in phase 3 trials. EPIT therapy involves the administration of allergen through the skin with a patch that is applied daily, such as the Viaskin Peanut patch developed by DBV Technologies. Although the Viaskin patch has been shown to be very safe and well-tolerated in early studies at the 250μg dose, during PEPITES, the phase 3 study with 4- to 11-year-old children, the difference observed between the treatment and placebo group was not sufficient to achieve their predefined primary end point. DBV is now undertaking a global phase 3 study for children between 1-3 years, known as EPITOPE, to determine the effectiveness of the 250μg patch in toddlers.

“[P]atients and families will have to determine whether the demands of treatment are feasible.”

When comparing AIT options, there are important considerations in terms of safety and long-term effectiveness. Although OIT trials have higher efficacy rates than EPIT and SLIT, this is accompanied by a considerable increase in side effects. OIT trials typically report more study withdrawals and frequent adverse events, with several cases requiring epinephrine usage. Some of the most common complaints during OIT were abdominal pain and gastrointestinal symptoms, especially during the up-dosing phase. There is also a small percentage of patients that develop eosinophilic esophagitis while on treatment, which is associated with an increase in inflammatory white blood cells (eosinophils) in the esophagus that can cause difficulty with swallowing. In contrast, the major complaint of EPIT trials have been mild, localized skin reactions at the site of application. Therefore, a large focus of ongoing and future studies is the reduction of the side effects associated with OIT. One promising strategy is a combination therapy using OIT and omalizumab, an anti-IgE antibody, which has been reported to reduce the frequency of adverse side effects and allow for a quicker initial up-dosing period of the allergen. Multifood AIT is also being explored, with omalizumab, and so far, has been shown to have a comparable safety profile to single-food immunotherapy.

These new treatment options for food allergies may soon be available on the market, and research has shown that AIT can be safe and effective particularly in young children. Ongoing studies aim to optimize the tolerability and efficacy, as well as expand the array of food allergies that can be targeted. Until then, patients and families will have to determine whether the demands of treatment are feasible for their daily life and worth the potential peace of mind.

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Jennifer Hoang

Jennifer is a Master's student in the Department of Immunology at the University of Toronto working to develop new diagnostic tools for allergy and to improve our understanding of the atopic march.

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