Abstract

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Food allergies are a major health burden globally1. There is currently no cure so management relies on allergen avoidance, which causes significantly reduced quality of life2. Intense research effort has focused on developing treatments that induce remission of allergy. Progress has been hampered by a limited understanding of the immune mechanisms that drive the transition from allergy to remission. Few therapies under investigation have been reported to induce remission.

Oral immunotherapy (OIT) shows promise but has major drawbacks including: (i) limited efficacy; (ii) loss of efficacy over time - two thirds of patients lose their remission within 12 months of stopping treatment3-5; and (iii) frequent adverse events that occur more frequently than with allergen avoidance (current standard of care), particularly gastrointestinal (GI) and systemic reactions, which results in treatment withdrawal. Safety and efficacy concerns have caused experts to question whether OIT offers greater benefit over allergen avoidance. Treatments that induce lasting remission with fewer side effects are needed.

The Allergy Immunology Research Group at MCRI has been investigating a treatment that combines a probiotic adjuvant alongside OIT (Probiotic Peanut OIT; PPOIT) with the aim of improving safety and/or efficacy of OIT. Our studies have shown that PPOIT is highly effective at inducing lasting remission, with 70% of initial treatment responders still having remission 4 years after stopping treatment1,2. Importantly, PPOIT was associated with low rates of GI symptoms, few systemic reactions and no cases of eosinophilic esophagitis. We recently completed a phase 2b randomized trial (PPOIT003) comparing PPOIT vs peanut OIT vs Placebo in 200 children with peanut allergy aged 1-10 years, which showed that both PPOIT and OIT are effective at inducing remission of peanut allergy compared with placebo3; addition of the probiotic to 18 months of peanut OIT treatment did not improve efficacy but provided an important and significant safety benefit, particularly in children aged 1-5 years, who had 30% - 50% reduction in GI symptoms, 40% reduction in systemic reactions and no cases of eosinophilic esophagitis.

A follow-on study is currently underway to compare the durability of PPOIT- vs OIT-induced remission. Early treatment of preschool aged children can increase the likelihood of achieving remission; however, safety is a major concern because this vulnerable population has a limited ability to voice pain and distress. PPOIT offers a novel approach to induce long-lasting remission with improved safety in young children.

The immune changes that underpin long-lasting remission remain unknown. We have completed two phase 2 studies which showed PPOIT induces lasting remission, with 60%-70% of treatment responders still having remission at 3-4 years post-treatment. By contrast, peanut OIT alone induces remission that is short-lived, with two thirds (67%) of treatment responders losing their remission state by 12 months post-treatment4,5. Our preliminary gene expression data shows that remission following PPOIT treatment is associated with comprehensive shutdown of T helper 2 (Th2) signaling and emergence of dominant regulatory signals that persist months after stopping treatment6.

We have also shown that the probiotic in PPOIT is a potent inducer of tolerogenic plasmacytoid DC (pDC)7. In contrast, published studies of OIT report downregulation of Th2 signaling and transient induction of FOXP3 (a regulator of T regulatory cell development and function) gene expression that is lost over time5. Long term follow-up mechanistic studies following oral immunotherapy are lacking. The PPOIT003 follow-on study is now approaching 2-3 years post-treatment and we seek funding to collect biospecimens at the 4-year post-treatment window, including a blood sample and stool, to make use of an invaluable opportunity to study longer term effects following treatment.

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