Exploring mechanisms to optimise the duration of oral immunotherapy for peanut allergy

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Peanut allergy affects 1 in 30 children and is the commonest trigger for life-threatening reactions (anaphylaxis) in this age group. It is a major public health issue, with practical implications for industry, education and healthcare systems.Oral immunotherapy (OIT) is an emerging treatment option, where small, increasing doses of a food allergen are used to cause "desensitisation", so that patients no longer experience symptoms upon exposure to the food. However, frequent allergic reactions to OIT (including anaphylaxis) are common, and thus a limiting factor. Furthermore, treatment effect requires ongoing OIT dosing: over half of patients lose their desensitisation after stopping OIT for 4 weeks. This is a problem, as patients are usually averse to the taste of the food they are allergic too, which affects compliance and treatment success. Persistence of desensitisation, without the need for ongoing regular maintenance dosing, is arguably the most important outcome for patients and their families. The biological mechanism(s) underlying OIT - and in particular, the persistence of desensitisation - are unclear. This significantly limits our ability to identify patients who may need a different protocol to minimise adverse reactions, achieve longer-lasting desensitisation, and improve patient safety. Immunotherapy is widely undertaken for the treatment of hay fever and allergy to insect stings - where treatment success is dependent on the duration of treatment. We therefore expect that for food allergy, the duration of OIT may be of critical importance in achieving longer-term efficacy.In the Boiled Oral Peanut Immunotherapy (BOPI) study (NCT02149719; part-funded through an MRC Fellowship to TURNER), 75% of participants achieved the primary outcome for the study, and tolerated a dose of 1.4 grams peanut protein (approximately 6-8 peanuts) at double-blind, placebo-controlled food challenge after 1 year of treatment. 53% maintained their desensitisation after stopping peanut OIT for 4 weeks; this increased to 72% after up to 2 years of further maintenance treatment.PROJECT PLANWe will evaluate the impact of longer durations of peanut-OIT (up to 3 years) on changes in the immune system, and how this corresponds to clinical outcomes, including desensitisation (and whether this is sustained) and safety, in patients undergoing peanut-OIT. We will apply novel techniques to study not just the initial changes that result in desensitisation, but also what happens when patients subsequently stop OIT doses and the treatment effect may be lost. We have successfully applied this approach to hay fever immmunotherapy. We will therefore be able to better understand the impact of OIT on the immune system, and how the desensitisation effect is sustained. We will analyse blood samples which have been bio-banked from patients in the original BOPI study who have undergone OIT for up to 3 years (under existing ethics approval). Together with existing clinical and laboratory data from BOPI, this will form the most comprehensive dataset evaluating how duration of OIT impacts on both clinical and mechanistic outcomes. Where we identify key findings, we will seek to replicate (and therefore validate) these in a further peanut-OIT study (BOPI-2 study; NCT03937726; currently underway) which also follows patients through to 3 years).This robust approach will allow us to assess the mechanisms associated with both the induction and loss of desensitisation in peanut-allergic children undergoing up to 3 years of OIT. We will use machine learning approaches to understand how these immune changes correlate to clinical outcomes, and so build a model (including both patient characteristics and initial response to treatment) which can predict longer-term treatment outcomes. If successful, this will facilitate the personalisation of OIT protocols, maximising treatment success and leading to safer patient outcomes.