D2.499 - Immunoregulatory Effects of Dupilumab Added to Omalizumab-Facilitated Multi-Allergen Oral Immunotherapy in the COMBINE clinical trial

Omalizumab-facilitated multi-allergen oral immunotherapy (mOIT) has been shown to be safe and effective in treating food allergy. It remains unclear whether the addition of dupilumab, an anti–IL-4R monoclonal antibody, provides additional benefit. We hypothesize that combining dupilumab with omalizumab-facilitated mOIT induces phenotypic and functional changes in T-cell subsets that lead to improved clinical outcomes.

In a phase 2, multi-center, double-blind, randomized, placebo-controlled trial (COMBINE, NCT03679676), 108 participants (aged 4-55) with multiple food allergies (peanut plus one or two additional foods) were randomized to three arms: (1) omalizumab followed by mOIT (arm 1, n=49); (2) omalizumab followed by dupilumab plus mOIT (arm 2, n=49); or (3) placebo followed by dupilumab plus mOIT (arm 3, n=10; mechanistic-only arm). Omalizumab or placebo was administered during weeks 0–8, followed by dupilumab or placebo and mOIT during weeks 8–32. High-dimensional spectral flow cytometry was used to characterize T-cell subsets in PBMCs collected at baseline and week 32 under unstimulated conditions and following in vitro stimulation with peanut antigen.

At week 32, participants in arm 2 exhibited a significantly higher proportion of regulatory T cells (CD25⁺CD127dim) within the total CD4⁺ T-cell population compared with those in arm 1; this difference was not observed at baseline. Similar increases in regulatory T-cell frequencies were observed under both peanut-stimulated and unstimulated conditions, indicating a consistent shift toward a regulatory phenotype. 

At week 44, participants underwent peanut challenge. Sustained unresponsiveness (SU) to peanut alone was achieved by 19 of 49 participants (39%) in arm 1 and 27 of 49 participants (55%) in arm 2. SU to peanut plus one additional allergen was observed in 17 of 49 participants (35%) in arm 1 and 24 of 49 participants (49%) in arm 2. SU to peanut plus two additional allergens was achieved by 6 of 31 participants (19%) in arm 1 and 9 of 30 participants (30%) in arm 2.

Dupilumab added to omalizumab-facilitated mOIT is associated with increased regulatory T cells and improved clinical outcomes, supporting its potential role in enhancing immune tolerance during oral immunotherapy.