Immune changes beyond Th2 pathways during rapid multifood immunotherapy enabled with omalizumab

Abstract

Background: Multifood oral immunotherapy (mOIT) with adjunctive anti-IgE (omalizumab, XOLAIR ® ) treatment affords safe, effective, and rapid desensitization to multiple foods, although the specific immune mechanisms mediating this desensitization remain to be fully elucidated. Methods: Participants in our phase 2 mOIT trial (NCT02643862) received omalizumab from baseline to week 16 and mOIT from week 8 to week 36. We compared the immune profile of PBMCs and plasma taken at baseline, week 8, and week 36 using high-dimensional mass cytometry, component-resolved diagnostics, the indirect basophil activation test, and Luminex. Results:We found (i) decreased frequency of IL-4 + peanut-reactive CD4 + T cells and a marked downregulation of GPR15 expression and CXCR3 frequency among γδ and CD8 + T-cell subsets at week 8 during the initial, omalizumab-alone induction phase;(ii) significant upregulation of the skin-homing receptor CCR4 in peanut-reactive | INTRODUC TI ONFood allergy, a major public health concern in the United States, affects ~8% of children under the age of 18, nearly 40% of whom suffer from allergies to multiple foods, 1 a prevalence that is rising. 2 Multifood oral immunotherapy (mOIT), during which several food allergens are gradually introduced at increasing doses, provides safe and efficacious desensitization to multiple (2-5) offending foods. 3 We and others have previously demonstrated that anti-IgE (omalizumab, XOLAIR ® ) combined with single-allergen OIT rapidly desensitized patients to single allergens such as milk or peanuts. [4][5][6][7][8] Our phase 1/2 clinical trials [9][10][11] have demonstrated that incorporating omalizumab with mOIT also safely desensitizes patients with allergies to multiple foods. mOIT using omalizumab induction treatment is currently being tested in a phase multicenter, placebo-controlled clinical trial (NCT03881696) under breakthrough designation by the FDA.

Peanut oral immunotherapy differentially suppresses clonally distinct subsets of T helper cells

“…Despite this limitation, the study of peripheral peanut-reactive T cells during OIT has considerable translational value, as changes in the peripheral blood can be easily monitored in a clinical setting. Moreover, we and others have successfully identified clinically relevant responses in peanut-reactive T cells from peripheral blood during OIT ( 17 , 22 , 62 ).…”

Oral Immunotherapy for Food-Allergic Children: A Pro-Con Debate

“…Subsequent studies showed that omalizumab facilitated a faster achievement of higher OIT maintenance doses as compared to regular OIT (32,(65)(66)(67)(68)(69). Importantly, while omalizumab used as an adjuvant to OIT improved its safety and tolerability, it did not lead to higher efficacy (67), although larger studies are required on this topic (70). In this context, biologics intended to block other pathways of the Th2 immune response, such as dupilumab have begun to be explored in FA patients (71).…”

Advances in allergen‐specific immune cell measurements for improved detection of allergic sensitization and immunotherapy responses

“…Using Ara h 2 peptide‐MHCII dextramers, Wang et al showed increased TGFβ production in allergen‐specific Th cells 74 . Adjunctive anti‐IgE (omalizumab) treatment enables rapid multifood oral immunotherapy and has been shown to reduce circulating IL‐4+ peanut‐specific Th cells 75 . In addition, the frequencies of peanut‐specific CD8+ and TCRγδ+ T cells were reduced, 75 suggesting reduced capacity of these inflammatory cells to migrate to the gastrointestinal tract.…”

“…58 treatment enables rapid multifood oral immunotherapy and has been shown to reduce circulating IL-4+ peanut-specific Th cells. 75 In addition, the frequencies of peanut-specific CD8+ and TCRγδ+ T cells were reduced, 75 suggesting reduced capacity of these inflammatory cells to migrate to the gastrointestinal tract.…”