PROJECT SUMMARY It is estimated that as many as 30% of people with food allergy (FA) suffer from multiple FAs. The immune mechanisms underlying different clinical outcomes of oral immunotherapy (OIT) are not well understood, particularly in multi-food allergic individuals, and it is not clear to what extent combining OIT with other immunomodulating therapies might improve the safety or efficacy of OIT in FA, or the durability of favorable clinical outcomes. There is an unmet need for new therapies in FA, since OIT is associated with refractory or fail-to-treat populations, likely due to a number of cellular and molecular endotypes and clinical phenotypes. Because the cytokines IL-4 and IL-13 are important immune drivers of FA that act upstream of IgE in generating an allergic response, to address these challenges, our approach is to conduct a pilot, phase 2, multiple food allergen OIT (mOIT) study to compare the safety, efficacy and durability of mOIT combined with the anti-IL- 4Rα antibody dupilumab (DmO) vs. mOIT alone, and vs. mOIT combined with the anti-IgE antibody, omalizumab (OmO). We hypothesize that such combination therapy could improve the safety, efficacy and/or durability of mOIT in multi-FA patients. We also hypothesize that DmO, but not OmO, will improve sustained unresponsiveness outcomes vs. mOIT alone, due to the effects of dupilumab on the actions of IL-4 and IL-13. Our study will provide samples at screening, throughout OIT, and long-term after OIT, for key bioassays in Projects 2 (B cells), 3 (T cells) and 4 (basophils). Our study thus offers an arguably unique opportunity to achieve our overall objective: creating a comprehensive dataset of the clinical and immune monitoring outcomes of OIT protocols to better understand mechanisms of FA and to improve the safety and efficacy of FA therapy. Our specific aims are to: 1) Test whether treatment with mOIT combined with either omalizumab or dupilumab vs. mOIT alone results in a higher proportion of participants being able to pass a food challenge at week 24 (primary endpoint) and after a period of allergen withdrawal at week 30 (a secondary endpoint);; 2) Determine whether these OIT protocols have lasting effects on the efficacy and safety of these treatments, and on changes in the subjects' immune responses that were induced by such treatments;; and 3) Obtain GI biopsies of participants to permit a detailed analysis of immune cells and their products in GI tissues, at entry into the trial to identify features associated with FA at the disease site, and over the course of OIT to evaluate whether and how these features might change. Project 1 will be the first study to evaluate and compare each immunomodulating drug combined with mOIT vs. mOIT alone: the novelty of the study design combined with detailed mechanistic studies of blood and GI biopsies will pe...