Clinical and Immunological Outcomes after Randomized Trial of Baked Milk Oral Immunotherapy for Milk Allergy

BACKGROUND. Cow’s milk allergy (CMA) is the most common food allergy in young children. Treatment with oral immunotherapy (OIT) has shown efficacy but also high rates of adverse reactions. We sought to determine if baked milk (BM) OIT could reduce adverse reactions while still inducing desensitization, and to identify immunological correlates of successful BMOIT. METHODS. This phase II, randomized trial evaluated the safety and efficacy of BMOIT in children age 3-18 years. After the initial placebo-controlled first year of treatment, placebo-treated participants crossed over to active BMOIT for year two. Double-blind, placebo-controlled food challenges (DBPCFC) were conducted to BM after year one and to both BM and unheated milk (UM) after year two. IgG/IgE antibodies were measured along with cow’s milk (CM)-specific CD4 memory T cell populations, profiled using flow cytometry and scRNA-Seq. RESULTS. Twenty-one of 30 (70%) reached the primary endpoint of tolerating 4044mg of BM protein at month-24, and 11/30 tolerated ≥2000mg of UM. Dosing symptoms were common, but >98% were mild with no severe reactions. Immunological changes associated with desensitization included increased CM IgG4, CM+ FOXP3+ cells, and Tregs and corresponding decreases in CM IgE, CM+ Th2A cells, and CD154+ cells. T cell and antibody measurements were combined to build a model that predicted UM oral food challenge (OFC) outcomes. CONCLUSION. BMOIT was well tolerated and induced a substantial level of desensitization to baked and unheated milk. This desensitization corresponded to significant redistribution within antigen specific antibody and T cell compartments that provide novel insight into the mechanistic changes that occur with OIT treatment.