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

Cow’s milk allergy (CMA) is a common pediatric food allergy, and traditional oral immunotherapy (OIT) with unheated milk is often limited by adverse reactions. This study evaluated the safety and efficacy of baked milk oral immunotherapy (BMOIT) as a potentially safer desensitization strategy in children with severe CMA, including those reactive to baked milk (BM).Thirty children aged 3 to 18 years with immunoglobulin E (IgE)–mediated CMA who reacted to less than or equal to 444 mg (<1 tablespoon) of BM protein were enrolled. Many participants had comorbid atopic conditions and multiple food allergies.This phase 2 randomized, double-blind, placebo-controlled trial was followed by a 12-month open-label extension. In year 1, participants received either BMOIT or placebo. In year 2, all received BMOIT. Clinical results were assessed using double-blind, placebo-controlled food challenges to BM at 12 and 24 months, and to unheated milk (UM) at 24 months if 2000 mg of BM was tolerated. Immunologic considerations included milk-specific IgE and IgG4 levels and CD4+ memory T-cell subset analysis via flow cytometry and single-cell RNA sequencing.By 24 months, 70% (21/30) of participants tolerated 4044 mg of BM protein (approximately ½ cup baked milk). Thirty-seven percent (11/30) tolerated greater than or equal to 2000 mg of UM, and 13% (4/30) tolerated the full 8030-mg UM dose (approximately 1 cup unheated milk). BMOIT was well tolerated as 12% of doses elicited mild symptoms (primarily oral or GI), with only 1 epinephrine-requiring reaction in the placebo crossover group. Six discontinued, 1 due to dosing-related symptoms. Clinical desensitization correlated with increased casein and β-lactoglobulin–specific IgG4, increased FOXP3+ Tregs, and decreased Th2A cells and CM-specific IgE. A predictive model incorporating FOXP3+/Th2A ratios and IgG/IgE ratios accurately predicted UM desensitization with an area under the curve = 0.91.BMOIT is a safe and effective desensitization strategy in children with severe CMA, including those initially reactive to BM. Immunologic shifts toward regulatory T-cell dominance and away from Th2A responses reflect important disease predictors. Predictive biomarkers may eventually guide individualized OIT.This well-designed, longitudinal study provides critical clinical and mechanistic insight into the utility of baked milk in OIT treatments. The ability to induce desensitization while minimizing severe reactions, combined with detailed immune profiling, makes BMOIT a compelling option for high-risk patients with CMA. Using CMA as a model, these findings are likely to influence the practices of pediatric allergists and promote use of biomarker-driven immunotherapy strategies.