Therapy
Recent years have witnessed significant developments in the pursuit of safe and effective treatment options for those with FA.59-61 (Table 1 ). Landmark studies demonstrating the safety, efficacy of desensitization, and improvements in patient quality of life with oral immunotherapy (OIT) for food allergens led to the approval of peanut (Arachis hypogaea ) Allergen Powder-dnfp, the first oral peanut agent approved by the FDA and EMA for use in FA8,19,29,60,62-70. Durability of desensitization following therapy, however, is still under question. The IMPACT study demonstrated that peanut OIT is safe in children 1-3 years of age, inducing desensitization up to 5000 mg of peanut protein in 71% of patients71. Remission rates were highly enriched in younger patients, suggesting that desensitization within a critical window may lead to more permanent immune changes. Similarly, the POISED study, a long-term trial of peanut OIT in patients aged 7-55 years highlights that SU is only achievable in less than 35% of those who are successfully desensitized, and SU through the course of a year is even less (13%)19.
Despite the efficacy of OIT in desensitization, the daily consumption of allergenic foods can be burdensome, stressful, and marked with dose-related AEs, making continued compliance challenging. Designed to counter some of these difficulties, epicutaneous immunotherapy (EPIT) employs a skin patch system for continuous, non-invasive delivery of the food allergen. Initial results have demonstrated modest success, with peanut EPIT providing improvements in quality of life and improving threshold sensitivity to one peanut (300 mg protein) in 35.3% after 12 months of therapy (PEPITES)72 and to 444 mg peanut protein in 21.7% of patients after 130 weeks of desensitization73. Rates of adherence with EPIT are high (96%) and although reactions are common (77.6%), they are mild and local. 73-75. Although EPIT achieves lower sensitivity thresholds than OIT initially, threshold sensitivity appears to improve over time. In addition to EPIT, sublingual immunotherapy (SLIT) is another alternative to OIT which has proven to be safe and effective76,77. Peanut SLIT induced desensitization in 25% and SU in 20.8% of patients after 3-5 years of treatment78. Other alternatives to oral exposure are currently under investigation, including a Phase I clinical trial assessing the safety and feasibility of INT301, a toothpaste containing peanut protein, targeting peanut concentrations between SLIT and OIT. Despite oral delivery, INT301 is hoped to elicit fewer systemic side effects compared to OIT as the majority of the agent is expelled after brushing, minimizing gastrointestinal (GI) contact with the allergen.
Growing data supports the link between the microbiota and immune system and modulation of gut microbiota through the introduction of new bacterial species or manipulation of existing microbes via specific probiotic supplementation has been proposed as treatment for FA79-81. In a phase II study of peanut OIT with adjunct Lactobacillus rhamnosus GG ATCC 53103, adjuvant probiotic therapy slightly, but significantly, reduced the exposure-adjusted incidence of AEs by about 8% in comparison to OIT with placebo probiotic; with a more notable (24%) reduction in exposure-adjusted incidence of AEs in children 1-5 years of age82. Further research into the use of an alternative probiotic,Bifidobacterium bifidum TMC3115, in infants aged 0.5 to 12 months of age with cow’s milk allergy found reduced allergic symptom scores in the GI tract (p = 0.001), respiratory tract (p = 0.002), and skin (p = 0.011) compared to placebo after 6 months of supplementation, with decreased serum levels of TNFα, IL-1β, and IL-6 (p ≤ 0.001)83.
In addition to studies investigation single bacterial strains as adjunctive treatment for FA, other clinical trials investigating the broader modulation of the microbiome in those with FA are underway. A phase I/II study, is currently evaluating the use of an orally administered combination of dormant commensal bacteria (VE416) prior to or in combination with peanut OIT, with or without pretreatment with vancomycin, in those with PA (NCT03936998). Another study is evaluating the efficacy of encapsulated fecal microbiota transplantation delivered orally with or without pretreatment with antibiotics in those with PA (NCT02960074). By attempting to augment or replace the microbiome with that of those without FA, the approach may display an advantage over strategies limited to a single strain. The relationship between the microbiome and the immune system is complex and further research is needed before we can leverage the microbiome for treatment of FA.
Initial OIT studies were restricted to treatment of patients with a single FA and did not address the approximately 30% and 45% of children and adults, respectively, who are allergic to more than one food3. In recent years, however, a growing number of trials have demonstrated that simultaneous desensitization to multiple food allergens can be facilitated through the concomitant use of biologic agents. By selectively inhibiting specific mediators of the allergic pathway, these adjunct therapies are proposed to transiently reduce the likelihood of allergic reaction (Figure 3). The most studied biologic, omalizumab, an anti-IgE antibody, has proven to be safe and effective as an adjunct to multi-allergen OIT 84-86, achieving desensitization to amounts of allergen beyond accidental ingestion (1-2 g protein per food)87-89. Compared to placebo, participants receiving adjunct omalizumab prior to and during multi-food OIT experienced reductions in the severity of AEs and a lower median per-participant percentage of their OIT doses associated with any AE (68% vs 27%; p=0·0082), with GI events reported as the most common AE in both groups87,90-93. Ligelizumab, another anti-IgE agent with higher binding affinities for free IgE compared to omalizumab, is currently under investigation for peanut allergic patients (NCT04984876)94-96.
Despite promising data thus far, questions remain regarding the optimal use of biologics, such as dosing, inter-patient variability in response to therapy, and duration of pre- and concomitant treatment85. Studies investigating these questions are currently underway, including the BOOM and OUtMATCH studies. The BOOM study seeks to evaluate the use of an alternative weight-based dosing strategy for omalizumab in combination with multi-allergen OIT (NCT04045301). In parallel, OUtMATCH, a largescale, multi-stage phase III study sponsored by the National Institutes of Health is investigating the use of variable-duration omalizumab therapy for multi-food allergy, with or without multi-allergen OIT, in addition to long-term follow-up monitoring the post-treatment transition to daily consumption of real-food equivalents (NCT03881696).
While omalizumab has shown significant promise in promoting safe and rapid desensitization to multiple foods through IgE suppression, other clinical trials are focusing on broader targets in the allergic pathway in efforts to further minimize AEs and promote SU87,90-93. Dupilumab, an IL-4Rα antibody, blocks downstream signaling of both IL-4 and IL-13, key mediators involved in the promotion of B cell IgE class-switching, macrophage polarization toward the pro-inflammatory M2 phenotype, and the induction of peripheral and esophageal eosinophilia97. With potential benefits over anti-IgE therapy through broader inhibition of inflammatory pathways, multiple phase II clinical trials are currently evaluating the use of dupilumab for FA. These include trials investigating its use with and without concomitant peanut OIT for PA, as well as the MAGIC study evaluating its use as an adjunct to cow’s milk OIT for milk-allergic patients (Table 1 ). In a first-of-its-kind trial, the COMBINE study, a phase II multi-center trial, is investigating the combined use of biologics for the first time in FA, aiming to simultaneously target multiple allergenic pathways. In the study, the step-wise use of omalizumab followed by dupilumab during concomitant multi-allergen OIT will evaluate safety and efficacy related to desensitization and the induction of SU.
Upstream of the allergic pathway, the interruption of early signaling pathways involving an alarmin, IL-33, with etokimab has shown modest promise in a pilot study (Table 1 ). A single dose of etokimab improved desensitization in peanut allergic patients in a DBPCFC 15 days after treatment (73% of patients tolerated 275mg peanut vs 0% placebo). Beyond each of the biologics present here, trials investigating strategies aimed at novel targets continue to emerge at a consistent pace. Some recent examples include a co-stimulatory inhibitor (Abatacept) and Bruton tyrosine kinase inhibitor (Acalabrutinib) (Table 1).
While the use of biologic therapies aims to selectively inhibit or modify components of the allergic pathway with or without concomitant allergen exposure, an alternative therapeutic strategy centers on allergen exposure in ways that promote desensitization while avoiding recognition by allergic mediators altogether. Studies investigating the safety and efficacy of intravenously delivered nanoparticle-encapsulated purified peanut extract (CNP-201) are currently underway for those with PA (Table 1). By shielding the peanut antigen from recognition by IgE and other mediators within a nanoparticle matrix, investigators aim to prevent allergic reactions while the allergen is in circulation and present allergen to naïve T cells in a tolerogenic environment in the liver and spleen.