Peanut Oral Immunotherapy Research Articles

Real-world adoption of FDA-approved peanut oral immunotherapy with palforzia

Peanut allergy (PA) affects 1% to 2% of individuals in the United States, and significantly impacts quality of life (QoL).1,2 With current management of strict avoidance, the incidence of accidental exposure to peanut is approximately 10% annually, with 30% of exposures requiring epinephrine and medical attention.3,4 In 2020, the U.S. Food and Drug Administration (FDA) approved peanut oral immunotherapy (POIT) with Arachis hypogaea allergen powder (Palforzia, Aimmune, Brisbane, Calif) for the management of PA.

Real-world peanut OIT in infants may be safer than non-infant preschool OIT and equally effective

Early introduction of peanut reduces the risk for peanut allergy, as noted in the landmark Learning Early About Peanut Allergy study1; however, some infants fail primary prevention and still develop peanut allergy.2 There is evidence that preschoolers tend to have milder, more modifiable food allergy,3 which may make them excellent candidates for immunotherapy.4 Real-world data from our group have shown peanut oral immunotherapy (P-OIT) to be particularly safe and effective in preschoolers (aged <70 months),5,6 but there was no specific focus on infants (aged <12 months).

Maximum Dose Food Challenges Reveal Transient Sustained Unresponsiveness in Peanut Oral Immunotherapy (POIMD Study)

The maximum tolerated dose of peanut protein following peanut oral immunotherapy (POIT) is unknown because most research studies have not examined very high thresholds. To define the maximum dose tolerated by patients on POIT and severity of allergic reactions after a 1-month period of treatment discontinuation. In a phase 2 3-year POIT open-label study, we enrolled participants age 5 to 13 years with a 1-year build-up period followed by a 2-year daily maintenance dose of 3900 mg with assessment of the maximum tolerated dose using double-blind placebo-controlled food challenges (DBPCFCs) of 26,225 mg cumulative dose of peanut protein. The DBPCFC was performed at baseline, after 12-month build-up, at 2 year of maintenance, and after a 1-month period of treatment discontinuation. Biomarkers were assessed every 6 weeks for the first 6 months of therapy. A general linear mixed model was used for analysis. The mean maximum cumulative tolerated dose after 12 months increased by 12,063 mg (P < .001) (n= 12), slightly decreased during maintenance (n= 11), and significantly decreased by 7593 mg after avoidance for 1 month (P= .03) (n= 6). Biomarker analysis revealed decreases in cytokine expression within the first 6 weeks of initiation of POIT and decreased peanut-IgG4 and increased cytokine expression after 1 month of discontinuation. The DBPCFC reaction severity, examined through a symptom score with 1 point for each defined symptom, decreased after 12 months, but did not significantly change after 1 month of POIT discontinuation. The evaluation of POIT and sustained unresponsiveness by maximum tolerated dose by DBPCFCs in this small phase 2 trial showed that desensitization is diminished, with 100% loss of tolerated dose after 1 month of avoidance following 3 years of treatment.

First Real-World Effectiveness Analysis of Preschool Peanut Oral Immunotherapy

To examine the effectiveness and safety of peanut oral immunotherapy (POIT) after 1 year of maintenance in preschool-aged children.In the study, researchers included 161 patients aged 9 to 70 months who successfully completed 1 year of maintenance POIT and were eligible for follow-up oral food challenge (OFC). The inclusion criteria were having a history of objective reaction to peanut and a positive test result (either a skin-prick test [SPT] or peanut-specific immunoglobulin E [ps-IgE]) or at least 1 objective reaction with dosing during build-up, along with a predetermined ps-IgE level and SPT wheal size.Preschoolers enrolled in the study were given gradually increasing peanut protein doses over 16–22 weeks at clinic visits, building up to a maintenance dose of 300 mg. The children then ingested 300 mg of peanut protein daily for a year. After ∼12 months, the participants were invited to participate in a follow-up peanut OFC. SPT and/or ps-IgE were obtained at baseline and selectively throughout the maintenance and follow-up OFC visits. Symptoms of allergic reactions occurring were recorded and graded 1 to 5.Of the patients who received a year of maintenance therapy and underwent follow-up OFC (n = 117), 92 (78.6%) tolerated a cumulative dose of 4000 mg peanut protein without any symptoms, and 115 (98.3%) tolerated at least 1000 mg. The dose tolerated had increased on average by 3969 mg in those with a negative follow-up OFC and by 3376 mg in those with a positive follow-up OFC. SPT wheal size was also significantly decreased after a year regardless of follow-up OFC result; however, the decrease in ps-IgE was not statistically significant. Those with reactions at the follow-up OFC had either grade 1 (14.5% of all who underwent OFC), grade 2 (6%), or grade 3 (0.85%). No one had a grade 4 or 5 reaction. Of the 124 patients with safety outcomes analyzed during maintenance therapy, 111 (89.5%) were symptom-free during POIT dosing, 10 (8.1%) had grade 1 reactions, 3 (2.4%) had grade 2 reactions, and only 2 (1.6%) required epinephrine for POIT dosing reactions.POIT is effective for preschoolers, protecting against at least 1000 mg peanut protein exposure after one year of maintenance therapy in 98.3% of children and allowing consumption of up to 4000 mg in 78.6%. It is also safe during maintenance, with nearly 90% of children symptom-free during maintenance dosing.POIT has emerged as a patient-preference–sensitive option to increase tolerance to peanut protein and protect against accidental exposure. Previous studies have revealed that increasing the peanut threshold to 1000 mg provides 99% protection from accidental exposures, and commercial POIT product is now approved in children 4 to 17 years old. This is the first real-world study revealing that the majority of preschoolers (98.3%) are able to tolerate 1000 mg after a year of POIT maintenance therapy. Mounting evidence suggests POIT may be safer and more effective when initiated at younger ages, likely because of a milder allergic phenotype, less patient aversion, and opportunity for better adherence from close parental supervision. Preschool POIT is a promising disease-modifying intervention that, in the context of shared decision-making with an experienced pediatric allergist, is likely to dramatically improve health and economic outcomes for patients and families.

Quality of Life Improves Significantly After Real-World Oral Immunotherapy for Children With Peanut Allergy

To evaluate the quality of life (QoL) of patients with peanut allergy receiving peanut oral immunotherapy (POIT) at an academic center.Patients aged 4 to 17 years with a physician-established diagnosis of peanut allergy who opted to receive POIT.A total of 21 patients underwent POIT between June 2018 and August 2019. QoL scores were assessed with the use of a validated food allergy QoL questionnaires. Changes in QoL scores were measured for each patient before and after POIT.There was a significant improvement between baseline and successful desensitization to 300 mg peanut protein in the overall food allergy QoL score. Significant improvements were seen for the subscales regarding social and dietary limitations and concerns about accidental exposure and allergic reaction severity. There was a high rate of successful treatment completion (95%).This group reports on successful POIT with improvement in QoL. After treatment, patients had fewer concerns about unintentional exposures and the severity of allergic reactions, with fewer limitations in dietary choices and social interactions.Previous studies regarding QoL after POIT were done in research settings in controlled trials. This group shows that the improvement in QoL can also be found in clinical settings outside of these controlled trials. QoL is an important outcome of therapy for patients and their families and may help in the decision to undergo OIT or not. Although this was a small, uncontrolled study, results support what many of us have found in clinical settings, that most families want protection from a potentially severe reaction from accidental ingestion.

Exploring barriers to commercial peanut oral immunotherapy treatment during COVID-19

Among children in the United States, the prevalence of peanut allergy has continued to rise and contributes substantially to the mortality and morbidity associated with food allergies.1-3 Although the standard of care for peanut allergy is strict allergen avoidance in addition to early use of rescue medications, accidental ingestions often occur and can result in severe allergic reactions across the life span.4,5 Despite significant patient and caregiver motivation to reduce the risk for these accidental reactions, treatment options for peanut allergy have not been widely accessible until recently.

A010 MASS CYTOMETRY ANALYSIS REVEALS DAMPENING OF TH2 PHENOTYPE AMONG PEANUT-REACTIVE CD4+ T CELLS FOLLOWING PEANUT-OIT

Oral Immunotherapy (OIT) is a promising intervention to treat food allergies. OIT induces desensitization, defined as lack of clinical reactivity to previously offending food allergen, while under active therapy. We sought to understand the immune mechanism of desensitization among study participants successfully desensitized to peanut following peanut OIT.

A052 EXPLORATORY STUDIES ON HUMAN GI-RESIDENT GAMMA DELTA T CELLS BEFORE AND AFTER PEANUT ORAL IMMUNOTHERAPY

Gamma delta T cells comprise a major T-cell subset in the epithelial layer of mucosa, where they exert regulatory and homeostatic functions, although their role in tolerance to food allergens in humans remains unexplored. To this end, we studied gamma delta T cells among upper-GI tract biopsies taken from peanut allergic study participants undergoing peanut oral immunotherapy.

High-resolution epitope mapping by AllerScan reveals relationships between IgE and IgG repertoires during peanut oral immunotherapy

SummaryPeanut allergy can result in life-threatening reactions and is a major public health concern. Oral immunotherapy (OIT) induces desensitization to food allergens through administration of increasing amounts of allergen. To dissect peanut-specific immunoglobulin E (IgE) and IgG responses in subjects undergoing OIT, we have developed AllerScan, a method that leverages phage-display and next-generation sequencing to identify the epitope targets of peanut-specific antibodies. We observe a striking diversification and boosting of the peanut-specific IgG repertoire after OIT and a reduction in pre-existing IgE levels against individual epitopes. High-resolution epitope mapping reveals shared recognition of public epitopes in Ara h 1, 2, 3, and 7. In individual subjects, OIT-induced IgG specificities overlap extensively with IgE and exhibit strikingly similar antibody footprints, suggesting related clonal lineages or convergent evolution of peanut-specific IgE and IgG B cells. Individual differences in epitope recognition identified via AllerScan could inform safer and more effective personalized immunotherapy.

Home-Based Peanut Oral Immunotherapy for Low-Risk Peanut-Allergic Preschoolers During the COVID-19 Pandemic and Beyond.

The coronavirus disease 2019 (COVID-19) pandemic has led to the deprioritization of non-emergency services, such as oral food challenges and the initiation of oral immunotherapy (OIT) for food-allergic children. Recent studies have suggested that home-based peanut OIT could be a safe and effective option for low-risk peanut-allergic children. In the period between September 1, 2020, and January 31, 2021, nine preschoolers with a history of mild allergic reactions to peanut underwent home-based peanut OIT. Eight of them (88.9%) completed the build-up phase at home in 11–28 weeks, tolerating a daily maintenance dose of 320 mg peanut protein. During the build-up, six patients (75.0%) reported urticaria, three (33.3%) reported gastrointestinal tract symptoms, and one (14.3%) reported oral pruritis. None of the patients developed anaphylaxis, required epinephrine, or attended emergency services related to OIT. One or two virtual follow-up visits were completed per patient during the build-up phase. Our case series shows that home-based OIT could be offered to the low-risk preschoolers during the COVID-19 pandemic when non-emergency services are limited and could be considered beyond the pandemic, especially for the families living in the rural or remote areas that may otherwise be unable to access OIT.

Immunologic assessments from ARTEMIS: A European, phase 3, randomized, double-blind, placebo-controlled trial of AR101 in peanut-allergic subjects aged 4–17 years

In ARTEMIS, 58% of AR101-treated subjects vs. 2% of placebo-treated subjects tolerated 1000 mg peanut protein as a single dose at exit double-blind, placebo-controlled food challenge (DBPCFC; P < 0.0001) following treatment with AR101, an investigational oral biologic drug product for peanut oral immunotherapy. Immune responses to AR101 were assessed at 3 timepoints and compared with the placebo treatment group. All enrolled subjects had a clinical history of peanut allergy, demonstrated sensitization to peanut (skin prick test [SPT] mean wheal diameter ≥ 3 mm and/or peanut-specific immunoglobulin E [psIgE] ≥ 0.35 kUA/L), and reacted to ≤ 300 mg peanut protein at screening DBPCFC. SPT wheal diameter (mm), psIgE (kUA/L) and psIgG4 (mgA/L) assessments were performed at screening, end of dose escalation and study completion (following 3 months at 300 mg/day). Differences between treatment groups from screening to exit were analyzed using an ANCOVA model with terms fitted for group, country and screening value. A total of 175 ARTEMIS subjects (AR101 n = 132, placebo n = 43) were treated. SPT wheal diameter, psIgE levels, psIgG4 levels and psIgE/IgG4 ratio are summarized in Table 1 . From baseline to exit (AR101 vs. placebo), psIgG4 levels increased ( P < 0.0001); SPT wheal diameter ( P < 0.0001) and psIgE/psIgG4 ( P < 0.0001) decreased. In AR101-treated subjects, psIgE levels 2 increased at the end of dose escalation and decreased back to baseline levels, with no change between treatment groups ( P = 0.6089) from baseline to exit. Exposure to AR101 was associated with immunologic changes consistent with immunomodulation: increased psIgG4, decreased peanut SPT wheal size and transient changes in psIgE levels, as reported in previous peanut oral immunotherapy trials.

Safety and efficacy comparison : ARTEMIS and PALISADE phase 3 studies of AR101 in peanut allergy

AR101, an investigational oral biologic drug for peanut oral immunotherapy, was studied in PALISADE and ARTEMIS phase 3 trials. Efficacy and safety are compared. Subjects demonstrated clinical history of peanut allergy; peanut-specific immunoglobulin E ≥ 0.35 kUA/L and/or skin-prick test ≥ 3 mm; reacted to ≤ 100 mg (PALISADE)/≤ 300 mg peanut protein (ARTEMIS) at screening double-blind, placebo-controlled food challenge (DBPCFC). After dose escalation to 300 mg/day (6 months), 300 mg/day dosing continued (PALISADE, 6 months; ARTEMIS, 3 months). Results are reported in subjects 4-17-years-old (intention-to-treat/safety populations). A total of 496 PALISADE (AR101 n = 372, placebo n = 124) and 175 ARTEMIS ( n = 132, n = 43) subjects were treated. Ability to tolerate 300 mg, 600 mg or 1000 mg peanut protein at exit DBPCFC was similar (PALISADE vs ARTEMIS; AR101 : 76.6% vs 73.5%, 67.2% vs 68.2%, 50.3% vs 58.3%; placebo : 8.1% vs 16.3%, 4.0% vs 9.3%, 2.4% vs 2.3%). Most treatment-emergent adverse events (TEAEs) were mild/moderate (AR101, placebo : PALISADE 94.4%, 94.4%; ARTEMIS 97.7%, 97.7%); frequency decreased from dose-escalation to 300 mg/day dosing (X). For dose-escalation in-clinic TEAEs, range of median times to symptom onset following ingestion and times from first symptom onset to last symptom resolution were similar (AR101, placebo: PALISADE onset 4.0–5.5 min, 8.0–38.5 min; resolution 16.0–32.5 min, 15.0–38.0 min; ARTEMIS onset 2.0–10.0 min, 1.5–15.0 min; resolution 14.0–47.8 min, 7.0–85.0 min) ( Fig. 1 ). AR101 efficacy and safety results are consistent across trials despite different entry criteria. Most TEAEs were mild/moderate and transient. AR101 has a readily manageable safety profile with high desensitization rates possible as early as 3 months after 300 mg/day dosing.

Onset of eosinophilic esophagitis during a clinical trial program of oral immunotherapy for peanut allergy

Onset of eosinophilic esophagitis during a clinical trial program of oral immunotherapy for peanut allergy

Long-term benefit of probiotic peanut oral immunotherapy on quality of life in a randomized trial

Food allergy prevalence has increased globally in recent decades.1-3 Management relies on avoidance of trigger foods, but accidental ingestion is common, causing frequent and sometimes life-threatening reactions.4 With no reliable means to predict reaction severity or timing, patients and caregivers live in fear of unpredictable life-threatening allergic reactions. This uncertainty gives rise to extreme anxiety and avoidance on the one hand, or frustration and risky behaviors on the other.5,6 Intense effort has been directed toward identifying an effective food allergy treatment that can improve health-related quality of life (QoL).

Memory and naïve gamma delta regulatory T-cell gene expression in the first 24-weeks of peanut oral immunotherapy

BackgroundPeanut oral immunotherapy (POIT) has provided desensitization to peanut allergic individuals. Limited immunological evaluation exists during the first 24-weeks of POIT. ObjectiveRegulatory T-cells (Tregs) are antigen induced immunosuppressive T-cells important in establishing tolerance. Delineation of early immunologic changes contributing to the development of peanut desensitization would help clarify the mechanism of action in POIT. We performed single-cell RNA sequencing (scRNAseq) on Tregs in pediatric subjects undergoing POIT during the first 24-weeks of therapy to evaluate early immunological changes induced by POIT. MethodsPBMC samples from peanut allergic subjects between 5 and 12 years of age enrolled in a Phase 1/2a POIT study were collected and analyzed at 0, 6, and 24-weeks after POIT initiation and samples were compared to healthy non-peanut allergic controls. Tregs were enriched from PBMCs and scRNAseq analysis performed. Cell Ranger 3.1.0 (10× Genomics) was utilized to identify cell clusters and differentially expressed genes, and results were analyzed with Seurat suite version 3.0.0. ResultsGene analysis revealed 10 major clusters corresponding to different cell types observed to change during POIT when compared to the healthy, non-peanut-allergic state. scRNAseq analysis of Tregs revealed strong CD3G expression correlating with gdTregs. scRNAseq analysis of gdTregs revealed dynamic changes occurring within the first 6-weeks of treatment and cell frequencies of naïve and memory gdTregs at 24-weeks of treatment reducing to levels similar to healthy controls. Analysis of transcriptomic cell identity analysis using SingleR showed gene expression in gdTregs similar to healthy control after 24-weeks of POIT treatment. scRNAseq analysis revealed alterations in gene expression for memory and naïve gdTregs during this timeframe. Specifically, expression of OX40R (TNFRSF4), GITR (TNFRSF18), TGFB1, CTLA4, ISG20, CD69 were upregulated in memory gdTregs compared to naive gdTregs by 24-weeks of POIT, while IL7R and SELL were downregulated in memory gdTregs compared to naïve gdTregs. ConclusionsThere are specific expression profiles of peripheral naïve and mature gdTreg cells in peanut allergic patients undergoing POIT in the first 24-weeks of treatment implicating pathways involved in maintenance of immune homeostasis. gdTreg cells may contribute to the tolerogenic effect of POIT within the first 24-weeks of POIT treatment. These findings suggest that gdTregs cells may be an early marker of desensitization in subjects undergoing POIT.

Urinary prostaglandin D2 metabolite appears to be a useful biomarker for evaluating the status of egg oral immunotherapy in children

Food allergy (FA) is an increasingly prevalent global health problem.1 Previously, the only management for FA was the avoidance of food allergens. However, oral immunotherapy (OIT) has become increasingly popular as a potential treatment option for FA.2,3 Recently, a product for peanut OIT, Palforzia (Aimmune Therapeutics, Brisbane, Calif), was approved by the US Food and Drug Administration for use in children aged 4 to 17 years. OIT involves the continued daily consumption of a progressively escalating dose of food allergen, which can induce a state of desensitization or tolerance in patients with FA after a maintenance period ranging from months to years.

The Risk Reduction of Accidental Exposure-Related Systemic Allergic Reactions Extrapolated Based on Food Challenge Data After 1 Year of Peanut Oral Immunotherapy.

IntroductionThe phase 3 trial PALISADE, comparing peanut (Arachis hypogaea) allergen powder-dnfp (PTAH) oral immunotherapy versus placebo in peanut-allergic children, reported that a significantly higher percentage of PTAH-treated participants tolerated higher doses of peanut protein after 1 year of treatment. This study used PALISADE data to estimate the reduction in the risk of systemic allergic reaction (SAR) after accidental exposure following 1 year of PTAH treatment.MethodsParticipants (aged 4–17 years) enrolled in PALISADE were included. Parametric interval-censoring survival analysis with the maximum likelihood estimation was used to construct a real-world distribution of peanut protein exposure using lifetime SAR history and highest tolerated dose (HTD) from a double-blind, placebo-controlled food challenge conducted at baseline. The SAR risk reduction was extrapolated using the exposure distribution and the HTD were collected at baseline and trial exit for PTAH- and placebo-treated participants.ResultsAssuming a maximum peanut protein intake of 1500 mg, participants were estimated to have < 1% probability of ingesting > 0.01 mg during daily life. The mean annual SAR risk at trial entry was 9.25–9.98%. At trial exit, the relative SAR risk reduction following accidental exposure was 94.9% for PTAH versus 6.4% for placebo. For PTAH-treated participants with exit HTD of 600 or 1000 mg without dose-limiting symptoms, the SAR risk reduction increased to 97.2%. The result was consistent in the sensitivity analysis across different parametric distributions.ConclusionOral immunotherapy with PTAH is expected to result in a substantially greater reduction in risk of SAR following accidental exposure compared to placebo among children with peanut allergy.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01843-2.

Addressing Common Misconceptions in Food Allergy: A Review.

Background: Food allergies are common, affecting 1 in 13 school children in the United States and their prevalence is increasing. Many misconceptions exist with regards to food allergy prevention, diagnosis and management. Objective: The main objective of this review is to address misconceptions with regards to food allergies and discuss the optimal, evidence-based approach for patients who carry this diagnosis. Observations: Common misconceptions in terms of food allergy prevention include beliefs that breastfeeding and delayed introduction of allergenic foods prevent the development of food allergies. In terms of diagnosis, statements such as ‘larger skin prick tests or/and higher levels of food-specific IgE can predict the severity of food-induced allergic reactions’, or ‘Tryptase is always elevated in food-induced anaphylaxis’ are inaccurate. Additionally, egg allergy is not a contraindication for receiving the influenza vaccine, food-allergy related fatalities are rare and peanut oral immunotherapy, despite reported benefits, is not a cure for food allergies. Finally, not all infants with eczema will develop food allergies and epinephrine auto-injectors may unfortunately be both unavailable and underused in food-triggered anaphylaxis. Conclusions and relevance: Healthcare professionals must be familiar with recent evidence in the food allergy field and avoid common misunderstandings that may negatively affect prevention, diagnosis and management of this chronic disease.

Grass pollen allergy as an anaphylaxis cofactor during peanut oral immunotherapy

Grass pollen allergy, typically associated with non–life-threatening symptoms, such as rhinoconjunctivitis, is one of the most common allergies worldwide.1 Rarely, anaphylaxis occurs after grass pollen exposure in children.2 Oral immunotherapy (OIT) for the treatment of food allergy has been gaining popularity in the last decade as evidence on methodology, effectiveness, and safety has progressed.3,4 Studies have revealed that patients with peanut allergy on OIT with seasonal allergic rhinitis experience dose-related adverse events more frequently with seasonal patterns.

The clinical advances of the peanut oral immunotherapy

Food allergy is a global problem. Peanut is one of the most common food allergens that can result in anaphylaxis, even with milligram exposure. Most peanut allergies could persist lifelong. The current standard of care for peanut allergy is strict dietary avoidance and immediate treatment of allergic reaction triggered by accident exposure. Oral immunotherapy (OIT) induces an increased reactivity threshold via modulation of the immune system. In recent years, peanut OIT has been developed to protect peanut-allergic individuals against severe or life-threating allergic reaction. This review discussed the update of the mechanism, efficacy, safety and impact on quality of life of peanut OIT for peanut allergy.