Peanut-specific type 1 regulatory T cells induced in vitro from allergic subjects are functionally impaired.

BACKGROUND: Peanut allergy (PA) is a life-threatening condition that lacks regulator-approved treatment. Regulatory T type 1 (TR1) cells are potent suppressors of immune responses and can be induced in vivo upon repeated antigen exposure or in vitro by using tolerogenic dendritic cells. Whether oral immunotherapy (OIT) leads to antigen-specific TR1 cell induction has not been established. OBJECTIVES: We sought to determine whether peanut-specific TR1 cells can be generated in vitro from peripheral blood of patients with PA at baseline or during OIT and whether they are functional compared with peanut-specific TR1 cells induced from healthy control (HC) subjects. METHODS: Tolerogenic dendritic cells were differentiated in the presence of IL-10 from PBMCs of patients with PA and HC subjects pulsed with the main peanut allergens of Arachis hypogaea, Ara h 1 and 2, and used as antigen-presenting cells for autologous CD4+ T cells (CD4+ T cells coincubated with tolerogenic dendritic cells pulsed with the main peanut allergens [pea-T10 cells]). Pea-T10 cells were characterized by the presence of CD49b+ lymphocyte-activation gene 3 (LAG3)+ TR1 cells, antigen-specific proliferative responses, and cytokine production. RESULTS: CD49b+LAG3+ TR1 cells were induced in pea-T10 cells at comparable percentages from HC subjects and patients with PA. Despite their antigen specificity, pea-T10 cells of patients with PA with or without OIT, as compared with those of HC subjects, were not anergic and had high TH2 cytokine production upon peanut-specific restimulation. CONCLUSIONS: Peanut-specific TR1 cells can be induced from HC subjects and patients with PA, but those from patients with PA are functionally defective independent of OIT. The unfavorable TR1/TH2 ratio is discussed as a possible cause of PA TR1 cell impairment.

Observational long-term follow-up study of rapid food oral immunotherapy with omalizumab.

BACKGROUND: A number of clinical studies focused on treating a single food allergy through oral immunotherapy (OIT) with adjunctive omalizumab treatment have been published. We previously demonstrated safety and tolerability of a rapid OIT protocol using omalizumab in a phase 1 study to achieve desensitization to multiple (up to 5) food allergens in parallel, rapidly (7-36 weeks; median = 18 weeks). In the current long-term, observational study, we followed 34 food allergic participants for over 5 years, who had originally undergone the phase 1 rapid OIT protocol. METHODS: After reaching the maintenance dose of 2 g protein for each of their respective food allergens as a part of the phase 1 study, the long-term maintenance dose was reduced for some participants based on a pragmatic team-based decision. Participants were followed up to 62 months through standard oral food challenges (OFCs), skin prick tests, and blood tests. RESULTS: Each participant passed the 2 g OFC to each of their offending food allergens (up to 5 food allergens in total) at the end of the long-term follow-up (LTFU) study. CONCLUSION: Our data demonstrate the feasibility of long-term maintenance dosing of a food allergen without compromising the desensitized status conferred through rapid-OIT. Trial registration Registry: Clinicaltrials.gov. Registration numbers: NCT01510626 (original study), NCT03234764 (LTFU study). Date of registration: November 29, 2011 (original study); July 26, 2017 (LTFU study, retrospectively registered).

Feasibility of sustained response through long-term dosing in food allergy immunotherapy.

BACKGROUND: Clinical trials using oral immunotherapy (OIT) for the treatment of food allergies have shown promising results. We previously demonstrated the feasibility of desensitization for up to 5 food allergens simultaneously through OIT. In this observational study, we report the findings of long-term follow-up (LTFU) of the participants treated through a single site OIT phase 1 trial. METHODS: The participants (n = 46) were followed up to 72 months since the time they reached 2 g maintenance dose per food in the initial phase 1 trial. During the long-term maintenance dosing, participants continued or reduced the initial maintenance dose of food allergen protein to high (median 2 g protein) vs. low (median 300 mg protein). Participant follow-up included clinical monitoring, standardized OFCs, and in some cases, skin prick tests and measurement of allergen-specific IgE and IgG4. RESULTS: Irrespective of the high vs. low long-term maintenance dose during LTFU, all participants were able to ingest 2 g protein of each food allergen protein during OFCs performed at the end of our LTFU. CONCLUSION: Our LTFU cohort of food OIT participants from a single site, phase 1 OIT study, supports the feasibility of sustained desensitization through long-term maintenance dosing. Trial registration Registry: Clinicaltrial.gov. Registration numbers: NCT01490177 (original study); NCT03234764 (LTFU study). Date of registration: November 29, 2011 (original study); July 26, 2017 (LTFU study, registered).

Omalizumab facilitates rapid oral desensitization for peanut allergy.

BACKGROUND: Peanut oral immunotherapy is a promising approach to peanut allergy, but reactions are frequent, and some patients cannot be desensitized. The anti-IgE medication omalizumab (Xolair; Genentech, South San Francisco, Calif) might allow more rapid peanut updosing and decrease reactions. OBJECTIVE: We sought to evaluate whether omalizumab facilitated rapid peanut desensitization in highly allergic patients. METHODS: Thirty-seven subjects were randomized to omalizumab (n = 29) or placebo (n = 8). After 12 weeks of treatment, subjects underwent a rapid 1-day desensitization of up to 250 mg of peanut protein, followed by weekly increases up to 2000 mg. Omalizumab was then discontinued, and subjects continued on 2000 mg of peanut protein. Subjects underwent an open challenge to 4000 mg of peanut protein 12 weeks after stopping study drug. If tolerated, subjects continued on 4000 mg of peanut protein daily. RESULTS: The median peanut dose tolerated on the initial desensitization day was 250 mg for omalizumab-treated subjects versus 22.5 mg for placebo-treated subject. Subsequently, 23 (79%) of 29 subjects randomized to omalizumab tolerated 2000 mg of peanut protein 6 weeks after stopping omalizumab versus 1 (12%) of 8 receiving placebo (P < .01). Twenty-three subjects receiving omalizumab versus 1 subject receiving placebo passed the 4000-mg food challenge. Overall reaction rates were not significantly lower in omalizumab-treated versus placebo-treated subjects (odds ratio, 0.57; P = .15), although omalizumab-treated subjects were exposed to much higher peanut doses. CONCLUSION: Omalizumab allows subjects with peanut allergy to be rapidly desensitized over as little as 8 weeks of peanut oral immunotherapy. In the majority of subjects, this desensitization is sustained after omalizumab is discontinued. Additional studies will help clarify which patients would benefit most from this approach.

Erratum to: Safety and feasibility of oral immunotherapy to multiple allergens for food allergy.

[This corrects the article DOI: 10.1186/1710-1492-10-1.].

Multiple-allergen oral immunotherapy improves quality of life in caregivers of food-allergic pediatric subjects.

BACKGROUND: Food allergy (FA) negatively affects quality of life in caregivers of food-allergic children, imposing a psychosocial and economic burden. Oral immunotherapy (OIT) is a promising investigational therapy for FA. However, OIT can be a source of anxiety as it carries risk for allergic reactions. The effect of OIT with multiple food allergens (mOIT) on FA-specific health-related quality of life (HRQL) has never been studied in participants with multiple, severe food allergies. This study is the first to investigate the effects of mOIT on FA-related HRQL in caregivers of pediatric subjects. METHODS: Caregiver HRQL was assessed using a validated Food Allergy Quality of Life - Parental Burden (FAQL-PB) Questionnaire (J Allergy Clin Immunol 114(5):1159-1163, 2004). Parents of participants in two single-center Phase I clinical trials receiving mOIT (n = 29) or rush mOIT with anti-IgE (omalizumab) pre-treatment (n = 11) completed the FAQL-PB prior to study intervention and at 2 follow-up time-points (6 months and 18 months). Parents of subjects not receiving OIT (control group, n = 10) completed the FAQL-PB for the same time-points. RESULTS: HRQL improved with clinical (change < -0.5) and statistical (p < 0.05) significance in the mOIT group (baseline mean 3.9, 95% CI 3.4-4.4; 6-month follow-up mean 2.5, 95% CI 2.0-3.0; 18-month follow-up mean 1.8, 95% CI 1.4-2.1) and rush mOIT group (baseline mean 3.9, 95% CI 3.1-4.7; 6-month follow-up mean 1.7, 95% CI 0.9-2.6; 18-month follow-up mean 1.3, 95% CI 0.3-2.4). HRQL scores did not significantly change in the control group (n = 10). CONCLUSION: Multi-allergen OIT with or without omalizumab leads to improvement in caregiver HRQL, suggesting that mOIT can help relieve the psychosocial and economic burden FA imposes on caregivers of food-allergic children.

Phase 1 results of safety and tolerability in a rush oral immunotherapy protocol to multiple foods using Omalizumab.

BACKGROUND: Up to 30% of patients with food allergies have clinical reactivity to more than one food allergen. Although there is currently no cure, oral immunotherapy (OIT) is under investigation. Pilot data have shown that omalizumab may hasten the ability to tolerate over 4 g of food allergen protein. OBJECTIVE: To evaluate the safety and dose tolerability of a Phase 1 Single Site OIT protocol using omalizumab to allow for a faster and safe desensitization to multiple foods simultaneously. METHODS: Participants with multiple food allergies received OIT for up to 5 allergens simultaneously with omalizumab (rush mOIT). Omalizumab was administered for 8 weeks prior to and 8 weeks following the initiation of a rush mOIT schedule. Home reactions were recorded with diaries. RESULTS: Twenty-five (25) participants were enrolled in the protocol (median age 7 years). For each included food, participants had failed an initial double-blind placebo-controlled food challenge at a protein dose of 100 mg or less. After pre-treatment with omalizumab, 19 participants tolerated all 6 steps of the initial escalation day (up to 1250 mg of combined food proteins), requiring minimal or no rescue therapy. The remaining 6 were started on their highest tolerated dose as their initial daily home doses. Participants reported 401 reactions per 7,530 home doses (5.3%) with a median of 3.2 reactions per 100 doses. Ninety-four percent (94%) of reactions were mild. There was one severe reaction. Participants reached their maintenance dose of 4,000 mg protein per allergen at a median of 18 weeks. CONCLUSION: These phase 1 data demonstrate that rush OIT to multiple foods with 16 weeks of treatment with omalizumab could allow for a fast desensitization in subjects with multiple food allergies. Phase 2 randomized controlled trials are needed to better define safety and efficacy parameters of multi OIT experimental treatments with and without omalizumab.

Safety and feasibility of oral immunotherapy to multiple allergens for food allergy.

BACKGROUND: Thirty percent of children with food allergy are allergic to more than one food. Previous studies on oral immunotherapy (OIT) for food allergy have focused on the administration of a single allergen at the time. This study aimed at evaluating the safety of a modified OIT protocol using multiple foods at one time. METHODS: Participants underwent double-blind placebo-controlled food challenges (DBPCFC) up to a cumulative dose of 182 mg of food protein to peanut followed by other nuts, sesame, dairy or egg. Those meeting inclusion criteria for peanut only were started on single-allergen OIT while those with additional allergies had up to 5 foods included in their OIT mix. Reactions during dose escalations and home dosing were recorded in a symptom diary. RESULTS: Forty participants met inclusion criteria on peanut DBPCFC. Of these, 15 were mono-allergic to peanut and 25 had additional food allergies. Rates of reaction per dose did not differ significantly between the two groups (median of 3.3% and 3.7% in multi and single OIT group, respectively; p = .31). In both groups, most reactions were mild but two severe reactions requiring epinephrine occurred in each group. Dose escalations progressed similarly in both groups although, per protocol design, those on multiple food took longer to reach equivalent doses per food (median +4 mo.; p < .0001). CONCLUSIONS: Preliminary data show oral immunotherapy using multiple food allergens simultaneously to be feasible and relatively safe when performed in a hospital setting with trained personnel. Additional, larger, randomized studies are required to continue to test safety and efficacy of multi-OIT. TRIAL REGISTRATION: Clinicaltrial.gov NCT01490177.

Two year effects of food allergen immunotherapy on quality of life in caregivers of children with food allergies.

BACKGROUND: Food allergy (FA) can have serious psychosocial and economic repercussions on food-allergic children and their caregivers and be associated with negative effects on their quality of life. Food allergen immunotherapy (IT) is a promising experimental therapy but can be linked to anxiety. This study investigated the effects of IT on FA-specific health-related quality of life (HRQL) over a 24 month-follow-up in caregivers of children with single and multiple food allergies. We hypothesized that characteristics such as age, asthma at baseline and respiratory allergic reactions during therapy were key characteristics that influenced HRQL scores. METHODS: A validated Food Allergy Quality of Life - Parental Burden Questionnaire (FAQL-PB) was used to assess HRQL. It was randomly distributed to and filled out by caregivers of 57 food-allergic children enrolled in clinical trials of IT. The same parent answered the FABQL-PB questionnaire at baseline and for 6-month, 12- month, 18- month, and 24-month time points on IT. RESULTS: Caregiver HRQL improved significantly (change < - 0.5, p <0.0001) at each follow-up time point compared to baseline. The percentages of caregivers with improvement in HRQL progressively increased (92% at 24 month-follow-up time point compared to baseline). HRQL improved more in caregivers of participants older than 10 years or desensitized to more than 4 food allergens than those who were not (p <0.0001). Caregivers of participants with pre-existing asthma or dose-related respiratory allergic reactions had less improvement in HRQL than those who did not (p <0.01). CONCLUSION: IT lead to improvement in caregiver HRQL. Certain characteristics were associated with greater improvements in caregiver HRQL.