Oral Immunotherapy (OIT)

Oral immunotherapy is the therapeutic approach most explored in clinical trials for food allergy to date. Unlike other therapies that have been adapted from preclinical studies or treatment models shown to be effective in other diseases, OIT trials began in earnest over 10 years ago in small, uncontrolled trials using commercially available food products. Early open-label trials have shown a beneficial response to OIT to a variety of allergens, such as milk, egg and fish, with evidence of clinical desensitization in up to 80% of subjects treated. More recent trials have expanded to multicenter, randomized controlled OIT trials that have taken advantage of the foods as ‘therapeutic tools’. OIT products are viewed by the FDA as new therapeutics and are bound by FDA regulation for labeling and widespread, safe usage in the clinical setting. Most clinical trials to date are FDA registered and accessible through the NIH clinical trials registry ( www.clinicaltrials.gov ).

Typically, OIT protocols encompass three phases of allergen delivery using a standard protocol in a well-controlled setting: (1) initial escalation dosing of 6 to 8 doses of allergen given rapidly during a single day under medical supervision; (2) build-up dosing under observation weekly or biweekly until a target dose is reached after 6 to 12 months; and (3) daily maintenance dosing at home (typically for years). OIT is associated with beneficial short-term and longer-term treatment responses for most individuals through immunomodulation that involves tissue and circulating effector cells. Despite the benefits seen, safety concerns further highlight the need for larger trials and FDA registration before widespread use is acceptable.

Recent randomized, controlled, multicenter clinical trials have provided valuable efficacy and safety data for evaluation of OIT as an active treatment. In a trial of peanut OIT, 28 children (ages 1–16 years) were randomized to receive peanut OIT (maintenance dose = 4,000 mg) versus placebo OIT. Peanut OIT treatment was associated with clinical desensitization when compared to placebo OIT treatment after 12 months (5,000 mg [~20 peanuts] vs 280 mg [~1 peanut], P < .001). In a recent randomized trial, 62% of children (ages 7–16 years) on active OIT could be desensitized to a dose of 1,400 mg (~5 peanuts) of peanut after 6 months of OIT at a dose up to 800 mg compared to none of placebo OIT subjects ( P < .001). Similar findings were noted during a 6-month milk OIT trial in 20 milk-allergic children (ages 6–21 years) randomized to milk OIT (maintenance dose = 500 mg) compared to placebo OIT when assessing change in reaction threshold at baseline oral food challenge (OFC) compared to 6-month OFC (5,100 mg [~160 mL] vs 0 mg, P = .002). Other milk OIT trials in children have shown similar clinical findings. In a study from the Consortium of Food Allergy Research (CoFAR), 55 egg-allergic children (ages 5–18 years) were randomized to egg versus placebo OIT. After 10 months of OIT (maintenance dose = 2,000 mg), 55% of egg OIT subjects were desensitized to 5 g of egg (~ whole egg) compared to 0% of placebo OIT subjects (5,000 mg vs 50 mg; P < .001), and 75% of egg OIT subjects passed a 10 g (~1.5 whole egg) OFC at 22 months. These studies highlight the efficacy of OIT induction of desensitization and treatment-specific immunomodulation (as described below).

In a recent study, investigators delivered combination OIT to participants (ages 4–25 years) sensitized to up to five foods ( N = 25 subjects) compared to those that were mono-allergic ( N = 15) and reported that multi-allergen OIT could be delivered with similar safety and efficacy to single-allergen OIT. Alternatively, in a multisensitized mouse model of tree nut allergy, OIT with a single tree nut induced desensitization to multiple nuts with associated immune changes. Further clinical studies are ongoing to evaluate the efficacy and safety of multi-allergen OIT and cross-reactive allergen OIT.

S everal studies have evaluated longer-term outcomes of OIT, including sustained unresponsiveness. All of these studies have been either uncontrolled, open-label studies or open-label extension phases of randomized, controlled trials that include years of OIT dosing. In an open-label study of 6 egg-allergic children (ages 3–13 years), all passed an OFC after 33 months of OIT and introduced egg into their diet. After 5 years of peanut OIT (maintenance dose = 4,000 mg), 50% of subjects demonstrated sustained unresponsiveness to 5 g of peanut protein and were considered treatment successes with incorporation of a median of 555 mg/day (range, 0–4,000 mg/day) of peanut in their diets ~3 days/week. During a 60-week trial of milk OIT compared to milk SLIT, OFCs were performed after 1 and 6 weeks off therapy in subjects demonstrating desensitization at week 60; 10% failed at week 1 and 20% failed at 6 weeks. In the CoFAR egg OIT trial, sustained unresponsiveness treatment successes improved as therapy was extended, with 27.5% noted at 24 months, 47.5% at 36 months and 55% at 48 months. Among peanut OIT subjects surveyed about duration of treatment effects, none of the treatment successes reported symptoms with peanut consumption after 3 to 4 years. Follow-up of successful milk OIT yielded 22% of subjects reporting limitations with milk consumption due to symptoms, although for various reasons only 20% were ingesting milk on an unlimited basis. Another study found that twice-weekly ingestion (150–200 mL) was effective to maintain desensitization. Following 2 to 3 years after completion of egg OIT, 67% of egg OIT subjects compared to 18.2% of placebo OIT subjects could consume both baked and concentrated egg. Overall, sustained unresponsiveness is possible in a subset of subjects, but the long-term impact of OIT remains unclear. To address this issue further, the Immune Tolerance Network IMPACT trial is evaluating long-term tolerance among peanut-allergic children (ages 1–4 years) in a randomized, controlled 3-year peanut OIT trial.

Immunologic changes associated with clinical findings following successful OIT have been compelling. Single-allergen OIT has been associated with beneficial immunomodulatory effects including reduced basophil and mast cell activation, down-regulation of Th2 effector cells and cytokine production, as well as initial increased T regulatory cell activity and reduced IgE antibodies with increased IgG4 antibodies. Some of these changes following peanut OIT, in particular those related to basophil activation, are antigen specific but some are also associated with nonspecific stimuli including evidence of basophil suppression after anti-IgE stimulation or after nonspecific antigen (egg) stimulation. Peanut OIT has also been shown to induce transient tolerance with associated increase in antigen-induced T _REG function and intracellular IL-10 levels and decreases in methylation of Foxp3, a known indicator of T _REG cell suppressive function. Following long-term peanut OIT, treatment successes were associated with reduced peanut-specific IgE and Ara h 1 and 2, and skin prick tests (SPT) when compared to treatment failures, parameters that were predictive of outcomes. Low baseline specific IgE levels were predictive of treatment success for desensitization in both milk and egg OIT studies, but not predictive of success in the multicenter CoFAR egg OIT study. Analysis of IgE and IgG4 binding epitopes before and after milk and peanut OIT is particularly interesting. Reductions in IgE binding and increases in IgG4 binding with overlap of key binding epitopes are associated with response to therapy; however, in some individuals significant discordance indicates that antigen-nonspecific changes may play a role. Overall, the immunodulation following OIT is often robust and strongly linked to clinical outcomes.

OIT trials have been conducted through study protocols under close monitoring by experienced research staff in clinical research centers with necessary rescue equipment and procedures in place. Although OIT has demonstrated clinical efficacy, meta-analyses highlight the fact that insufficient data exist for full efficacy assessments and safety concerns persist. Generally, side-effects associated with OIT treatment trials are mild to moderate, predominantly oropharyngeal and easily treated; however, more severe reactions have been reported. Currently, the highest rate of adverse events related to OIT occurs during the first year of therapy with up to ~10–15% of subjects withdrawing, often due to gastrointestinal side-effects. During blinded peanut OIT, symptoms were noted in most active treatment subjects when compared to placebo treated subjects. During OIT, ~45% of active subjects compared to ~10% of placebo subjects experienced dose-associated symptoms, primarily mild and oropharyngeal, but with ~1% requiring epinephrine. During the first year of blinded egg OIT, 75% of 11,860 OIT doses were symptom free versus 96% of 4,018 placebo doses. During years 3 and 4, 95% of OIT doses were symptom free.

Acute illness with viral infections, menses and exercise have been associated with lowering the reaction threshold for subjects on stable OIT dosing and often require dose adjustments in the face of acute illness. Additionally, eosinophilic esophagitis has been reported in association with OIT, adding potential risks for a subset of children. The implementation of rush OIT protocols has been associated with increased adverse symptoms and has been generally abandoned as a viable treatment option. Pre-treatment with omalizumab has shown promise for reducing side-effects and shortening time to maintenance therapy. Overall, additional studies in larger study cohorts are needed before OIT can be sanctioned and encouraged for widespread use. Larger scale Phase II and Phase III studies are underway currently for peanut OIT and are planned for other allergens.

Treatment with extensively heated (baked) milk and/or egg allergen may prove to be an important treatment option that mirrors allergen immunotherapy. Clinical trials performed in milk and egg allergic children have demonstrated that ~70–80% of milk or egg allergic children can safely ingest baked milk or egg products. Daily consumption of 1 to 3 servings of baked allergen products was safe and associated with accelerated tolerance development and immunomodulation when compared to age-matched controls. Questions remain regarding the best way to identify those patients tolerant of baked milk/egg, the effective dose required, the degree of heating needed, the role of the food matrices and the ability of heated proteins to induce lasting tolerance.

Sublingual Immunotherapy (SLIT)

Sublingual immunotherapy (SLIT) has been employed in asthma and allergic rhinitis in the form of allergen extracts and sublingual allergen tablets with favorable safety and efficacy profiles. SLIT presumably works by allergen interaction with pro-tolerogenic Langerhans cells in the oral mucosa, leading to down-regulation of the allergic response. Several clinical trials have been conducted using SLIT for food allergy. As with OIT, SLIT protocols include escalation and maintenance dosing, although SLIT doses are smaller, generally less than 10 mg daily. Participants administer SLIT by placing a gradually increasing dose of allergen extract under the tongue, holding it there for several minutes and then spitting out or swallowing.

The first published reports of SLIT for food allergy appeared more than a decade ago, when SLIT for kiwi allergy was described in a case report in which a 29-year-old woman with a history of multiple anaphylactic reactions to kiwi was desensitized. That patient subsequently underwent approximately 5 years of maintenance therapy with a solution made from fresh kiwi pulp and became tolerant of the fruit. In a study of hazelnut SLIT, 22 adults received 8 to 12 weeks of treatment with hazelnut SLIT or placebo SLIT. In the subsequent food challenge, almost half of patients in the hazelnut SLIT group consumed 20 g of hazelnut compared to only 9% of the placebo SLIT group. Systemic symptoms were noted in only 0.2%. Oropharyngeal symptoms were observed in 7.4% of subjects, many with oral allergy syndrome reported at baseline. In a study of peach SLIT, 49 adults received peach SLIT ( N = 33) or placebo SLIT ( N = 16) during 6 months of treatment. During the post-therapy food challenge, the peach SLIT group consumed peach at levels that were 3-fold higher than those in the placebo SLIT group before experiencing symptoms.

SLIT studies have expanded to include both pediatric and adult patients with milk or peanut allergy in the last few years. In a 6-month, open-label study of 8 children (age >6 years) with cow’s milk allergy, milk SLIT led to an increase in the mean volume of milk that elicited allergy symptoms from 39 mL to 143 mL. In a study of 30 milk-allergic children (ages 6–17 years), milk SLIT was compared to milk OIT in a two-center study. Participants were randomly assigned to receive SLIT alone (7 mg) or SLIT followed by OIT at two different doses (1 or 2 g) during 60 weeks of immunotherapy. At the end of the study, 1 of 10 SLIT-only participants achieved desensitization to 8 g of milk protein, while 6 of 10 participants in the lower-dose SLIT+OIT group and 8 of 10 patients in the higher-dose SLIT+OIT group achieved desensitization. Overall, SLIT in combination with OIT was associated with more robust clinical benefits than SLIT alone; however, systemic side-effects occurred only in the SLIT+OIT groups with higher levels of antihistamine and epinephrine usage. Symptoms reported with milk SLIT were limited to the oropharynx.

The first randomized, controlled trial of peanut SLIT was performed in a single-center study of 18 children (ages 1–11 years) receiving 12 months of SLIT (maintenance dose = 2 mg daily) with peanut or placebo. At the conclusion of 1 year of treatment, those receiving peanut SLIT were able to safely consume 1,710 mg (~8 peanuts) of peanut protein, compared to only 85 mg (<0.5 peanut) in those receiving peanut SLIT ( P = .011), representing a 20-fold increase in peanut consumption. During dosing, side-effects were minimal and localized to the oropharynx, noted in 11.5% of peanut SLIT subjects compared to 8.6% of placebo SLIT subjects. Symptoms were typically untreated, and no participant required epinephrine during treatment. Immunologic changes were noted in peanut SLIT subjects when compared from baseline to OFC at 12 months including decreased peanut-specific IgE ( P = .003), SPT size ( P = .02), basophil activation ( P = .009), and IL-5 levels ( P = .015) with increase in peanut-specific IgG4 ( P = .014). Clinical benefits in addition to evidence of immunomodulation suggested modification of the allergic response by peanut SLIT in these young children. A subsequent multicenter study from CoFAR of 40 peanut-allergic patients (ages 12–40 years) evaluated the efficacy of peanut SLIT vs placebo SLIT. Treatment success was defined during OFC when 5 g of peanut protein was consumed or when a 10-fold or higher increase in peanut protein consumption was achieved when comparing baseline to follow-up OFC. After 44 weeks of therapy (target maintenance dose = 1,386 µg), 14 (70%) of 20 subjects who received peanut SLIT compared to only 3 (15%) of 20 subjects who received placebo SLIT demonstrated treatment success: primarily greater than a 10-fold increase in eliciting dose over baseline challenge. The median dose of peanut consumed at the 44-week OFC compared to baseline OFC was significantly higher for peanut SLIT subjects (371 mg [about 1 peanut] vs 21 mg, P = .01) when compared to placebo SLIT subjects (146 mg vs 71 mg, P = .14). When evaluation took place at week 68 the mean consumed dose rose to 996 mg, which was significantly higher than at week 44 ( P = .05). For the 12 of 17 placebo subjects that crossed over to higher dose SLIT (target maintenance dose = 3,696 µg) and completed a 5 g OFC, the median consumed dose was higher than at baseline OFC (603 mg vs 71 mg, P = .02). Although the results were encouraging, none of the subjects treated with low-dose or high-dose SLIT was able to consume the full 5 g OFC during the desensitization phase. Peanut SLIT was well tolerated with 95% of doses being symptom free when local oropharyngeal symptoms were excluded. Clinical outcomes were associated with only modest immunologic changes including reductions in basophil activation and modest changes in titrated skin tests. No significant changes were noted in peanut-specific IgE or IgG4 levels. Differences in the two peanut SLIT studies may be explained by the difference in ages of the study cohorts, subject selection and differences in target maintenance doses, indicating that further study is warranted.

A retrospective comparison study of peanut-allergic children treated with either peanut OIT or SLIT indicated that after 12 months of therapy patients who received SLIT reacted at lower eliciting dose thresholds and were less likely to pass food challenges evaluating desensitization. Thus, available evidence for milk and peanut allergy suggests that SLIT therapy is less effective than OIT for desensitization but has a better safety profile. Studies of SLIT have also largely excluded patients with a history of severe allergic reactions. Among patients who have undergone treatment, response has been variable and potentially age dependent and allergen dependent. Therefore, the applicability of SLIT in the general food-allergic population remains unclear. There are ongoing SLIT studies in younger age groups and using different SLIT delivery systems that should help us better understand the possible role of this type of immunotherapy for food allergy for the future.

Epicutaneous Immunotherapy (EPIT)

Epicutaneous immunotherapy is a newer form of immunotherapy that utilizes a novel delivery of allergen to the skin surface through application of an allergen-containing patch. EPIT has been utilized for grass pollen-induced allergic rhinitis with demonstrated efficacy and safety. In preclinical studies of EPIT for food allergy, effective antigen delivery and treatment outcomes have been noted and have led to clinical trials in milk and peanut allergy. EPIT acts by delivering a small dose of allergenic protein directly to the epidermal layer of the skin where it is taken up, activating Langerhans cells that subsequently traffic to regional lymph nodes and lead to down-regulation of effector cell responses. In mouse studies, fluorescently labeled allergen (Alexa488-ovalbumin) applied via an allergen patch remained in the epidermal layer without evidence of systemic absorption but with induction of downstream immunologic effects. In mouse studies, investigators sensitized mice to ovalbumin, peanut or aeroallergen and then treated with EPIT, SCIT or sham therapy for 8 weeks. Mice treated with EPIT showed reduced airway hyperreactivity to inhaled allergen, decreased allergen-specific IgE levels and increased allergen-specific IgG2a when compared to controls ( P < .05), changes that were similar to treatment-induced effects noted with SCIT. Reduced inflammation was also noted on bronchoalveolar lavage with evidence for decreased eosinophils, eotaxin and cytokines with both EPIT and SCIT when compared to controls ( P < .001). Further preclinical studies have demonstrated allergen-specific induction in tolerogenic regulatory T cells with repeated allergen patch application, a treatment effect that was eliminated when EPIT was applied to tape-stripped skin. In a mouse model of peanut-induced eosinophilic gastrointestinal disorders, peanut EPIT treatment resulted in expansion of a CD25+ T regulatory cell population that was long-lasting and that could be adoptively transferred to peanut-sensitized, untreated animals to provide protection. These findings from preclinical studies have highlighted the novel mechanistic action of EPIT and beneficial treatment effects that have paved the way for the first human studies in milk- and peanut-allergic individuals.

To date, all EPIT studies conducted for food allergy have employed the technology developed by DBV Technologies, Inc. (Paris, France). This technology consists of a small, adhesive patch, known as the Viaskin ^TM device, that has been electrostatically coated with allergen and is applied to the upper arm or interscapular space. The first study conducted was a 3-month double-blind, placebo-controlled pilot study in milk-allergic infants and children (3 months to15 years). Nineteen subjects were randomized to treatment with milk or placebo EPIT applied at 48-hour intervals during 3 months of treatment (using the Diallertest ^TM device, a precursor to Viaskin ^TM ). The cumulated dose of cow’s milk consumed during OFC (baseline vs 3 months) trended higher in the milk EPIT group (1.77 ± 2.98 mL vs 23.61 ± 28.61 mL) compared to the placebo group (4.36 ± 5.87 mL vs 5.44 ± 5.88 mL) ( P = .13). Adverse events were higher among milk EPIT treated subjects when compared to placebo treatment and were limited to mild skin reactions at the patch site and increased risk of local eczema (OR 8.20; 2.72–24.5; P < .001). This limited duration pilot study of EPIT in food-allergic children provided early evidence that EPIT could be used safely with potential for beneficial clinical outcomes.

Since completion of the EPIT pilot study in children, the focus of clinical trials for EPIT has been on peanut allergy, with both Phase I and Phase II studies conducted using the Viaskin ^TM patch device. A Phase I safety trial was conducted among 100 peanut-allergic participants (ages 6–25 years), categorized as severe and nonsevere based on reaction history, using a randomized, double-blind, placebo-controlled trial design comparing placebo Viaskin ^TM to four different doses of peanut Viaskin ^TM patches administered over 2 weeks of therapy. The peanut Viaskin ^TM proved safe and convenient up to a dose of 250 µg for children and up to 500 µg in adolescents and adults. Overall, 2 of 80 active EPIT and 1 of 20 placebo EPIT subjects dropped out due to adverse events; 90% experienced mild or moderate local symptoms, and systemic symptoms were mostly mild and transient, with no severe reactions and no epinephrine use.

The first peanut efficacy trial (ARACHILD), a randomized, controlled study, included 54 peanut-allergic children (ages 5–17 years), all treated with the peanut patch (100 µg pp) and challenged after 6 months of blinded therapy. OFCs were conducted at 6-month intervals over an 18-month period to assess reaction threshold. Safety data after 12 to 18 months were satisfactory and consistent with Phase I results. Treatment was associated with some level of desensitization with up to 67% responders (defined as ≥10-fold increase in cumulative reactive dose from baseline) at 18 months with 4 subjects reaching 1–2.5 g of peanut protein (~3.5–8 peanuts).

A large randomized, controlled Phase IIb trial (VIPES) has enrolled 221 highly peanut-allergic individuals (ages 6–55 years) in 22 centers in the USA and Europe, for a 1-year treatment comparison of peanut EPIT vs placebo EPIT. Results are expected for 2015 with a planned extension phase up to 36 months. Additionally, the CoFAR study group has initiated a randomized, controlled study of peanut EPIT planned for 30 months of treatment in 75 children and young adults (ages 4–25 years). Additional EPIT studies with other allergens are in planning and implementation stages.

Novel Immunotherapy Approaches in Early Development

Novel immunotherapeutic applications in food allergy are under investigation in murine models. Modified or recombinant allergen immunotherapy has taken advantage of recombinant technology to alter the host response to allergen through modification of the antigenic features of the protein and has been used in preclinical trials and a single Phase I study. Based on positive findings from a peanut mouse model using heat-killed Escherichia coli (HKE) in combination with modified Ara h1, 2, and 3 proteins (HKE-EMP123), a Phase I clinical trial using HKE-EMP123 delivered rectally was conducted in nonallergic adults and peanut-allergic adults. In peanut-allergic subjects, 50% had significant allergic reactions preventing further dosing (30% required epinephrine), while healthy controls tolerated the treatment. Other immune-specific approaches in preclinical studies include peptide vaccine immunotherapy, plasmid DNA immunotherapy, cytokine-modulated immunotherapy, immunostimulatory sequence-conjugated protein-modulated immunotherapy, human immunoglobulin fusion proteins, sugar-conjugated BSA and antigen-fixed leukocytes. These approaches may provide an important first step in organ-targeted immunotherapy with molecules that induce immunomodulation with improved safety profiles.