Current and Emerging Immunotherapeutic Approaches to Treat and Prevent Peanut Allergy

Darren S Miller; Michael P Brown; Paul M Howley; John D Hayball

Disclosures

Expert Rev Vaccines. 2012;11(12):1471-1481. 

In This Article

Humanized Monoclonal Anti-IgE Antibodies

This approach accepts that peanut exposure is unavoidable and seeks instead to neutralize the maladaptive IgE responses made to food allergens. This tactic is being evaluated in Phase I and Phase II trials as monthly injections of humanized recombinant anti-IgE antibodies, which bind to freely-circulating IgE and not to mast cell-bound or basophil-bound IgE. Once circulating IgE antibodies are bound by anti-IgE, they cannot bind to specific high-affinity Fc receptors on mast cells and basophils. The complexes of anti-IgE bound to IgE are then cleared from the circulation. Thus, activation of allergic responses, at least to small amounts of peanut protein, can be prevented.

A randomized, double-blind, dose-ranging trial in 84 patients with peanut hypersensitivity treated with anti-IgE (Hu-901) has shown that patients who received the highest dose of anti-IgE for 4 months were able to tolerate increased doses of peanut on post-treatment food challenge compared with the pretreatment challenge.[79] Specifically, the threshold for clinical symptoms increased from 178 mg, approximately half of a peanut, to 2805 mg, an amount approximately equal to nine peanuts. This specific antibody preparation (Hu-901) was not selected for further clinical development but another humanized monoclonal anti-IgE (Omalizumab) has been approved for clinical testing in moderate to severe asthma. This same antibody was tested in a follow-up double-blind placebo-controlled clinical trial aimed at reducing the risk of peanut allergy in patients with moderate-to-severe asthma. Unfortunately this study was halted early owing to two severe allergic responses during the initial prescreening period, which therefore had nothing to do with administration of the antibody, and thus only 14 subjects reached the study's primary end point. The placebo group were tolerant to 4.07-times the baseline dose of peanut flour, while the omilizumab-treated group were able to tolerate 80.9-times the baseline of peanut protein after 24 weeks of antibody treatment (0.016 mg/kg/IgE every 4 weeks).[80] Although the study did not meet its predetermined end point, future studies with IgE-immunotherapy may provide useful outcomes for patients with pre-existing peanut allergy. However, this approach does also raise the obvious question of treatment durability and related cost–benefit aspects of sustained use of these types of very expensive biotherapeutics.

Some approaches rely on nonconventional routes of delivery of peanut proteins in order to bypass the gut mucosal immune system and the inevitably vigorous responses it will mount to peanut allergens in susceptible individuals. These include epicutaneous immunotherapy (EPIT), peanut oral immunotherapy (peanut OIT), sublingual immunotherapy (SLIT), rectal immunotherapy and peptide immunotherapy.

Epicutaneous Immunotherapy

Following promising results in mice,[81] a clinical trial using EPIT is currently being conducted. EPIT Epicutaneous Immunotherapy in Peanut Allergy in Children (ARACHILD; clinicaltrials.gov identifier: NCT01197053)[202] is a double-blind, placebo-controlled food challenge clinical trial in children 5–17 years of age using an epicutaneous delivery system named Viaskin®. The novelty of the device is in its ability to deliver peanut allergens only to the epidermis of the skin without damaging the dermal layers and thereby avoiding direct contact with the bloodstream. Children will receive the EPIT or placebo control daily for 6 months and then a double-blind placebo-controlled food challenge (DBPCFC) will be conducted every 6 months. The primary outcome measure is the proportion of patients able to consume >1 g of peanut protein symptom-free or a tenfold increase in tolerability over base line.

Peanut OIT

The use of oral immunotherapy for peanut allergy appears superficially to be counter-intuitive given that ingestion of peanuts or peanut-containing products is the likely causative agent of the disease. However, peanut OIT has a manageable safety profile and unlike subcutaneous immunotherapy, few adverse reactions have been reported; despite the fact that patients often do react during increases in dosing, the reactions tend to be mild and controllable. In one OIT study, the incidence of adverse reactions were reported at 3.5% under a home dosing regimen.[82] Furthermore, in a meta-analysis of all clinical trials investigating the efficacy of OIT, approximately 50–75% of patients undergoing OIT tolerate the maintenance dose.[83] With such a low incidence of adverse reactions, the moderate success rate and the noninvasiveness of the treatment, several concurrent clinical trials are now in progress. For example, a 9-year study nearing completion[202] (identifier: NCT00598039) is assessing the ability of increasing doses of defatted peanut flour in 1–16 year-old children. Approximately 40 subjects are enrolled with the primary outcome measure being the subject's ability to pass a double-blind placebo–food challenge (DBPFC) after the tolerisation period and again 1 month after abstinence from peanuts. The completion date is late 2012.

Although the reasons for induced peanut tolerability and success of OIT are not fully understood, some interesting observations alluding to probable mechanisms have been described. The relative cellular make up of the oral immune system is thought to be pivotal. The mucosal presence of tolerogenic APCs known as Langerhans cells, which are involved in driving the immune response toward a TH1 bias via secretion of cytokines such as IL-10 and IL-12,[84] combined with the relative absence of proinflammatory cells such as mast cells and eosinophils,[85] establishes an environment primed for induction of oral tolerance.

Sublingual Immunotherapy

SLIT is another exciting advance in the field of peanut immunotherapy. The procedure involves placing emulsified purified peanut protein under the tongue for 2 min and then swallowing. In one study, 4182 doses of SLIT were administered to 18 children (ages 1–12 years) over a 12-month period. Remarkably, only 0.26% of subjects required antihistamine for mild allergic symptoms and epinephrine treatment was not required. At the end of the study, a double-blind placebo-controlled food challenge was administered. The median peanut protein dose tolerated in the active arm was 170 mg (approximately 6–7 peanuts) while the placebo arm could only tolerate a median of 85 mg of peanut protein. Additionally, a significantly decreased skin test wheal was recorded on those subjects who underwent SLIT.[86] Consequently, another larger trial due for completion in 2014 is currently in progress. This trial is a randomized, cross-over Phase I/II clinical trial of approximately 172–216 weeks duration in subjects aged 12–40 years of age receiving either a gradual dose escalation of peanut SLIT or placebo. The subjects will receive a series of six oral food challenges over a 44-week timeframe with maintenance therapy being continued for a further 2 years. The primary outcome measure is the percentage of desensitized participants while on daily SLIT, as measured by either tolerance to a 5-g oral food challenge or a tenfold increase in the amount of peanut powder (ClinicalTrials.gov identifier: NCT00580606).[202]

Rectal Immunotherapy

An alternative form of mucosal immunotherapy currently being trialled involves heat-killed Escherichia coli expressing Ara h 1, 2 and 3 proteins. In a mouse model of peanut allergy, rectally-administered high (90 µg) and medium (9 µg) doses of the recombinant bacteria induced immune tolerance, thus preventing anaphylaxis reactions following peanut challenge for a period of up to 10 weeks.[77] Rectal delivery of antigens may be advantageous because E. coli and its expressed antigens are able to be delivered directly to the rectal mucosa as native proteins, resulting in enhanced presentation to the immune system. Consequently, the harsh and degradative milieu of the upper digestive tract is avoided. A Phase I clinical trial where capsules containing peanut protein are administered rectally is currently being performed to assess safety (ClinicalTrials.gov identifier: NCT00850668).[202]

Peptide Immunotherapy

Peptide immunotherapy is a rapidly developing area within the field. The basis of this therapy is to target allergen reactive CD4+ T cells and hence, eliminate or minimize downstream allergic responses. Several possible scenarios regarding the mode of action of peptide immunotherapy include, targeted deletion of CD4+ T cells,[87] causation of anergy in previously activated CD4+ T cells[88] and/or the regulation of CD4+ T cells by regulatory T-cells.[89] Typically though, peptides are selected and identified for immunotherapy applications by laborious methodologies, comprised of testing ex vivo-propagated CD4+ T cell lines and clones from reactive individual in various assay formats for reactivity against pools of overlapping synthetic peptides with sequences derived from the corrosponginf relevant antigens. However, more recently systematic approaches to this are being utilised, including peptide microarray platforms[90] and more readiliy available MHC class II tetramers,[91] which may facilitate future epitope identification. Early work in the field of peanut allergy demonstrated that a series of overlapping peptides comprising T cell epitopes of peanut protein, reversed sensitivity to peanuts in a murine model of peanut-induced anaphylaxis, without triggering IgE-mediated acute reactions.[92] More recently, the mapping of the major T cell epitopes of Ara h 2 has produced a series of peptides suitable for targeting allergy specific-pathogenic T cells. Using overlapping, Ara h 2 peptide libraries and Ara h 2-specific CD4+ T cells lines generated from peanut allergy patients, five immune-dominant Ara h 2 epitopes were discovered. Three short HLA diverse and variant peptides that did not bind patient serum IgE but were still able to bind to pathogenic CD4+ T cells were tested.[93] These short immunotherapeutic-peptides mitigated the significant anaphylactic potential associated with low-dose administration with whole peanut proteins to peanut allergic patients, while theoretically maintaining the ability to induce a tolerising immune response. This is due to the fact that the peptides are unable to cross-link IgE antibodies and therefore unable to activate mast cells. Clinical trials are currently planned and if successful, could provide a new therapeutic avenue for peanut allergic individuals.

Chinese Herbal Medicine

Chinese physicians have for centuries known about the healing and therapeutic potential of various plants and animals. In respect to peanut allergy, a Chinese herbal medicine known as FAHF-2 demonstrated excellent results in a mouse peanut allergy model.[94] Mice were fed the compound twice daily throughout the model's sensitization period and then challenged with the peanut allergen. Remarkably, all mice tested were protected from anaphylactic responses and elicited significantly reduced serum IgE responses. This study has recently been followed by a mouse model of multiple food allergy (peanut, codfish and egg). Similarly, those mice fed FAHF-2 exhibited no anaphylactic reactions following challenge and also had reduced allergen-specific IgE levels.[95] Finally, a Phase I safety trial in humans was conducted, which concluded that FAHF-2 administration was a safe approach for prevention of allergies with only mild gastric irritation reported.[96] A Phase II safety/efficacy trial is currently enrolling participants.

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