Peanut allergy: Beyond the oral immunotherapy plateau

Abstract Background There are a lack of disease‐modifying treatments for peanut allergy, which is lifelong in most instances. Oral immunotherapy has remained at the forefront of prospective treatments, though its efficacy is consistently undermined by the risk of adverse reactions and meager sustained effects. Aim This review discusses the current state of oral immunotherapy, its strengths and limitations, and the future of therapeutics for the treatment of peanut allergy. Conclusion The persistence of peanut allergy is currently attributed to reservoirs of peanut‐specific memory B cells and Th2 cells, though the cellular and molecular interplay that facilitates the replenishment of peanut‐specific IgE remains elusive. Uncovering these events will prove critical for identification of novel targets as we forge ahead to a new age of peanut allergy treatment with biotherapeutics.


| INTRODUCTION
Food allergies are an increasing global health burden, with prevalence approaching 8% in developed countries. 1 The standard of care is strict allergen avoidance, where accidental exposures leading to anaphylaxis are treated with emergency epinephrine autoinjectors. 2 The lack of disease-modifying treatments for food allergy is alarming, given that the disease course is often lifelong -as in the case of allergy to peanut (PN) and tree nuts -and can be lifethreatening. 3,4

| EFFICACY OF PEANUT ORAL IMMUNOTHERAPY
Oral immunotherapy (OIT) has been in the spotlight as an emerging treatment for PN allergy, though its core methodology has not changed since its original description in 1908. 5 OIT involves the introduction of a particular allergen at minute oral doses (1-50 mg) to establish a starting dose below the threshold of reactivity. Subsequently, patients enter a dose escalation phase that occurs over a long-term maintenance dose of >400 mg PN. The primary assessment of OIT success is clinical desensitization, which is defined as an increased threshold of allergen consumption during a supervised oral food challenge (OFC). OIT has proven efficacious with regard to the induction of desensitization, 6 with two recent clinical trials reporting 67.2% and 85% success rates. 7,8 Notably, OIT trials often differ in their inclusion criteria (e.g., age) and protocol (e.g., maintenance dosage and follow-up schedule), perhaps, providing reason as to the variance in success rates. The underlying immunological mechanisms that support the induction of a desensitized state are ambiguous.
Generally, desensitization is attributed to decreased IgE, increased IgG4 and regulatory T cells (Tregs), and Th2 cell exhaustion, though many of these contentions are drawn from correlations with limited or no causative proof.
The therapeutic strategy post-desensitization remains unresolved and, with the relatively poor compliance, lifelong treatment seems unlikely. A growing body of literature suggests that some patients exhibit lasting clinical benefits following cessation of OIT. This phenomenon has been termed sustained unresponsiveness (SU) and refers to the continuance of a desensitized state (assessed by OFC) following discontinuation of the maintenance dose. SU has been almost exclusively assessed at 1-2 months post-cessation, where half or more of desensitized patients pass an in-clinic supervised OFC. However, beyond this arbitrary 1-2 months timeframe the prevalence of SU declines, with the POISED study reporting only 13% SU (vs. 4% on placebo) at 1 year post-OIT. 8 Again, the biological events that enable a period of clinical tolerance and, ultimately, undermine SU are poorly described.

| SAFETY OF PEANUT ORAL IMMUNOTHERAPY
Recently, evidence has emerged that critically appraises the safety of OIT. In the process of allergen up-dosing and maintenance, numerous adverse reactions can occur. Reactions involve mild to severe gastrointestinal, respiratory, and/or dermatological symptoms, with the most severe unintended effect being anaphylaxis. The safety profile of PN-OIT has been systematically reviewed in the PACE study, 9 where it was established that OIT increased the risk of anaphylaxis, epinephrine use, and other allergic symptoms compared to the current standard of care (strict avoidance). 9 However, as noted by Eiwegger et al., 10 there are issues that remain to be clarified. For example, the PACE study did not distinguish between those adverse events that were the result of treatment versus those that resulted from the accidental exposures. While this could enhance the assessment of treatment-related risk, it is not intuitive how this distinction could be ascertained given that patients take the treatment daily. Furthermore, PN allergy is lifelong in most patients and the efficacy of OIT, understood as desensitization, requires continued administration of PN. Therefore, an assessment of the safety profile of PN OIT over long-term treatment, not only during the induction/ initial maintenance phase, is still needed. The same logic applies to the assessment of quality of life (QoL) over the long term as most adverse effects emerge during the up-dosing phase. 11 OIT is no different than most other treatments in that its implementation must be decided after a comprehensive risk-benefit evaluation. Ultimately, understanding of the findings pertaining to the efficacy, safety and impact on QoL advocates for informed shared decision-making between patients, their families, and health care professionals when considering OIT, and safer management approaches to its implementation. 12 OIT has been a dominant theme in the field of food allergy research. However, the same core approach has been researched and implemented for over 20 years 5,13,14 through endless protocol modifications and arguably, a plateau as to what OIT can and cannot do has been reached. The path forward to the discovery of diseasemodifying therapies is hampered by our limited understanding of the cellular and molecular mechanisms that perpetuate IgE responses to food allergens. A progression towards the use of targeted biotherapeutics with the potential to modify the underlying disease process requires remedying this knowledge gap.

| IMMUNOLOGICAL MEMORY IN FOOD ALLERGY
In IgE-mediated disease, IgE levels have been shown to decline in periods of non-allergen exposure. In humans affected by seasonal allergic rhinitis, there is documented evidence of this decline, where IgE titers are cyclical coinciding with allergen exposure. 15 Moreover, IgE titers specific to the fish parasite, Anisakis spp., drastically decline following 10 months without fish consumption in Anisakis spp.-allergic humans. 16 This is difficult to observe in food-allergic individuals due to the high incidence of accidental exposures 17 ; however, experimental models of food allergy in mice, where allergen exposure can be precisely controlled, support this notion. 18 As the half-life of IgE is <72 hours in serum, this evidence would suggest that declining IgE titers are, in fact, due to a loss of IgE + plasma cells  22 Adoptive transfer of IgG1 + MBCs and IL4-transcribing CD4 + T cells from Th2-immunized mice have been shown to drive IgE responses in recipient mice, demonstrating that IgG1 + MBCs are sufficient for the perpetuation of IgE responses. 23 MBCs, however, require crosstalk with CD4 + T cells to undergo PC differentiation. A specific subset of Th2-polarized CD4 + T cells, termed "Th2A" cells, has been proposed to drive allergic responses. 24 Wambre et al. 24 demonstrated that this CD4 + T cell subset uniquely expands and contracts in pollen-allergic individuals, concordant with on-and offseason allergen peaks. Moreover, in patients achieving clinical desensitization following a 20-week PN-OIT regimen, the Th2A cell subset declined, but remained at detectable levels. 24 This residual population may represent a reservoir of allergen-specific CD4 + T cells capable of subverting SU. An overview of immunological memory to food allergens is provided in Figure 1.

| FUTURE OF THERAPEUTICS
The current understanding on the maintenance of allergy posits both IgG1 + MBCs and Th2A as direct targets for biotherapeutics. In recent years, the field of oncology has seen the rise of approaches, such as CAR-T cells among others, aimed towards the destruction of malignant cells. Such approaches could theoretically be adopted for food allergy, with an aim to specifically kill pathogenic allergen-specific cell repertoires (Figure 2A). However, while the off-target effects of cytotoxic therapies are often accepted in patients suffering from cancer given their potential to improve lifespan, these types of therapies may need to see significant refinement before they could be applied to diseases that are typically of a more benign nature, such  OIT may be instrumental in administering significant doses of allergen in the safest way possible in order to incite the immune system to reprogram pathogenic cell types or expand cells that will eventually maintain lifelong tolerance in a previously food-allergic patient. Optimizing the safety and efficacy of OIT is sensical, given that its clinical benefits are appealing for some patients. However, OIT at its current stage does not appear to be a cure for food allergy. The lack of diseasemodifying therapies beckons towards gathering further fundamental insights into the cellular and molecular mechanisms that drive and perpetuate food allergy, and the subsequent implementation of targeted therapies with curative potential.