Researchers have discovered two peanut allergy treatments for children that are both highly effective at inducing remission.
The research, led by the Murdoch Children’s Research Institute (MCRI), found the treatments – a combination of a probiotic together with oral immunotherapy (the gradual introduction of the allergenic food) and oral immunotherapy alone – significantly induced remission and desensitization.
About half of the children achieved remission, allowing them to stop treatment and safely eat peanut freely. Both treatments also provided substantial improvement in quality of life compared with current standard care.
The randomized controlled trial conducted at The Royal Children’s Hospital in Melbourne, Perth Children’s Hospital, and the Women’s and Children’s Hospital in Adelaide involved 201 children aged between 1-10 years. The trial was staged over four years, with participants followed up to 12-months post-treatment.
The team led by MCRI Professor Mimi Tang had previously shown that the combination treatment resulted in 74 percent achieving remission after 18 months of treatment, and 70 percent of those initial responders remained in remission and were eating peanut safely four years later.
The next step was to test whether adding a probiotic gave a benefit over and above oral immunotherapy on its own and to compare long-term outcomes following treatment.
The new research, published in The Lancet Child & Adolescent Health, found after 18 months of treatment, 46 percent and 51 percent of children who received the combination treatment or the oral immunotherapy alone, respectively, were in clinical remission compared to 5 percent in the placebo group.
The children who reached clinical remission were able to stop treatment and eat around a standard serve of peanut freely. Both treatments also led to a significant improvement in quality of life, with those children who achieved clinical remission experiencing the biggest improvement, greater than those who only achieved desensitization.
“The results show that high dose peanut oral immunotherapy provides meaningful benefit to treated children,” Professor Tang said. After 18 months of treatment, 74 percent of children who received the oral immunotherapy tolerated roughly a standard serve of peanut, equal to a snack pack of peanut M&Ms, 51 percent achieved clinical remission and were able to stop treatment altogether, while the remaining 24 percent were desensitized to this amount of peanut.”
“Addition of a probiotic did not significantly improve effectiveness compared to oral immunotherapy, however it appeared to enhance tolerability of the treatment, with fewer gastrointestinal symptoms, especially in children between one and five years of age.”
The results also showed that treatment with oral immunotherapy, with or without a probiotic for childhood peanut allergy, provides a significant and substantial improvement in quality of life compared with current standard care, which is peanut avoidance.
“Children who were in clinical remission had fewer reactions to peanut compared with those who were just desensitized,” he said.
“Being desensitized still requires continued daily treatment and allergen avoidance so remission appears to be a better outcome for children. Importantly, children in remission had a significantly improved quality of life compared with allergic children, suggesting that no longer having to avoid peanut provides greater benefit than continued allergen avoidance despite the risk of a possible reaction.”
The peanut oral immunotherapy approach used in the trial applies a proprietary high dose, rapid escalation regimen that is being developed by Prota Therapeutics as a lead candidate for the treatment of peanut allergy, PRT120.
Melbourne’s Kate Lawlor’s son Declan, 9, who took part in the trial, is now in clinical remission and eats peanuts weekly. Declan was diagnosed with a peanut allergy at age four after having a reaction to peanut butter.
Kate said it was a huge relief that her son could now eat peanut freely without fear of a reaction or having to avoid the nut for the rest of his life.
“Having a child with a food allergy is quite stressful,” she said. In the home you can control the environment around food but school, play dates and birthday parties are largely out of your hands.”
Peanut allergies are the most common cause of severe allergic reactions, called anaphylaxis, and one of the most frequent causes of death from food allergy. About 3 percent of babies have a peanut allergy.
“There is a need for disease modifying therapies that improve health and well-being and both the combination and standalone immunotherapy treatments provided a meaningful benefit. The combination therapy in particular could offer a safe and well tolerated approach to inducing clinical remission in young pre-school children with peanut allergies.
Starting treatment early seems to increase the chances of achieving remission and pre-school children are especially vulnerable, so a treatment that causes fewer side effects brings an important advantage.”
Researchers from The Royal Children’s Hospital, Monash Children’s Hospital, University of Melbourne, University of Adelaide, Women’s and Children’s Hospital in Adelaide, Perth Children’s Hospital, The University of Western Australia, Telethon Kids Institute, Monash University and University College Cork in Ireland also contributed to the study.
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 period of months until reaching predefined endpoints, such as 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. W
hile 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 years5, 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 disease‐modifying 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 exposures17; 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 (PCs).
Similarly, IgE‐secreting cells in peripheral blood of food‐allergic individuals were discovered to have an immature transcriptional profile with downregulated expression of plasma cell survival genes.19 Thus, a quiescent cell capable of regenerating the plasma cell pool is the probable reservoir of IgE responses.
In this regard, memory B cells (MBCs) have been a focal point of recent investigations on the maintenance of food allergy. Through the application of advanced flow cytometry strategies20 and single‐cell RNA‐sequencing,19 the extreme rarity of IgE+ MBCs has been described in human peripheral blood mononuclear cells of allergic subjects. This does not, however, discount the existence of IgE+ MBCs/PCs at secondary lymphoid or non‐lymphoid tissue sites.
In gastrointestinal biopsies from subjects with PN allergy, Hoh et al.21 identified reservoirs of IgE+ PCs (IgE+ CD138+) in the stomach and duodenum, but did not detect IgE+ B cells (IgE+ CD138‐ with small B lymphocyte morphology). The longevity of gastric and duodenal IgE+ PCs was not described, though identification of non‐IgE isotypes within IgE clonal lineages at the same tissue sites suggests local IgE class switch recombination.21
Most frequently, IgE class switch recombination occurs sequentially, where B cells express one or more intermediate isotypes with IgG1 as the dominant intermediary.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 off‐season 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.
reference link : https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8361810/
More information: Probiotic peanut oral immunotherapy versus oral immunotherapy and placebo in children with peanut allergy in Australia (PPOIT-003): a multicentre, randomised, phase 2b trial, The Lancet Child & Adolescent Health, DOI: 10.1016/S2352-46422200006-2