Exploring mechanisms to optimise the duration of oral immunotherapy for peanut allergy

探索优化花生过敏口服免疫治疗持续时间的机制

• 批准号: MR/W025639/1
• 负责人: Paul Turner
• 金额: $ 110.95万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW025639%2F1
• 关键词: Exploring; mechanisms; optimise; duration; oral

Peanut allergy affects 1 in 30 children and is the commonest trigger for life-threatening reactions (anaphylaxis) in this age group. It is a major public health issue, with practical implications for industry, education and healthcare systems.Oral immunotherapy (OIT) is an emerging treatment option, where small, increasing doses of a food allergen are used to cause "desensitisation", so that patients no longer experience symptoms upon exposure to the food. However, frequent allergic reactions to OIT (including anaphylaxis) are common, and thus a limiting factor. Furthermore, treatment effect requires ongoing OIT dosing: over half of patients lose their desensitisation after stopping OIT for 4 weeks. This is a problem, as patients are usually averse to the taste of the food they are allergic too, which affects compliance and treatment success. Persistence of desensitisation, without the need for ongoing regular maintenance dosing, is arguably the most important outcome for patients and their families. The biological mechanism(s) underlying OIT - and in particular, the persistence of desensitisation - are unclear. This significantly limits our ability to identify patients who may need a different protocol to minimise adverse reactions, achieve longer-lasting desensitisation, and improve patient safety. Immunotherapy is widely undertaken for the treatment of hay fever and allergy to insect stings - where treatment success is dependent on the duration of treatment. We therefore expect that for food allergy, the duration of OIT may be of critical importance in achieving longer-term efficacy.In the Boiled Oral Peanut Immunotherapy (BOPI) study (NCT02149719; part-funded through an MRC Fellowship to TURNER), 75% of participants achieved the primary outcome for the study, and tolerated a dose of 1.4 grams peanut protein (approximately 6-8 peanuts) at double-blind, placebo-controlled food challenge after 1 year of treatment. 53% maintained their desensitisation after stopping peanut OIT for 4 weeks; this increased to 72% after up to 2 years of further maintenance treatment.PROJECT PLANWe will evaluate the impact of longer durations of peanut-OIT (up to 3 years) on changes in the immune system, and how this corresponds to clinical outcomes, including desensitisation (and whether this is sustained) and safety, in patients undergoing peanut-OIT. We will apply novel techniques to study not just the initial changes that result in desensitisation, but also what happens when patients subsequently stop OIT doses and the treatment effect may be lost. We have successfully applied this approach to hay fever immmunotherapy. We will therefore be able to better understand the impact of OIT on the immune system, and how the desensitisation effect is sustained. We will analyse blood samples which have been bio-banked from patients in the original BOPI study who have undergone OIT for up to 3 years (under existing ethics approval). Together with existing clinical and laboratory data from BOPI, this will form the most comprehensive dataset evaluating how duration of OIT impacts on both clinical and mechanistic outcomes. Where we identify key findings, we will seek to replicate (and therefore validate) these in a further peanut-OIT study (BOPI-2 study; NCT03937726; currently underway) which also follows patients through to 3 years).This robust approach will allow us to assess the mechanisms associated with both the induction and loss of desensitisation in peanut-allergic children undergoing up to 3 years of OIT. We will use machine learning approaches to understand how these immune changes correlate to clinical outcomes, and so build a model (including both patient characteristics and initial response to treatment) which can predict longer-term treatment outcomes. If successful, this will facilitate the personalisation of OIT protocols, maximising treatment success and leading to safer patient outcomes.

花生过敏影响三分之一的儿童，是该年龄段危及生命的反应（过敏反应）的最常见诱因。这是一个重大的公共卫生问题，对工业、教育和医疗保健系统具有实际影响。口服免疫疗法 (OIT) 是一种新兴的治疗选择，使用小剂量、递增剂量的食物过敏原来引起“脱敏”，从而使患者不再敏感。接触食物后不再出现症状。然而，对 OIT 的频繁过敏反应（包括过敏反应）很常见，因此是一个限制因素。此外，治疗效果需要持续的 OIT 给药：超过一半的患者在停止 OIT 4 周后失去脱敏作用。这是一个问题，因为患者通常也讨厌他们过敏的食物的味道，这会影响依从性和治疗成功。持续脱敏，无需持续定期维持给药，可以说是患者及其家人最重要的结果。 OIT 背后的生物学机制，特别是脱敏的持续性，尚不清楚。这极大地限制了我们识别可能需要不同方案的患者的能力，以尽量减少不良反应、实现更持久的脱敏并提高患者安全。免疫疗法广泛用于治疗花粉症和昆虫叮咬过敏，治疗的成功取决于治疗的持续时间。因此，我们预计，对于食物过敏，OIT 的持续时间对于实现长期疗效可能至关重要。在煮口服花生免疫疗法 (BOPI) 研究（NCT02149719；部分由 TURNER 的 MRC 奖学金资助）中，75%的参与者达到了研究的主要结果，并耐受了 1.4 克花生蛋白（约 6-8 颗花生）的剂量治疗一年后进行双盲、安慰剂对照食物挑战。 53% 的人在停止花生 OIT 4 周后仍保持脱敏；经过长达 2 年的进一步维持治疗后，这一数字增加到 72%。项目计划我们将评估较长时间的花生-OIT（长达 3 年）对免疫系统变化的影响，以及这与临床结果的对应关系，包括接受花生-OIT 的患者的脱敏（以及脱敏是否持续）和安全性。我们将应用新技术不仅研究导致脱敏的最初变化，而且研究当患者随后停止 OIT 剂量并且治疗效果可能丧失时会发生什么。我们已成功地将这种方法应用于花粉症免疫治疗。因此，我们将能够更好地了解 OIT 对免疫系统的影响，以及脱敏效果如何持续。我们将分析原始 BOPI 研究中接受 OIT 长达 3 年（根据现有伦理批准）的患者的生物银行血样。与 BOPI 现有的临床和实验室数据一起，这将形成最全面的数据集，评估 OIT 持续时间如何影响临床和机械结果。当我们确定关键发现时，我们将寻求在进一步的花生-OIT 研究（BOPI-2 研究；NCT03937726；目前正在进行）中复制（并因此验证）这些结果，该研究也跟踪患者长达 3 年）。这种稳健的方法将允许我们评估与花生过敏儿童接受长达 3 年 OIT 脱敏的诱导和丧失相关的机制。我们将使用机器学习方法来了解这些免疫变化如何与临床结果相关，从而建立一个可以预测长期治疗结果的模型（包括患者特征和对治疗的初始反应）。如果成功，这将有助于 OIT 方案的个性化，最大限度地提高治疗成功率并带来更安全的患者结果。

项目成果

Evaluation of clinical outcomes of efficacy in food allergen immunotherapy trials, COFAITH EAACI task force.

COFAITH EAACI 工作组对食物过敏原免疫治疗试验临床疗效的评估。

• DOI: http://dx.10.1111/all.16027
• 发表时间: 2024
• 期刊: Allergy
• 影响因子: 12.4
• 作者: Rodríguez Del Río P

Updated grading system for systemic allergic reactions: Joint Statement of the World Allergy Organization Anaphylaxis Committee and Allergen Immunotherapy Committee

更新的全身过敏反应分级系统：世界过敏组织过敏反应委员会和过敏原免疫治疗委员会的联合声明

• DOI: http://dx.10.1016/j.waojou.2024.100876
• 发表时间: 2024
• 期刊: World Allergy Organization Journal
• 影响因子: 5.1
• 作者: Turner P

Impact of using less objective symptoms to define tolerated dose during food challenges: A data-driven approach

使用不太客观的症状来定义食物挑战期间耐受剂量的影响：数据驱动的方法

• DOI: http://dx.10.1016/j.jaci.2022.12.818
• 发表时间: 2023
• 期刊: Journal of Allergy and Clinical Immunology
• 影响因子: 14.2
• 作者: Turner P

Flex-IT! Applying "platform trials" methodology to immunotherapy for food allergy in research and clinical practice

弹性IT！

• DOI: http://dx.10.1016/j.jaip.2024.01.009
• 发表时间: 2024
• 期刊: In Practice
• 影响因子: 0.3
• 作者: Mack D

Food Allergy and Eosinophilic Gastrointestinal Diseases-The Next 10 Years.

食物过敏和嗜酸细胞性胃肠道疾病 - 未来 10 年。

• DOI: http://dx.10.1016/j.jaip.2022.10.038
• 发表时间: 2023
• 期刊: The journal of allergy and clinical immunology. In practice
• 作者: Turner PJ