The combination of allergen immunotherapy with anti-IL-4 receptor-alpha antibody (dupilumab) for induction of human allergen-specific tolerance

Hay fever is caused by seasonal pollen exposure, particularly grass pollen. It affects one in four of the UK population and has a significant impact on sleep, interferes with usual daily activities and may impair performance at work or school. Antihistamines and corticosteroid nasal sprays may be effective but only provide short-term benefit. 40% of patients in a primary care setting fail to respond to these medicines. An alternative in these patients is grass pollen sublingual allergen immunotherapy (SLIT) which involves taking a daily allergen tablet under the tongue. SLIT is effective and when given continuously for 3 years and provides benefits that persist for years after stopping the treatment (long-term tolerance).

Hay fever is caused by an abnormally strong immune response to seasonal pollen. The immune system recognizes the allergen and makes antibodies called immunoglobulin (Ig)E against the allergen. When exposed to the allergen again, it rapidly binds to IgE, causing the swelling and inflammation that leads to symptoms. A vital part of this response involves substances that signal from one cell to another, causing them to act in an allergic manner and help make IgE. Interleukin 4 and interleukin 13 are particularly important signaling molecules in this process. They act on cells via receptors which a share a common subunit.

Allergen immunotherapy gradually causes the immune system to stop reacting to the given allergen. The immune response changes from being allergic to becoming tolerant. If allergic inflammation could be suppressed at the same time as the administration of immunotherapy this might allow immunotherapy to re-train the immune system faster and more effectively.
Dupilumab is a licensed medicine in the UK and is given by subcutaneous injection (under the skin), every other week in severe eczema (and recently in the USA for severe asthma as well). Dupilumab suppresses allergic inflammation by blocking the shared receptor of interleukin 4 and interleukin 13. To date, no trials have studied dupilumab in hay fever, nor has dupilumab been combined with allergen immunotherapy.

In this study we shall take blood samples from volunteers with severe hay fever. We shall study the effects of dupilumab plus grass pollen in the test tube on patients' immune cells purified from blood samples. In this way we can assess the effect of dupilumab in blocking the immune response to the allergen and suppressing allergic inflammation.

If successful, we shall perform a randomised controlled trial of dupilumab (DUPIXENT) alongside SLIT tablet (GRAZAX) over 2 years in patients with moderate-severe hay fever. Control groups for comparison will include patients receiving SLIT alone and patients receiving placebo treatment only. All 3 groups will be followed in blinded fashion for a further year after stopping treatment. We shall undertake nasal allergen challenges where we administer grass pollen into a person's nose and assess their symptoms. We will do this before treatment, during treatment and one year after treatment has finished to assess the long-term effects. We will also assess their hay fever symptoms during the grass pollen season over the 3 years.

In summary, this study will explore the ability of dupilumab to block human allergen-stimulated allergic responses and explore the underlying mechanisms. This will be achieved first by studying the combination of dupilumab + grass pollen on patients' blood samples in the test tube, and secondly in the context of a controlled clinical trial of dupilumab + SLIT in patients with moderate-severe hay fever. We propose that the combination will provide more effective long-term tolerance and enable a shorter course of SLIT with fewer side-effects.

Aims: Neutralising allergic inflammation with an anti-IL-4 receptor a antibody (dupilimab) may enhance allergen-stimulated induction of immune tolerance in vitro and allow sublingual allergen immunotherapy (SLIT) to induce faster, more effective long-term tolerance in vivo with fewer side effects.
Objectives
1. Investigate whether addition of dupilumab to human allergen-stimulated PBMCs and purified cell subsets in vitro inhibits Th2 responses and explore the underlying mechanism.
2. Investigate whether the combination of dupilumab+SLIT inhibits allergen-stimulated Th2 responses in vivo and explore the underlying mechanism.
3. Assess in a randomized controlled trial (RDBPCT) whether the combination SLIT+dupilumab for 2 years induces long-term benefits and whether the associated cellular and humoral changes correlate with clinical response to treatment.

Methodology: In vitro studies will explore effects of dupilumab on PBMC, naïve T cell and allergen-stimulated B cell-T cell co-cultures, looking at T cell proliferation, phenotypic differentiation and transcriptome analysis. Dupilumab will be combined with SLIT in a RDBPCT in patients with severe hay fever. Efficacy will be assessed by nasal allergen challenge before and after treatment. Nasal fluid, brushings and blood will be sampled in/out the pollen season. Basophil activation, T cell phenotype (Th2, Treg, Th1, Th17), systemic and local antibodies, IgE-blocking activity, cytokine and chemokine responses will be evaluated.
Scientific and medical opportunities: This study will explore mechanisms of dupilumab with allergen in vitro and whether the combination of dupilumab+SLIT is more effective than SLIT alone, permitting a shorter course of SLIT with fewer side effects whilst synergistically achieving disease modification and long-term tolerance. This trial may be a pre-cursor to future trials for clinical use. The results should enable discovery of biomarkers of response and inform novel strategies.

Academic impact: As detailed in the Academic Beneficiaries, in addition to the personal benefits I will gain, the insights into mechanisms of tolerance and the action of dupilumab are relevant to those in the field and in other disciplines.

Benefit the research community: This study will help train a wide variety of staff including doctors, research nurses, study coordinators, statisticians, post-doctoral scientists, masters' students and undergraduates. There are multiple transferable skills that may be learnt during the study, both in clinic and the research laboratory. We are confident that the study will inspire our colleagues within Imperial College and at other academic institutions involved in Allergy to undertake further research in the field.

Improved treatment of patients with allergic rhinitis and other allergic disease: Allergic rhinitis significantly effects quality of life and impairs work and school performance. There is scope for improvement in allergic rhinitis treatment. The ideal is a short course of treatment leading to immune tolerance and long-term symptom control for many years after discontinuation.
The study offers a group of patients with severe allergic rhinitis access to grass pollen SLIT (Grazax), (currently very limited on the NHS) plus dupilumab which has been shown to be highly effective in other Th2 diseases. The strong expectation is that patients randomized to Grazax plus dupilumab or Grazax plus placebo will have significantly improved hay fever control for at least 2 years. All participants randomized will have free access to standard treatments including anti-histamines and intranasal corticosteroids.
A positive study will encourage the manufacturers of dupilumab, Regeneron, to broaden the use of dupilumab to allergic rhinitis and other allergic diseases. Immunotherapy companies, such as ALK-Abello, Denmark have licensed sublingual immunotherapy products for grass pollen, ragweed and house dust mite, and requested licenses for Birch pollen and Japanese cedar pollens. This work will inform whether to progress to a phase 3 trial of the combination of dupilumab and SLIT for grass and other allergens.

Foster an economic collaboration between countries, academia and industry: The collaboration between the ITN in the USA and Imperial College in the UK will strengthen the academic and economic relationship between countries and institutions. The ITN funding for the current substantial single centre clinical trial arose directly from the group's success in completing the 4-year GRASS trial, with publication in high impact journals and influencing international treatment guidelines globally. We hope this will inspire new innovations and knowledge that is mutually beneficial.
ALK-Abello is the leading manufacturer of allergen immunotherapy products in Europe, with an increasing market share in the US. This collaboration undertaken with ALK is likely to provide future capital investment, employment and income and impact on healthcare internationally.

Inform medicines regulatory authorities: The Medicines and Healthcare Products Regulatory Authority, European Medicines Agency, Food and Drug Administration have licensed SLIT (Grazax) treatment for allergic rhinitis and dupilumab treatment for atopic eczema. The results of this and subsequent work will inform these agencies if the combination treatment can be licensed for use in allergic rhinitis or, potentially, other allergic conditions, including allergic asthma.

Promote the need for allergy services and treatments in UK: NHS England has identified the growing need for allergy services in the UK (B09/S/b2013/14 NHS Standard Contract for Specialised Allergy Services) as the burden of allergic disease increases. The impact of allergic rhinitis has been underestimated. This and similar studies increase awareness and the need for allergy related research.