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

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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.