Human Chimeric Antigen Receptor T Cells (CAR-T) Targeting Human IgE B Cell Receptors Abolish IgE Production By Eliminating IgE Producing Cells
23.Department of Otolaryngology- head and neck surgery,, Sheba medical center
3Laboratory of Allergy and clinical immunology Herbert Center of Mast Cell Disorders, Meir Medical Center
4Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA Division of Immunology, Allergy and Rheumatology, Department of Internal Medicine,, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
The prevalence of allergies has risen dramatically in the westernized world. IgE mediated diseases present in an array of symptoms and severity, ranging from acute, life-threatening anaphylaxis to chronic conditions such as allergic asthma and allergic rhinitis. Current treatment for allergic disorders is limited, and includes pharmacological agents, monoclonal antibodies, and allergen specific immunotherapy. Strict avoidance is the main approach in cases of food allergy, and is hard to achieve, carrying with it a heavy emotional, social, nutritional and economic burden to patients and society. We sought to treat IgE mediated allergies by harnessing cell therapy, to target IgE production by eliminating IgE expressing B cells. Here, we present a novel chimeric antigen receptor (CAR)-T cell therapy targeting M1’, a unique extracellular domain of the IgE B-cell receptor (BCR). This domain, absent from free IgE, enables selective targeting of IgE-producing cells. The 2nd generation CAR construct, with ectodomain derived from the monoclonal antibody Quilizumab, demonstrated robust and selective cytotoxicity against primary human IgE-secreting cells and significantly reduced IgE production in vitro. In an in vivo NSG mouse model, CAR-T cells targeting M1’ inhibited the growth of IgE-expressing leukemia and extended survival. Our findings pave the way for further investigation in transgenic mice of allergy models, with the ultimate goal of clinical translation. CAR-T cells targeting M1’ , are thus envisioned as a “living drug” that will provide sustained surveillance against IgE B cell resurgence and relieve the patient from all his atopic diseases.
