A novel application of chimeric antigen receptor (CAR) T cells for treating severe allergic diseases

Abstract IgE suppression by Omalizumab has shown to be highly efficacious at controlling severe allergic asthma. The antibody-based drug, however, has a relative short half-life and requires repeated administrations resulting in high costs. To develop a therapy that can suppress IgE with a single treatment, we designed an adoptive T cell therapy (ACT) approach that targets the source of IgE, IgE-expressing B cells. To this end, we constructed chimeric antigen receptors (CARs) that recognize the extracellular membrane-proximal domain (EMPD) of membrane IgE (mIgE), which is exclusively expressed on all IgE-producing B cells. EMPD exists only on mIgE but not on secreted IgE, therefore EMPD-specific CARs cannot be blocked by secreted IgE. Two peptides composing the EMPD region were used to create four hybridomas that produced EMPD-specific monoclonal antibodies. The variable regions were cloned and used to construct single chain variable fragments (scFvs) for second generation CARs including the 4-1BB co-stimulatory domain. EMPD-specific CARs were efficiently expressed on primary human T cells through lentiviral transduction. One of the CARs, 2E3E10, produced potent cytotoxicity and IFN gamma in response to U266 cells and Daudi cells expressing mIgE. The response to U266 cells was especially impressive since the expression level of mIgE is very low. The results show proof of concept that redirecting T cells with EMPD-specific CARs can mediate potent T cell response and eliminate mIgE-expressing B cells. Exploiting the ability of CAR-expressing T cells to continuously eliminate IgE-expressing B cells, this cell-based immunotherapy approach has the potential to control severe allergic diseases with a single treatment.