A recent study in Nature Immunology describes the development of a chimeric antigen receptor (CAR) T cell therapy that can alleviate type 2 airway inflammation in mouse models of asthma. These CAR T cells were engineered to deplete eosinophils and to block IL-4- and IL-13-mediated signalling. Moreover, owing to additional genetic modifications, the CAR T cells were able to expand, persist and protect against airway disease in vivo without the need for pre-conditioning of mice with chemotherapy.

CAR T cells that have been developed for cancer are delivered in combination with chemotherapeutic conditioning regimes that support the persistence and expansion of the CAR T cells. As it would be unacceptable to administer chemotherapy to patients with asthma, the authors used a different approach to promote the persistence of their CAR T cells. Previously, the same group reported that single-guide RNA-mediated knockout of Bcor (which encodes the BLC-6 corepressor) and Zc3h12a (which encodes the endoribonuclease ZC3H12A) in T cells leads to a cellular state they refer to as ‘TIF’ (T cells with an immortal-like and functional state). They combined this TIF programme with a new CAR T cell (5T cell) designed to deplete IL-5Rα+ cells, which are primarily eosinophils. Initial experiments showed that 5T cells could eradicate eosinophils in vitro, but the 5T cells were unable to undergo population expansion and deplete eosinophils in vivo. However, when 5TIF cells (lacking Bcor and Zc3h12a) were transferred to mice, these CAR T cells expanded, depleted eosinophils and persisted for more than a year.