Targeting inflammation with chimeric antigen receptor macrophages using a signal switch

Abstract Chimeric antigen receptor (CAR) T-cell immunotherapy has shown great success in clinical cancer, bringing hope to apply CAR strategies to other clinical settings. Here we developed a CAR macrophage (CAR-M) that recognizes the major inflammatory molecule tumour necrosis factor (TNF) and activates an intracellular IL-4 signalling pathway, thereby programming engineered macrophages for an anti-inflammatory function. CAR-M therapy has exhibited efficacy in mouse models of both acute and chronic inflammatory diseases. In kidney ischaemia reperfusion injury (IRI), infused CAR-Ms switched to an anti-inflammatory phenotype in inflamed kidney and attenuated kidney IRI. The anti-inflammatory phenotype of infused CAR-Ms switched off during the recovery phase of kidney IRI, coinciding with the disappearance of TNF. In Adriamycin-induced nephropathy, a model of chronic inflammatory disease, infused CAR-Ms maintained an anti-inflammatory phenotype for several weeks in response to sustained high levels of TNF and improved kidney function and structure. CAR-Ms also effectively reduced tissue injury in another organ, the liver. Human anti-TNF CAR-Ms exhibit anti-inflammatory phenotype and function in response to TNF. The CAR-M design, using signal switching, holds promise for the treatment of a broad range of acute and chronic inflammatory diseases.