Myeloid-lineage CAR knockin mice enable allogeneic immunotherapy for liver and lung fibrosis.

The preparation of chimeric antigen receptor immune cells (CAR-ICs) typically involves a costly and time-intensive process. Moreover, the transduction of CAR genes into ICs, particularly macrophages, presents inherent challenges. Here, we report a novel strategy to obtain CAR-modified macrophages (CAR-Ms) directly from living animals to treat pulmonary and hepatic fibrosis. We first validated adenovirus-transduced CAR-Ms targeting fibroblast activation protein (FAP) in vitro, as well as in mouse models of pulmonary and hepatic fibrosis. Using a Cre/LoxP strategy, we generated mice with myeloid-specific expression of FAP-CAR, which showed inherent resistance to induced fibrosis. Furthermore, transplantation of macrophages or allogeneic transfusion of whole blood from these transgenic mice alleviated fibrosis in recipient mice. This proof-of-concept study sourcing gene-modified ICs directly from living animals shows promise as a therapeutic platform to treat various diseases.