CAR T cell therapy for fighting IPF: perspectives on a living drug

Fibrotic interstitial lung disease (fILD), particularly idiopathic pulmonary fibrosis (IPF), represents an incurable progressive lung disorder characterized by a dismal prognosis. Fibroblasts constitute the principal cellular drivers of the fibrotic cascade. Although two pharmacological agents (pirfenidone and nintedanib) have secured regulatory approval for clinical application, they remain incapable of substantially attenuating disease progression. Persistent immune dysregulation driven alveolitis, occupies a critical upstream position in perpetuating fibroblast activation and extracellular matrix (ECM). Recent investigations have introduced an innovative strategy employing genetically engineered T cells to selectively target and eliminate activated fibroblasts. This approach involves generating chimeric antigen receptor (CAR) T cells <i>in vivo</i> by encapsulating mRNA encoding CARs within lipid nanoparticles (LNPs). These CAR T cells can specifically recognize and ablate fibroblasts expressing fibroblast activation protein (FAP). In this review, we summarize recently developed CAR T cell therapeutic strategies for IPF treatment with optimal targeting of FAP-fibroblasts, synthesize the existing preclinical studies and clinical trials evaluating anti-FAP CAR T cells to date, and critically discuss the adverse events associated with CAR T therapy alongside strategies to overcome current limitations of CAR T cell therapy in IPF management.