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

TL;DR

This paper reviews how CAR T cell therapy could be used to target and destroy harmful lung fibroblasts in IPF, a deadly lung disease with limited treatment options.

Contribution

The paper provides a comprehensive review of preclinical and clinical progress in using anti-FAP CAR T cells for IPF treatment.

Findings

CAR T cells can selectively target fibroblasts expressing fibroblast activation protein (FAP) in IPF.

Preclinical and early clinical studies show promise but also highlight challenges like off-target effects and toxicity.

Strategies to improve CAR T cell therapy for IPF include optimizing targeting and reducing adverse events.

Abstract

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 in vivo 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.

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