Human CAR-NK therapy for pathological fibrosis in the heart

About This Grant

Project summary: Cardiac fibrosis is a key pathological process contributing to heart failure, characterized by excessive deposition of extracellular matrix (ECM) that leads to increased ventricular stiffness, reduced compliance, and impaired cardiac function. Despite its central role in heart failure progression, current therapies primarily manage symptoms and do not reverse or eliminate the fibrotic burden. Targeting the activated fibroblasts responsible for ECM overproduction represents a promising therapeutic strategy. Recent advances have demonstrated that chimeric antigen receptor (CAR)-engineered immune cells can be redirected to target fibroblast activation protein (FAP), a marker of activated fibroblasts. However, the clinical application of CAR-T cells for fibrosis has been limited by significant safety concerns, including cytokine release syndrome, neurotoxicity, and long-term persistence. As an alternative, CAR natural killer (CAR-NK) cells offer a more favorable safety profile and have not been associated with these adverse effects, especially when derived from allogeneic sources. This project aims to develop universal CAR-NK cells derived from hypoimmunogenic human induced pluripotent stem cells (hiPSCs). These cells are engineered with inactivated HLA class I/II and overexpress CD47 to evade host immune recognition, allowing for off-the-shelf, allogeneic use without the need for lymphodepletion or immunosuppression. In this study, the CAR construct targets mouse FAP to enable selective elimination of activated cardiac fibroblasts. We will evaluate the therapeutic efficacy of these engineered CAR-NK cells in vitro and in vivo by cardiac fibrosis induction in NSG-SGM3-IL15 mice model. Outcomes will include fibroblast ablation, fibrosis regression, and recovery of cardiac function. This study has the potential to establish a new class of regenerative immunotherapies for cardiac fibrosis and heart failure.