Targeting Cardiac Fibrosis with Engineered T cells

Fibrosis is observed in nearly every form of myocardial disease(1). Upon injury, cardiac fibroblasts (CF) in the heart begin to remodel the myocardium via extracellular matrix deposition, resulting in increased tissue stiffness and reduced compliance. Excessive cardiac fibrosis is an important factor in the progression of various forms of cardiac disease and heart failure(2). However, clinical interventions and therapies targeting fibrosis remain limited(3). In this study, we demonstrate the efficacy of redirected T-cell immunotherapy to specifically target pathologic cardiac fibrosis. We find that cardiac fibroblasts expressing a xenogeneic antigen can be effectively targeted and ablated by adoptive transfer of antigen-specific CD8(+) T cells. Through expression analysis of cardiac fibroblast gene signatures from healthy versus diseased human hearts, we identified an endogenous CF target; fibroblast activation protein (FAP). Adoptive transfer of T cells expressing a chimeric antigen receptor (CAR) against FAP, results in a significant reduction in cardiac fibrosis and restoration of function after injury in mice. These results provide the proof-of-principle basis for a novel immunotherapeutic avenue for the treatment of cardiac disease.