INV03
CAR T cells produced in vivo to treat cardiac injury
J G Rurik ¹ I Tombácz † ² A Yadegari † ² P O Méndez Fernández ¹ S V Shewale ¹ L Li ¹ T Kimura ‡ ² O Y Soliman ² T E Papp ² Y K Tam ³ B L Mui ³ S M Albelda ² ⁴ E Puré ⁵ C H June ⁴ H Aghajanian * ¹ D Weissman * ² H Parhiz * ² J A Epstein * ¹ ²
1: Department of Cell and Developmental Biology, Penn Cardiovascular Institute, & Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA 2: Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA 3: Acuitas Therapeutics, Vancouver, BC V6T 1Z3, Canada 4: Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA 5: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
† The second authors contributed equally
‡ Present address: Department of General Thoracic Surgery, Osaka International Cancer Institute, Osaka, JAPAN
* Corresponding authors
Fibrosis is a common pathologic finding among many cardiac diseases, afflicting millions of people globally. To address the significant clinical burden of cardiac fibrosis, we have developed a novel approach to make transient anti-fibrotic chimeric antigen receptor (CAR) T cells entirely in vivo by delivering modified mRNA in lymphocyte-targeted lipid nanoparticles (LNP). This new technology significantly improves the safety profile and bypasses the manufacturing challenges associated with CAR T therapy. We demonstrate the efficacy of this approach in vitro and in vivo using a mouse model of pressure-overload cardiac injury. We show that an intravenous injection of antibody targeted LNP loaded with mRNA encoding a CAR designed against activated fibroblasts, efficiently transforms T cells into transient, effective CAR T cells. We also demonstrate that anti-fibrotic CAR T cells trogocytose and retain the target antigen as they accumulate in the spleen after injection. Most importantly, injured mice treated with a single dose of modified mRNA encapsulated in targeted lipid nanoparticles improves cardiac function and decreases fibrosis. In vivo generation of CAR T cells holds promise to treat various forms of heart disease.