CAR T cells produced in vivo to treat cardiac injury

  • Science. 2022 Jan 7;375(6576):91-96. doi: 10.1126/science.abm0594.
Joel G Rurik  1  2  3 ,  István Tombácz  #  4 ,  Amir Yadegari  #  4 ,  Pedro O Méndez Fernández  1  2  3 ,  Swapnil V Shewale  2 ,  Li Li  1  2 ,  Toru Kimura  4 ,  Ousamah Younoss Soliman  4 ,  Tyler E Papp  4 ,  Ying K Tam  5 ,  Barbara L Mui  5 ,  Steven M Albelda  4  6 ,  Ellen Puré  7 ,  Carl H June  6 ,  Haig Aghajanian  1  2  3 ,  Drew Weissman  4 ,  Hamideh Parhiz  4 ,  Jonathan A Epstein  1  2  3  4
Affiliations
  • 1. Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • 2. Penn Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • 3. Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • 4. Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • 5. Acuitas Therapeutics, Vancouver, British Columbia V6T 1Z3, Canada.
  • 6. Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 7. Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • # Contributed equally.
PMID: 34990237 DOI: 10.1126/science.abm0594
Abstract

Fibrosis affects millions of people with cardiac disease. We developed a therapeutic approach to generate transient antifibrotic chimeric antigen receptor (CAR) T cells in vivo by delivering modified messenger RNA (mRNA) in T cell–targeted Lipid Nanoparticles (LNPs). The efficacy of these in vivo–reprogrammed CAR T cells was evaluated by injecting CD5-targeted LNPs into a mouse model of Heart Failure. Efficient delivery of modified mRNA encoding the CAR to T lymphocytes was observed, which produced transient, effective CAR T cells in vivo. Antifibrotic CAR T cells exhibited trogocytosis and retained the target antigen as they accumulated in the spleen. Treatment with modified mRNA-targeted LNPs reduced fibrosis and restored cardiac function after injury. In vivo generation of CAR T cells may hold promise as a therapeutic platform to treat various diseases.