Targeting cardiac fibrosis with engineered T cells

Haig Aghajanian, Toru Kimura, Joel G. Rurik, Aidan S. Hancock, Michael S. Leibowitz, Li Li, John Scholler, James Monslow, Albert Lo, Wei Han, Tao Wang, Kenneth Bedi, Michael P. Morley, Ricardo A. Linares Saldana, Nikhita A. Bolar, Kendra McDaid, Charles-Antoine Assenmacher, Cheryl L. Smith, Dagmar Wirth, Carl H. June, Kenneth B. Margulies, Rajan Jain, Ellen Puré, Steven M. Albelda and Jonathan A. Epstein ()
Additional contact information
Haig Aghajanian: University of Pennsylvania
Toru Kimura: University of Pennsylvania
Joel G. Rurik: University of Pennsylvania
Aidan S. Hancock: University of Pennsylvania
Michael S. Leibowitz: University of Pennsylvania
Li Li: University of Pennsylvania
John Scholler: University of Pennsylvania
James Monslow: University of Pennsylvania
Albert Lo: University of Pennsylvania
Wei Han: Hospital of the University of Pennsylvania
Tao Wang: University of Pennsylvania
Kenneth Bedi: University of Pennsylvania
Michael P. Morley: University of Pennsylvania
Ricardo A. Linares Saldana: University of Pennsylvania
Nikhita A. Bolar: University of Pennsylvania
Kendra McDaid: University of Pennsylvania
Charles-Antoine Assenmacher: University of Pennsylvania
Cheryl L. Smith: University of Pennsylvania
Dagmar Wirth: Helmholtz Centre for Infection Research
Carl H. June: University of Pennsylvania
Kenneth B. Margulies: University of Pennsylvania
Rajan Jain: University of Pennsylvania
Ellen Puré: University of Pennsylvania
Steven M. Albelda: University of Pennsylvania
Jonathan A. Epstein: University of Pennsylvania

Nature, 2019, vol. 573, issue 7774, 430-433

Abstract: Abstract Fibrosis is observed in nearly every form of myocardial disease1. Upon injury, cardiac fibroblasts in the heart begin to remodel the myocardium by depositing excess extracellular matrix, resulting in increased stiffness and reduced compliance of the tissue. Excessive cardiac fibrosis is an important factor in the progression of various forms of cardiac disease and heart failure2. However, clinical interventions and therapies that target fibrosis remain limited3. Here we demonstrate the efficacy of redirected T cell immunotherapy to specifically target pathological cardiac fibrosis in mice. We find that cardiac fibroblasts that express a xenogeneic antigen can be effectively targeted and ablated by adoptive transfer of antigen-specific CD8+ T cells. Through expression analysis of the gene signatures of cardiac fibroblasts obtained from healthy and diseased human hearts, we identify an endogenous target of cardiac fibroblasts—fibroblast activation protein. Adoptive transfer of T cells that express a chimeric antigen receptor against fibroblast activation protein results in a significant reduction in cardiac fibrosis and restoration of function after injury in mice. These results provide proof-of-principle for the development of immunotherapeutic drugs for the treatment of cardiac disease.

Date: 2019
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DOI: 10.1038/s41586-019-1546-z

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