Senolytic CAR T cells reverse senescence-associated pathologies

Corina Amor, Judith Feucht, Josef Leibold, Yu-Jui Ho, Changyu Zhu, Direna Alonso-Curbelo, Jorge Mansilla-Soto, Jacob A. Boyer, Xiang Li, Theodoros Giavridis, Amanda Kulick, Shauna Houlihan, Ellinor Peerschke, Scott L. Friedman, Vladimir Ponomarev, Alessandra Piersigilli, Michel Sadelain () and Scott W. Lowe ()
Additional contact information
Corina Amor: Memorial Sloan Kettering Cancer Center
Judith Feucht: Center for Cell Engineering, Memorial Sloan Kettering Cancer Center
Josef Leibold: Memorial Sloan Kettering Cancer Center
Yu-Jui Ho: Memorial Sloan Kettering Cancer Center
Changyu Zhu: Memorial Sloan Kettering Cancer Center
Direna Alonso-Curbelo: Memorial Sloan Kettering Cancer Center
Jorge Mansilla-Soto: Center for Cell Engineering, Memorial Sloan Kettering Cancer Center
Jacob A. Boyer: Memorial Sloan Kettering Cancer Center
Xiang Li: Memorial Sloan Kettering Cancer Center
Theodoros Giavridis: Center for Cell Engineering, Memorial Sloan Kettering Cancer Center
Amanda Kulick: Memorial Sloan Kettering Cancer Center
Shauna Houlihan: Memorial Sloan Kettering Cancer Center
Ellinor Peerschke: Memorial Sloan Kettering Cancer Center
Scott L. Friedman: Icahn School of Medicine at Mount Sinai
Vladimir Ponomarev: Memorial Sloan Kettering Cancer Center
Alessandra Piersigilli: Rockefeller University, Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center
Michel Sadelain: Center for Cell Engineering, Memorial Sloan Kettering Cancer Center
Scott W. Lowe: Memorial Sloan Kettering Cancer Center

Nature, 2020, vol. 583, issue 7814, 127-132

Abstract: Abstract Cellular senescence is characterized by stable cell-cycle arrest and a secretory program that modulates the tissue microenvironment1,2. Physiologically, senescence serves as a tumour-suppressive mechanism that prevents the expansion of premalignant cells3,4 and has a beneficial role in wound-healing responses5,6. Pathologically, the aberrant accumulation of senescent cells generates an inflammatory milieu that leads to chronic tissue damage and contributes to diseases such as liver and lung fibrosis, atherosclerosis, diabetes and osteoarthritis1,7. Accordingly, eliminating senescent cells from damaged tissues in mice ameliorates the symptoms of these pathologies and even promotes longevity1,2,8–10. Here we test the therapeutic concept that chimeric antigen receptor (CAR) T cells that target senescent cells can be effective senolytic agents. We identify the urokinase-type plasminogen activator receptor (uPAR)11 as a cell-surface protein that is broadly induced during senescence and show that uPAR-specific CAR T cells efficiently ablate senescent cells in vitro and in vivo. CAR T cells that target uPAR extend the survival of mice with lung adenocarcinoma that are treated with a senescence-inducing combination of drugs, and restore tissue homeostasis in mice in which liver fibrosis is induced chemically or by diet. These results establish the therapeutic potential of senolytic CAR T cells for senescence-associated diseases.

Date: 2020
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DOI: 10.1038/s41586-020-2403-9

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