Abstract
In mice, senescence-targeted CAR T cells extended survival in lung cancer and improved liver fibrosis.
Major Finding: In mice, senescence-targeted CAR T cells extended survival in lung cancer and improved liver fibrosis.
Concept: Senescence is associated with pathogenesis of several diseases, such as cancer and liver fibrosis.
Impact: Targeting senescent cells using CAR T cells could be a useful strategy in cancer and other diseases.
Pathologic accumulation of senescent cells is associated with inflammation that can lead to disease states such as liver fibrosis, cancer, and many others. Several small-molecule inhibitors that preferentially target senescent cells have been identified as senolytic agents, but issues including low potency and high side-effect potential have limited their utility. Amor, Feucht, Leibold, and colleagues investigated whether chimeric antigen receptor (CAR) T cells directed at the cell-surface and secreted protein urokinase-type plasminogen activator receptor (uPAR), which they found to be highly expressed by senescent cells in vitro and in vivo, could act as selective senolytics and overcome the barriers associated with previously explored small-molecule drugs. uPAR-directed CAR T cells exhibited selective cytotoxicity toward uPAR-expressing cancer cells in vitro and were capable of clearing hepatocytes with oncogene-induced senescent phenotypes in immunodeficient mice without showing evidence of T-cell exhaustion 15 days following administration. In immunocompetent mouse models of lung adenocarcinoma and carbon tetrachloride– or diet-induced liver fibrosis, treatment with uPAR-directed CAR T cells extended survival or reduced established fibrosis, respectively. Although toxicity was not noted in the mice treated in this study at therapeutic doses, future work will be necessary to determine whether uPAR-directed CAR T-cell treatment has an acceptable safety profile in patients. In summary, this work provides promising preliminary evidence that uPAR-directed CAR T cells effectively target senescent cells and shows that this CAR T-cell treatment has a measurable impact on disease states in immunocompetent hosts. Notably, accumulation of senescent cells contributes to the pathogenesis of several diseases not examined in this study, such as osteoarthritis, diabetes, and atherosclerosis, suggesting that testing uPAR-directed CAR T cells in models of these diseases may be of interest as well.
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