Chimeric antigen receptor (CAR) T cell therapies target specific surface features on other cells by providing T cells with a way to recognize that feature - the CAR. T cells so equipped will selectively destroy other cells with the target surface feature. To produce a CAR T cell therapy, a patient's T cells are taken, genetically engineered to introduce the CAR, expanded, and then reintroduced. This is presently used as a form of cancer therapy. Given a surface feature sufficiently specific to senescent cells, CAR T cell immunotherapy can be turned into a senolytic treatment, however. Senescent cell accumulation is one of the important causes of degenerative aging, and effective clearance of senescent cells is a form of rejuvenation. Researchers here claim to have identified a suitably specific surface marker of senescence, and use it to demonstrate benefits in mice via CAR T cell therapy. It will be interesting to see how this develops.
Cellular senescence is characterized by stable cell-cycle arrest and a secretory program that modulates the tissue microenvironment. Physiologically, senescence serves as a tumour-suppressive mechanism that prevents the expansion of premalignant cells and has a beneficial role in wound-healing responses. 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 osteoarthritis. Accordingly, eliminating senescent cells from damaged tissues in mice ameliorates the symptoms of these pathologies and even promotes longevity.
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) 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.