A Senolytic Chimeric Antigen Receptor T Cell Therapy
Chimeric antigen receptor (CAR) T cell therapies involve engineering a patient's T cells to add receptors complementary to a specific surface feature of a target cell population that one wants destroyed. This approach to therapy was pioneered in the cancer research community, and has performed well to date. Here, researchers demonstrate that it is possible to use a CAR-T approach to target senescent cells. Clearance of senescent cells in older individuals produces rejuvenation and reversal of many different age-related conditions in animal studies, and we might hope that the same will occur in humans.
Cellular senescence, characterized by stable cell cycle arrest, plays an important role in aging and age-associated pathologies. Eliminating senescent cells rejuvenates aged tissues and ameliorates age-associated diseases. Here, we identified that natural killer group 2 member D ligands (NKG2DLs) are up-regulated in senescent cells in vitro, regardless of stimuli that induced cellular senescence, and in various tissues of aged mice and nonhuman primates in vivo. Accordingly, we developed and demonstrated that chimeric antigen receptor (CAR) T cells targeting human NKG2DLs selectively and effectively diminish human cells undergoing senescence induced by oncogenic stress, replicative stress, DNA damage, or P16INK4a overexpression in vitro.
Targeting senescent cells with mouse NKG2D-CAR T cells alleviated multiple aging-associated pathologies and improved physical performance in both irradiated and aged mice. Autologous T cells armed with the human NKG2D CAR effectively delete naturally occurring senescent cells in aged nonhuman primates without any observed adverse effects. Our findings establish that NKG2D-CAR T cells could serve as potent and selective senolytic agents for aging and age-associated diseases driven by senescence.