ApoptoSENS - Senolytic CAR-NK cells

Background

When cells become damaged, they enter a state of cellular senescence where they no longer function properly and secrete proinflammatory factors. The immune system’s ability to eliminate senescent cells diminishes with age, resulting in their accumulation throughout the body. This accumulation leads to dysfunction in many different tissue types and accelerates aging. Current approaches to eliminate senescent cells are non-specific and their mechanisms of action are largely unknown. Also, due to the highly heterogeneous nature of senescent cells, including the existence of senescent cells with beneficial effects, there is currently a lack of knowledge regarding cell surface markers to identify populations of harmful senescent cells. The current focus on senescence as a therapeutic target was prompted by the discoveries that: Markers of cellular senescence accumulate with aging and accumulation is delayed by interventions that increase healthspan and lifespan. Removal of senescent cells increases healthspan in mouse models. Transplantation of a small number of senescent cells into previously healthy animals provokes multisystem dysfunction similar to what is seen in aged animals. A recent study used chimeric antigen receptor (CAR) T cells targeted against the uPAR receptor in a mouse model. Cytotoxic CAR T cells were able to selectively clear uPAR-expressing senescent cells in vitro and in vivo. However, CAR T cell dosing is associated with a proinflammatory cytokine profile, weight loss and hypothermia, suggesting that careful attention would need to be paid to initial dosing strategies, particularly in geriatric populations where a compromised immune system together with ongoing chronic inflammation may restrict the therapeutic window. Although senolytic CAR T cells appear to be self-limiting, their expansion and contraction occurs over a period of days, which is a risk in the case of an acute to subacute adverse reaction.