ApoptoSENS - Senolytic CAR-NK cells

Background

When cells become damaged, they may 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 progeroid mouse models, and transplantation of a relatively small number of senescent cells into previously healthy animals provokes multisystem dysfunction similar to what is seen in aged animals. Furthermore, it has been shown that the correlation of senescent cell accumulation with disease extends to humans. Since senescent cells are highly heterogeneous in both their molecular biology and their physiological function, targeted strategies are needed that ideally preserve senescent cells in beneficial contexts while eliminating effects that are detrimental. Broadly speaking, current therapies can be broken down into the major categories of senomorphic (targeting SASP, i.e., senescence-associated secretory phenotype, components) and senolytic (targeting senescent cells) drugs. While the first senolytics were developed using a bioinformatically informed approach aimed at disrupting SCAPs and other pro-survival networks, the class has expanded to take advantage of additional senescence features and enhance immune-mediated clearance. Most notably, characterization of senescent cells has revealed unique markers that serve as senescence-associated self-antigens, and these can be co-opted for immune system-mediated senolytic activity and clearance. Despite the pre-clinical promises of targeting senescent cells and/or SASP, clinical trials in humans thus far have been less encouraging. Nevertheless, significant interest remains in the general approach. A recent study took advantage of this approach using chimeric antigen receptor (CAR) T cells targeted against the urokinase-type plasminogen activator receptor (uPAR) in a mouse model (doi: 10.1038/s41586-020-2403-9). Cytotoxic CAR T cells were able to selectively clear uPAR-expressing senescent cells in vitro and in vivo. CAR T cell-mediated clearance of senescent cells led to survival and histopathologic benefit in murine models of both carbon tetrachloride- and diet-induced liver fibrosis, suggesting the feasibility and potential of this clearance strategy. However, supratherapeutic 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. Additionally, CAR T cell approaches in humans involve initial immune system suppression with considerable attendant morbidity and are expensive. 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. Overall, this strategy is highly promising given its preclinical efficacy and senescent cell specificity, but future optimization and testing is necessary before clinical administration.