Immunosenescence and CAR T-Cell Efficacy in CLL
Noll JH, Dersh D, Li JY, et al. T-Cell Immunosenescence Limits CD19 CAR T-Cell Function in Chronic Lymphocytic Leukemia. Blood. 2026; (doi: 10.1182/blood.2025032274).
Researchers suspect immunosenescence may be implicated when chimeric antigen receptor (CAR) T-cell therapy fails in the setting of chronic lymphocytic leukemia (CLL). Patients can achieve durable remission through treatment with CD19-targeted CAR T cells (CTL019), but when durable remission is not achieved, T-cell exhaustion is typically presumed to be the reason. However, scientists point to evidence supporting a contributing role of T-cell immunosenescence, an aging-like program characterized by costimulatory loss, DNA damage, inflammatory secretion, repertoire restriction, and proliferative arrest. Among recipients of preinfusion CTL019 products, markers of senescence and the senescence-associated secretory phenotype (SASP) were higher. Among nonresponders and short partial responders than among complete and partial responders and correlated with weak CAR T-cell expansion, low persistence, and suboptimal clinical outcomes. The researchers found immunosenescence to be a measurable barrier to CAR T-cell efficacy in CLL patients but see potential in targeting it for therapeutic modulation. Ibrutinib, for example, improved proliferative fitness and attenuated senescence-associated features and SASP output in paired patient and direct-exposure assays. It also improved CAR T-cell functional reserve.