Age-induced changes in the host microenvironment impact CAR T cell immunotherapy

Cancer disproportionately affects the elderly, who are less tolerant of traditional therapies and

could benefit from T cell-based immunotherapies. However, age-related immune changes

remain underexplored, with few studies including aged animals or patients. This study used a

Chimeric Antigen Receptor (CAR) T cell therapy model in mice to investigate the effects of

aging on CAR T cell production and anti-tumor activity in vivo. Aging reduced CAR T cell

production yield and altered their phenotype and function. Aged CAR T cells predominantly

consisted of effector memory CD4+ T cells, while young CAR T cells were largely central

memory CD8+ T cells. Functionally, aged CAR T cells exhibited non-specific cytotoxicity,

killing target cells independent of CAR expression or direct recognition, driven by constant

degranulation and heightened granzyme B secretion. This phenotype was induced by the aged

microenvironment, as young T cells transferred into aged hosts displayed similar dysfunction.

In vivo, young CAR T cells effectively reduced tumor burden in young leukemiabearing

hosts but were less effective in aged hosts, where the aged microenvironment impaired

CAR T cell expansion and cytotoxicity. These findings demonstrate that aging affects CAR T

cell therapy at multiple levels, from production to efficacy, underscoring the need to optimize

immunotherapy for elderly patients.