An Aged Microenvironment Increases CAR T Cell Cytotoxicity but Impairs Therapeutic Efficacy

Abstract

BackgroundCancer disproportionately affects the elderly, who are often less able to tolerate traditional cytotoxic therapies, and may benefit from T cell-based immunotherapies. However, studies evaluating the efficacy of T cell immunotherapy in aged mice are limited and yield inconsistent results, while clinical data are largely retrospective. MethodsHere, we used a murine model of Chimeric Antigen Receptor (CAR) T cell therapy to investigate how aging influences efficacy, from CAR T cell production to in vivo anti-tumor activity. ResultsWe found that aging reduced CAR T cell production yields and altered their phenotype and function. Aged CAR T cells were predominantly effector memory CD4 T cells, whereas young CAR T cells were primarily central memory CD8 T cells. Functionally, aged CAR T cells exhibited non-specific cytotoxicity, driven by constitutive degranulation and elevated granzyme B secretion independent of CAR expression. This phenotype was induced by the aged microenvironment, as young T cells transferred into aged hosts adopted similar behavior. In vivo, young CAR T cells efficiently reduced tumor burden in young leukemia-bearing hosts, but were not effective in aged hosts, where the aged microenvironment impaired CAR T cell persistence. ConclusionThese findings indicate that aging impacts CAR T cell therapy at multiple levels, from manufacturing to therapeutic efficacy, highlighting the need to design tailored immunotherapies for elderly patients.