Chimeric antigen receptor T-cell therapy in B-cell malignancies and DNA-methylation–based biological aging.

Abstract

2562 Background: Chimeric antigen receptor T-cell (CAR T-cell) therapy, a type of cancer immunotherapy which leverages genetically altered T cells to target cancer cells, has shown to be an effective option for patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). Despite its growing use, the effect of CAR T-cell therapy on the aging process remains limited and findings may have implications for disease relapse and age-related diseases among survivors. The purpose of this study was to investigate the association between CAR T-cell therapy and markers of biological aging. Methods: DNA methylation and clinical data from a publicly available dataset (GSE179414) were used in this analysis. Transduced and untransduced T cells from patients with ALL (n=77) and NHL (n=37) underwent DNA methylation profiling using the Illumina Infinium MethylationEPIC BeadChip. Six DNA methylation-based biological age metrics were calculated: intrinsic epigenetic age acceleration (IEAA), extrinsic epigenetic age acceleration (EEAA), PhenoAge acceleration (PhenoAA), GrimAge acceleration (GrimAA), telomere length attrition (TLA), and DunedinPACE (Pace of Aging Calculated from the Epigenome). Multiple linear regression analyses were performed to examine the association between CAR T-cell therapy and the aging metrics by B-cell malignancy. Interaction and stratified analyses by chronological age was additionally performed. Results: DunedinPACE ( P=0.002) was positively associated with CAR T-cell therapy among patients with ALL with an approximately 1-month higher pace of aging in transduced T cells compared to untransduced T cells after adjusting for chronological age and sex. Moreover, chronological age significantly ( P=0.016) modified the association between CAR T-cell therapy and TLA among ALL patients. Specifically, transduced T cells exhibited a 0.46 higher ( P=0.053) and a 0.39 lower ( P=0.142) rate of TLA among patients 16 years of age or older and those younger than 16 years of age, respectively. Conclusions: We observed CAR T-cell therapy was associated with greater biological aging as estimated from DNA methylation among ALL patients and these associations are modified by chronological age. These findings suggest CAR T-cell therapy may be associated with age-related changes to the epigenome in ALL patients and strategies to limit or reverse this effect may have implications for the aging process in cancer survivors. [Table: see text]