急性淋巴细胞白血病患者中 CD19-CAR-T 细胞发生耗竭 DNA 甲基化编程

CD19-CAR T cell therapy has evolved into the standard of care for relapsed/refractory B cell acute lymphoblastic leukemia (ALL); however, limited persistence of the CAR T cells enables tumor relapse for many patients. To gain a deeper understanding of the molecular characteristics associated with CAR T cell differentiation, we performed longitudinal genome-wide DNA methylation profiling of CD8 + CD19-CAR T cells post-infusion in ALL patients.

We report that CAR T cells undergo a rapid and broad erasure of repressive DNA methylation reprograms at effector-associated genes. The CAR T cell post-infusion changes are further characterized by repression of genes (e. g. , TCF7 and LEF1) associated with memory potential and a DNA methylation signature (e. g. , demethylation at CX3CR1, BATF, and TOX) demarcating a transition toward exhaustion-progenitor T cells.

Thus, CD19-CAR T cells undergo exhaustion-associated DNA methylation programming, indicating that efforts to prevent this process may be an attractive approach to improve CAR T cell efficacy.