CD19-CAR T cells undergo exhaustion DNA methylation programming in patients with acute lymphoblastic leukemia

• Published in: Cell reports (Cambridge) 2021-11, Vol.37 (9), p.110079-110079, Article 110079
• Main Authors: Zebley, Caitlin C, Brown, Charmaine, Mi, Tian, Fan, Yiping, Alli, Shanta, Boi, Shannon, Galletti, Giovanni, Lugli, Enrico, Langfitt, Deanna, Metais, Jean-Yves, Lockey, Timothy, Meagher, Michael, Triplett, Brandon, Talleur, Aimee C, Gottschalk, Stephen, Youngblood, Ben
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Antigens, CD19 - immunology; CD8-Positive T-Lymphocytes - immunology; Child; Child, Preschool; DNA Methylation; Female; Gene Expression Regulation, Neoplastic; Humans; Immunotherapy, Adoptive - methods; Infant; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - immunology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - therapy; Receptors, Antigen, T-Cell - immunology; Young Adult
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.110079

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.