Genetic Mutation and Epigenetic Silencing Drive Antigen-Negative Relapse in CD7 CAR-T Treated T-cell Lymphoid Malignancies.

Authors

Rongrong Chen, Haiqiong Zheng, Wenxin Wang, Shan Fu, Mingming Zhang, Jingjing Feng, Alex H Chang, Jiangtao Ren, Shanshan Pei, He Huang, Yongxian Hu

Published in

Blood cancer discovery. Jul 08, 2026. Epub Jul 08, 2026.

Abstract

CD7 is a promising target for chimeric antigen receptor (CAR) T-cell therapy in T-cell lymphoid malignancies; however, antigen loss-mediated relapse emerged as a major challenge. Herein, we systematically analyzed the genetic and epigenetic alterations of paired specimens (pre-treatment and relapsed) from 10 patients with T-cell lymphoma/leukemia receiving CD7 CAR-T cells. Overall, we identified three distinct mechanisms underlying CD7 loss: Firstly, frameshift insertion (Pt4; c.164dupG:p.R55fs) or deletion (Pt7; c.122delG:p.G41Efs*19) resulting in truncation of the CD7 transmembrane domain in two of ten patients; Secondly, hypermethylation of the CD7 promoter in seven of ten patients without CD7 mutation; Thirdly, simultaneous occurrence of promoter region hypermethylation and multiple in-frame mutations with predicted functional interference in one of ten patients (Pt2). Collectively, these findings demonstrated that both clonal heterogeneity and epigenetic plasticity drive antigen-negative relapse in T-cell lymphoid malignancies under the selective pressure of CD7 CAR-T therapy.

PMID:
42418709
Bibliographic data and abstract were imported from PubMed on 09 Jul 2026.

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