Epigenetic editing balances TCR suppression and persistence in CAR T cells

Publikation: Beitrag in Fachzeitschrift › Forschungsartikel › Beigetragen › Begutachtung

Beitragende

Abstract

Allogeneic chimeric antigen receptor (CAR) T cell therapies offer a scalable, off-the-shelf option for cancer treatment, but their clinical use is limited by the risk of graft-versus-host disease (GvHD), mediated by the endogenous T cell receptor (TCR). Conventional strategies to eliminate TCR expression rely on genome editing tools such as CRISPR-Cas9 or base editing, which introduce permanent DNA changes and pose safety concerns. Here, we present an epigenetic editing approach that enables efficient, specific, and reversible silencing of the CD3ε gene, a critical component of the TCR complex, without altering the genome. We systematically optimized the epigenetic editor and guide RNA in a cell line and achieved robust TCR silencing in primary T and CAR T cells while preserving CAR expression, activation, and effector function. Transcriptome analysis confirmed minimal off-target effects. In vivo observations suggest the epigenetically silenced T cells to prevent GvHD while persisting longer than TCR-knockout cells, supporting the notion that transient TCR suppression may help balance safety and long-term efficacy. Our findings establish epigenetic editing as a non-genotoxic alternative to genome editing, offering a flexible and safer route to generate next-generation allogeneic CAR T cells.

Details

OriginalspracheEnglisch
Aufsatznummer201712
FachzeitschriftMolecular therapy : Advances
Jahrgang34
Ausgabenummer2
PublikationsstatusVeröffentlicht - 11 Juni 2026
Peer-Review-StatusJa

Externe IDs

ORCID /0000-0002-5726-386X/work/226837334
ORCID /0000-0001-5084-1180/work/226837579

Schlagworte

ASJC Scopus Sachgebiete

  • Genetik - allogeneic therapy, CAR T cell, CRISPR/Cas, epigenetic editing, genome editing, graft-versus-host disease, T cell receptor
  • Molekularbiologie - allogeneic therapy, CAR T cell, CRISPR/Cas, epigenetic editing, genome editing, graft-versus-host disease, T cell receptor
  • Molekularmedizin - allogeneic therapy, CAR T cell, CRISPR/Cas, epigenetic editing, genome editing, graft-versus-host disease, T cell receptor

Schlagwörter

  • allogeneic therapy, CAR T cell, CRISPR/Cas, epigenetic editing, genome editing, graft-versus-host disease, T cell receptor