The allogeneic eDN70(-) CAR-T Cells Without TCR or MHC Editing Exhibit Enhanced Persistence and Function.

Authors

Wuling Li, Yanmin Xu, Zhi Yang, Juanjuan Shan, Huailong Xu, Huiyu Chen, Junjie Shen, Cheng Qian, Wenwei Yin

Published in

Molecular therapy : the journal of the American Society of Gene Therapy. Oct 16, 2026. Epub Oct 16, 2026.

Abstract

Allogeneic CAR-T therapy offers an "off-the-shelf" alternative to autologous CAR-T, but faces graft-versus-host rejection (GVH) and host-versus-graft rejection (HVG). Conventional TCR/MHC elimination compromises persistence and increase NK susceptibility. Here, we developed a next-generation UCAR-T strategy that avoids TCR/MHC disruption while addressing donor-cell alloreactivity and host-mediated rejection. First, we eliminated CD4/CD8 to reduce alloreactivity while preserving TCR integrity and potentially TCR/CD3-mediated fitness, although in vivo xGvHD protection remains to be determined. In parallel, we identified CD70 as a marker selectively upregulated on alloreactive immune cells, enabling targeted removal of HVG-driving subsets. Because CD70 is also induced during T-cell activation and further enhanced following CD4/CD8 knockout, we additionally deleted CD70 to prevent fratricide, generating a CD4/CD8/CD70 triple-negative UCAR-T backbone (eDN70(-) UCAR-T). As proof-of-concept, we incorporated both CD19- and CD70-targeting CARs to generate eDN70(-)19/70CAR-T cells, which showed superior expansion, reduced exhaustion, and greater resistance to HVG pressure. Furthermore, these cells demonstrated durable tumor control and robust recall responses in vivo, with preliminary tissue-level safety from the high-dose study. Collectively, our findings establish eDN70(-) UCAR-T cells as a versatile platform capable of overcoming the persistence limitations of current allogeneic CAR-T therapies, with the CD19/CD70 dual-target configuration serving as a representative implementation of this strategy.

PMID:
42888846
Bibliographic data and abstract were imported from PubMed on 17 Oct 2026.

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