Cyclosporine A-resistant CAR-T cells mediate antitumour immunity in the presence of allogeneic cells

Yixi Zhang, Hongyu Fang, Guocan Wang, Guangxun Yuan, Ruoyu Dong, Jijun Luo, Yu Lyu, Yajie Wang, Peng Li, Chun Zhou, Weiwei Yin, Haowen Xiao (), Jie Sun () and Xun Zeng ()
Additional contact information
Yixi Zhang: Zhejiang University School of Medicine
Hongyu Fang: Zhejiang University School of Medicine
Guocan Wang: Zhejiang University School of Medicine
Guangxun Yuan: Zhejiang University School of Medicine
Ruoyu Dong: Zhejiang University School of Medicine
Jijun Luo: Zhejiang University School of Medicine
Yu Lyu: Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, International Campus, Zhejiang University
Yajie Wang: Zhejiang University School of Medicine
Peng Li: Puluoting Health Technology Co., Ltd
Chun Zhou: Zhejiang University School of Medicine
Weiwei Yin: Zhejiang University
Haowen Xiao: Zhejiang University School of Medicine
Jie Sun: Zhejiang University School of Medicine
Xun Zeng: Zhejiang University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Chimeric antigen receptor (CAR)-T therapy requires autologous T lymphocytes from cancer patients, a process that is both costly and complex. Universal CAR-T cell treatment from allogeneic sources can overcome this limitation but is impeded by graft-versus-host disease (GvHD) and host versus-graft rejection (HvGR). Here, we introduce a mutated calcineurin subunit A (CNA) and a CD19-specific CAR into the T cell receptor α constant (TRAC) locus to generate cells that are resistant to the widely used immunosuppressant, cyclosporine A (CsA). These immunosuppressant-resistant universal (IRU) CAR-T cells display improved effector function in vitro and anti-tumour efficacy in a leukemia xenograft mouse model in the presence of CsA, compared with CAR-T cells carrying wild-type CNA. Moreover, IRU CAR-T cells retain effector function in vitro and in vivo in the presence of both allogeneic T cells and CsA. Lastly, CsA withdrawal restores HvGR, acting as a safety switch that can eliminate IRU CAR-T cells. These findings demonstrate the efficacy of CsA-resistant CAR-T cells as a universal, ‘off-the-shelf’ treatment option.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-44176-0 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-44176-0

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-44176-0

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().