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Epitope prime editing shields hematopoietic cells from CD123 immunotherapy for acute myeloid leukemia.

Authors :
Ji RJ
Cao GH
Zhao WQ
Wang MY
Gao P
Zhang YZ
Wang XB
Qiu HY
Chen DD
Tong XH
Duan M
Yin H
Zhang Y
Source :
Cell stem cell [Cell Stem Cell] 2024 Nov 07; Vol. 31 (11), pp. 1650-1666.e8. Date of Electronic Publication: 2024 Sep 30.
Publication Year :
2024

Abstract

Acute myeloid leukemia (AML) is a malignant cancer characterized by abnormal differentiation of hematopoietic stem and progenitor cells (HSPCs). While chimeric antigen receptor T (CAR-T) cell immunotherapies target AML cells, they often induce severe on-target/off-tumor toxicity by attacking normal cells expressing the same antigen. Here, we used base editors (BEs) and a prime editor (PE) to modify the epitope of CD123 on HSPCs, protecting healthy cells from CAR-T-induced cytotoxicity while maintaining their normal function. Although BE effectively edits epitopes, complex bystander products are a concern. To enhance precision, we optimized prime editing, increasing the editing efficiency from 5.9% to 78.9% in HSPCs. Epitope-modified cells were resistant to CAR-T lysis while retaining normal differentiation and function. Furthermore, BE- or PE-edited HSPCs infused into humanized mice endowed myeloid lineages with selective resistance to CAR-T immunotherapy, demonstrating a proof-of-concept strategy for treating relapsed AML.<br />Competing Interests: Declaration of interests Y.Z., G.-H.C., and R.-J.J. filed a PCT patent related to this work.<br /> (Copyright © 2024 Elsevier Inc. All rights reserved.)

Details

Language :
English
ISSN :
1875-9777
Volume :
31
Issue :
11
Database :
MEDLINE
Journal :
Cell stem cell
Publication Type :
Academic Journal
Accession number :
39353428
Full Text :
https://doi.org/10.1016/j.stem.2024.09.003