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Epitope prime editing shields hematopoietic cells from CD123 immunotherapy for acute myeloid leukemia.
- 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.)
- Subjects :
- Humans
Animals
Mice
Gene Editing
Immunotherapy, Adoptive methods
Receptors, Chimeric Antigen immunology
Receptors, Chimeric Antigen metabolism
Mice, Inbred NOD
Leukemia, Myeloid, Acute therapy
Leukemia, Myeloid, Acute immunology
Leukemia, Myeloid, Acute pathology
Interleukin-3 Receptor alpha Subunit metabolism
Hematopoietic Stem Cells immunology
Hematopoietic Stem Cells metabolism
Epitopes immunology
Immunotherapy methods
Subjects
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