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CAR-T cells targeting a nucleophosmin neoepitope exhibit potent specific activity in mouse models of acute myeloid leukaemia
Name
nihms-1656593.pdf
Description
Accepted version
Size
2.45 MB
Format
Adobe PDF
Checksum (MD5)
596bfaf471db7e26e46207ca697a1efe
Author(s)
Xie, Guozhu
Ivica, Nikola A
Jia, Bin
Li, Yingzhong
Dong, Han
Liang, Yong
Brown, Douglas
Romee, Rizwan
Chen, Jianzhu
Date Issued
2021
Journal
Nature Biomedical Engineering
Publisher
Springer Science and Business Media LLC
Version
Author's final manuscript
Abstract
© 2020, The Author(s), under exclusive licence to Springer Nature Limited. Therapies employing chimeric antigen receptor T cells (CAR-T cells) targeting tumour-associated antigens (TAAs) can lead to on-target–off-tumour toxicity and to resistance, owing to TAA expression in normal tissues and to TAA expression loss in tumour cells. These drawbacks can be circumvented by CAR-T cells targeting tumour-specific driver gene mutations, such as the four-nucleotide duplication in the oncogene nucleophosmin (NPM1c), which creates a neoepitope presented by the human leukocyte antigen with the A2 serotype (HLA-A2) that has been observed in about 35% of patients with acute myeloid leukaemia (AML). Here, we report a human single-chain variable fragment (scFv), identified via yeast surface display, that specifically binds to the NPM1c epitope–HLA-A2 complex but not to HLA-A2 or to HLA-A2 loaded with control peptides. In vitro and in mice, CAR-T cells with the scFv exhibit potent cytotoxicity against NPM1c+HLA-A2+ leukaemia cells and primary AML blasts, but not NPM1c–HLA-A2+ leukaemia cells or HLA-A2– tumour cells. Therapies using NPM1c CAR-T cells for the treatment of NPM1c+HLA-A2+ AML may limit on-target–off-tumour toxicity and tumour resistance.
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DOI of Published Version
10.1038/S41551-020-00625-5
