CAR-T cells targeting a nucleophosmin neoepitope exhibit potent specific activity in mouse models of acute myeloid leukaemia
© 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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Science and Business Media LLC
2021
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| Online Access: | https://hdl.handle.net/1721.1/133479 |
| _version_ | 1826194632543830016 |
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| author | Xie, Guozhu Ivica, Nikola A Jia, Bin Li, Yingzhong Dong, Han Liang, Yong Brown, Douglas Romee, Rizwan Chen, Jianzhu |
| author_facet | Xie, Guozhu Ivica, Nikola A Jia, Bin Li, Yingzhong Dong, Han Liang, Yong Brown, Douglas Romee, Rizwan Chen, Jianzhu |
| author_sort | Xie, Guozhu |
| collection | MIT |
| description | © 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. |
| first_indexed | 2024-09-23T09:59:21Z |
| format | Article |
| id | mit-1721.1/133479 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T09:59:21Z |
| publishDate | 2021 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1334792021-10-28T04:37:09Z CAR-T cells targeting a nucleophosmin neoepitope exhibit potent specific activity in mouse models of acute myeloid leukaemia Xie, Guozhu Ivica, Nikola A Jia, Bin Li, Yingzhong Dong, Han Liang, Yong Brown, Douglas Romee, Rizwan Chen, Jianzhu © 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. 2021-10-27T19:53:03Z 2021-10-27T19:53:03Z 2021 2021-07-14T18:26:19Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/133479 en 10.1038/S41551-020-00625-5 Nature Biomedical Engineering Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Springer Science and Business Media LLC PMC |
| spellingShingle | Xie, Guozhu Ivica, Nikola A Jia, Bin Li, Yingzhong Dong, Han Liang, Yong Brown, Douglas Romee, Rizwan Chen, Jianzhu CAR-T cells targeting a nucleophosmin neoepitope exhibit potent specific activity in mouse models of acute myeloid leukaemia |
| title | CAR-T cells targeting a nucleophosmin neoepitope exhibit potent specific activity in mouse models of acute myeloid leukaemia |
| title_full | CAR-T cells targeting a nucleophosmin neoepitope exhibit potent specific activity in mouse models of acute myeloid leukaemia |
| title_fullStr | CAR-T cells targeting a nucleophosmin neoepitope exhibit potent specific activity in mouse models of acute myeloid leukaemia |
| title_full_unstemmed | CAR-T cells targeting a nucleophosmin neoepitope exhibit potent specific activity in mouse models of acute myeloid leukaemia |
| title_short | CAR-T cells targeting a nucleophosmin neoepitope exhibit potent specific activity in mouse models of acute myeloid leukaemia |
| title_sort | car t cells targeting a nucleophosmin neoepitope exhibit potent specific activity in mouse models of acute myeloid leukaemia |
| url | https://hdl.handle.net/1721.1/133479 |
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