Memory-like NK cells armed with a neoepitope-specific CAR exhibit potent activity against NPM1 mutated acute myeloid leukemia
<jats:p> Acute myeloid leukemia (AML) remains a therapeutic challenge, and a paucity of tumor-specific targets has significantly hampered the development of effective immune-based therapies. Recent paradigm-changing studies have shown that natural killer (NK) cells exhibit innate...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Proceedings of the National Academy of Sciences
2022
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| Online Access: | https://hdl.handle.net/1721.1/146778 |
| _version_ | 1826195388534620160 |
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| author | Dong, Han Ham, James Dongjoo Hu, Guangan Xie, Guozhu Vergara, Juliana Liang, Yong Ali, Alaa Tarannum, Mubin Donner, Hannah Baginska, Joanna Abdulhamid, Yasmin Dinh, Khanhlinh Soiffer, Robert J Ritz, Jerome Glimcher, Laurie H Chen, Jianzhu Romee, Rizwan |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Dong, Han Ham, James Dongjoo Hu, Guangan Xie, Guozhu Vergara, Juliana Liang, Yong Ali, Alaa Tarannum, Mubin Donner, Hannah Baginska, Joanna Abdulhamid, Yasmin Dinh, Khanhlinh Soiffer, Robert J Ritz, Jerome Glimcher, Laurie H Chen, Jianzhu Romee, Rizwan |
| author_sort | Dong, Han |
| collection | MIT |
| description | <jats:p>
Acute myeloid leukemia (AML) remains a therapeutic challenge, and a paucity of tumor-specific targets has significantly hampered the development of effective immune-based therapies. Recent paradigm-changing studies have shown that natural killer (NK) cells exhibit innate memory upon brief activation with IL-12 and IL-18, leading to cytokine-induced memory-like (CIML) NK cell differentiation. CIML NK cells have enhanced antitumor activity and have shown promising results in early phase clinical trials in patients with relapsed/refractory AML. Here, we show that arming CIML NK cells with a neoepitope-specific chimeric antigen receptor (CAR) significantly enhances their antitumor responses to nucleophosphmin-1 (NPM1)-mutated AML while avoiding off-target toxicity. CIML NK cells differentiated from peripheral blood NK cells were efficiently transduced to express a TCR-like CAR that specifically recognizes a neoepitope derived from the cytosolic oncogenic NPM1-mutated protein presented by HLA-A2. These CAR CIML NK cells displayed enhanced activity against NPM1-mutated AML cell lines and patient-derived leukemic blast cells. CAR CIML NK cells persisted in vivo and significantly improved AML outcomes in xenograft models. Single-cell RNA sequencing and mass cytometry analyses identified up-regulation of cell proliferation, protein folding, immune responses, and major metabolic pathways in CAR-transduced CIML NK cells, resulting in tumor-specific, CAR-dependent activation and function in response to AML target cells. Thus, efficient arming of CIML NK cells with an NPM1-mutation-specific TCR-like CAR substantially improves their innate antitumor responses against an otherwise intracellular mutant protein. These preclinical findings justify evaluating this approach in clinical trials in HLA-A2
<jats:sup>+</jats:sup>
AML patients with NPM1c mutations.
</jats:p> |
| first_indexed | 2024-09-23T10:11:54Z |
| format | Article |
| id | mit-1721.1/146778 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T10:11:54Z |
| publishDate | 2022 |
| publisher | Proceedings of the National Academy of Sciences |
| record_format | dspace |
| spelling | mit-1721.1/1467782022-12-08T03:35:54Z Memory-like NK cells armed with a neoepitope-specific CAR exhibit potent activity against NPM1 mutated acute myeloid leukemia Dong, Han Ham, James Dongjoo Hu, Guangan Xie, Guozhu Vergara, Juliana Liang, Yong Ali, Alaa Tarannum, Mubin Donner, Hannah Baginska, Joanna Abdulhamid, Yasmin Dinh, Khanhlinh Soiffer, Robert J Ritz, Jerome Glimcher, Laurie H Chen, Jianzhu Romee, Rizwan Massachusetts Institute of Technology. Department of Biology <jats:p> Acute myeloid leukemia (AML) remains a therapeutic challenge, and a paucity of tumor-specific targets has significantly hampered the development of effective immune-based therapies. Recent paradigm-changing studies have shown that natural killer (NK) cells exhibit innate memory upon brief activation with IL-12 and IL-18, leading to cytokine-induced memory-like (CIML) NK cell differentiation. CIML NK cells have enhanced antitumor activity and have shown promising results in early phase clinical trials in patients with relapsed/refractory AML. Here, we show that arming CIML NK cells with a neoepitope-specific chimeric antigen receptor (CAR) significantly enhances their antitumor responses to nucleophosphmin-1 (NPM1)-mutated AML while avoiding off-target toxicity. CIML NK cells differentiated from peripheral blood NK cells were efficiently transduced to express a TCR-like CAR that specifically recognizes a neoepitope derived from the cytosolic oncogenic NPM1-mutated protein presented by HLA-A2. These CAR CIML NK cells displayed enhanced activity against NPM1-mutated AML cell lines and patient-derived leukemic blast cells. CAR CIML NK cells persisted in vivo and significantly improved AML outcomes in xenograft models. Single-cell RNA sequencing and mass cytometry analyses identified up-regulation of cell proliferation, protein folding, immune responses, and major metabolic pathways in CAR-transduced CIML NK cells, resulting in tumor-specific, CAR-dependent activation and function in response to AML target cells. Thus, efficient arming of CIML NK cells with an NPM1-mutation-specific TCR-like CAR substantially improves their innate antitumor responses against an otherwise intracellular mutant protein. These preclinical findings justify evaluating this approach in clinical trials in HLA-A2 <jats:sup>+</jats:sup> AML patients with NPM1c mutations. </jats:p> 2022-12-07T16:09:41Z 2022-12-07T16:09:41Z 2022 2022-12-07T16:02:38Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/146778 Dong, Han, Ham, James Dongjoo, Hu, Guangan, Xie, Guozhu, Vergara, Juliana et al. 2022. "Memory-like NK cells armed with a neoepitope-specific CAR exhibit potent activity against NPM1 mutated acute myeloid leukemia." Proceedings of the National Academy of Sciences of the United States of America, 119 (25). en 10.1073/PNAS.2122379119 Proceedings of the National Academy of Sciences of the United States of America Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Proceedings of the National Academy of Sciences PNAS |
| spellingShingle | Dong, Han Ham, James Dongjoo Hu, Guangan Xie, Guozhu Vergara, Juliana Liang, Yong Ali, Alaa Tarannum, Mubin Donner, Hannah Baginska, Joanna Abdulhamid, Yasmin Dinh, Khanhlinh Soiffer, Robert J Ritz, Jerome Glimcher, Laurie H Chen, Jianzhu Romee, Rizwan Memory-like NK cells armed with a neoepitope-specific CAR exhibit potent activity against NPM1 mutated acute myeloid leukemia |
| title | Memory-like NK cells armed with a neoepitope-specific CAR exhibit potent activity against NPM1 mutated acute myeloid leukemia |
| title_full | Memory-like NK cells armed with a neoepitope-specific CAR exhibit potent activity against NPM1 mutated acute myeloid leukemia |
| title_fullStr | Memory-like NK cells armed with a neoepitope-specific CAR exhibit potent activity against NPM1 mutated acute myeloid leukemia |
| title_full_unstemmed | Memory-like NK cells armed with a neoepitope-specific CAR exhibit potent activity against NPM1 mutated acute myeloid leukemia |
| title_short | Memory-like NK cells armed with a neoepitope-specific CAR exhibit potent activity against NPM1 mutated acute myeloid leukemia |
| title_sort | memory like nk cells armed with a neoepitope specific car exhibit potent activity against npm1 mutated acute myeloid leukemia |
| url | https://hdl.handle.net/1721.1/146778 |
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