{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T01:15:45Z","timestamp":1790817345923,"version":"4.1.0"},"reference-count":39,"publisher":"National Academy of Sciences","issue":"25","license":[{"start":{"date-parts":[[2022,6,13]],"date-time":"2022-06-13T00:00:00Z","timestamp":1655078400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,6,21]]},"abstract":"<jats:p>\n                    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\u00a0vivo 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\n                    <jats:sup>+<\/jats:sup>\n                    AML patients with NPM1c mutations.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2122379119","type":"journal-article","created":{"date-parts":[[2022,6,13]],"date-time":"2022-06-13T15:14:11Z","timestamp":1655133251000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":126,"title":["Memory-like NK cells armed with a neoepitope-specific CAR exhibit potent activity against NPM1 mutated acute myeloid leukemia"],"prefix":"10.1073","volume":"119","author":[{"given":"Han","family":"Dong","sequence":"first","affiliation":[{"name":"Department of Cancer Immunology and Virology, Dana\u2013Farber Cancer Institute, Boston, MA 02215"},{"name":"Department of Microbiology and Immunology, Harvard Medical School, Boston, MA 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Cambridge, MA 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana","family":"Vergara","sequence":"additional","affiliation":[{"name":"Division of Cellular Therapy and Stem Cell Transplant, Dana\u2013Farber Cancer Institute, Harvard Medical School, Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Liang","sequence":"additional","affiliation":[{"name":"Division of Cellular Therapy and Stem Cell Transplant, Dana\u2013Farber Cancer Institute, Harvard Medical School, Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alaa","family":"Ali","sequence":"additional","affiliation":[{"name":"Division of Cellular Therapy and Stem Cell Transplant, Dana\u2013Farber Cancer Institute, Harvard Medical School, Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mubin","family":"Tarannum","sequence":"additional","affiliation":[{"name":"Division of Cellular Therapy and Stem Cell Transplant, Dana\u2013Farber Cancer Institute, Harvard Medical School, Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Donner","sequence":"additional","affiliation":[{"name":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139"},{"name":"Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Baginska","sequence":"additional","affiliation":[{"name":"Center for Immuno-oncology, Dana\u2013Farber Cancer Institute, Harvard Medical School, Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmin","family":"Abdulhamid","sequence":"additional","affiliation":[{"name":"Division of Cellular Therapy and Stem Cell Transplant, Dana\u2013Farber Cancer Institute, Harvard Medical School, Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khanhlinh","family":"Dinh","sequence":"additional","affiliation":[{"name":"Division of Cellular Therapy and Stem Cell Transplant, Dana\u2013Farber Cancer Institute, Harvard Medical School, Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Soiffer","sequence":"additional","affiliation":[{"name":"Division of Cellular Therapy and Stem Cell Transplant, Dana\u2013Farber Cancer Institute, Harvard Medical School, Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5526-4669","authenticated-orcid":false,"given":"Jerome","family":"Ritz","sequence":"additional","affiliation":[{"name":"Division of Cellular Therapy and Stem Cell Transplant, Dana\u2013Farber Cancer Institute, Harvard Medical School, Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4971-0404","authenticated-orcid":false,"given":"Laurie H.","family":"Glimcher","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology and Virology, Dana\u2013Farber Cancer Institute, Boston, MA 02215"},{"name":"Department of Microbiology and Immunology, Harvard Medical School, Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5687-6154","authenticated-orcid":false,"given":"Jianzhu","family":"Chen","sequence":"additional","affiliation":[{"name":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139"},{"name":"Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rizwan","family":"Romee","sequence":"additional","affiliation":[{"name":"Division of Cellular 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Falini, E. Tiacci, M. P. Martelli, S. Ascani, S. A. Pileri, New classification of acute myeloid leukemia and precursor-related neoplasms: Changes and unsolved issues. Discov. Med. 10, 281\u2013292 (2010).","journal-title":"Discov. Med."},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1200503"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-05-283051"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-0728-z"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2020.100870"},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"a029538","DOI":"10.1101\/cshperspect.a029538","article-title":"Is there natural killer cell memory and can it be harnessed by vaccination? NK cell memory and immunization strategies against infectious diseases and cancer","volume":"10","author":"Sun J. C.","year":"2017","unstructured":"J. C. Sun, L. L. Lanier, Is there natural killer cell memory and can it be harnessed by vaccination? NK cell memory and immunization strategies against infectious diseases and cancer. Cold Spring Harb. Perspect. Biol. 10, a029538 (2017).","journal-title":"Cold Spring Harb. Perspect. 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