{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T07:31:18Z","timestamp":1792481478199,"version":"4.5.0"},"reference-count":50,"publisher":"BMJ","issue":"11","license":[{"start":{"date-parts":[[2022,11,1]],"date-time":"2022-11-01T00:00:00Z","timestamp":1667260800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2022,9,24]]},"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Natural killer (NK) cells hold great promise as a source for allogeneic cell therapy against hematological malignancies, including acute myeloid leukemia (AML). Current treatments are hampered by variability in NK cell subset responses, a limitation which could be circumvented by specific expansion of highly potent single killer immunoglobulin-like receptor (KIR)<jats:sup>+<\/jats:sup>NKG2C<jats:sup>+<\/jats:sup> adaptive NK cells to maximize missing-self reactivity.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We developed a GMP-compliant protocol to expand adaptive NK cells from cryopreserved cells derived from select third-party superdonors, that is, donors harboring large adaptive NK cell subsets with desired KIR specificities at baseline. We studied the adaptive state of the cell product (ADAPT-NK) by flow cytometry and mass cytometry as well as cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq). We investigated the functional responses of ADAPT-NK cells against a wide range of tumor target cell lines and primary AML samples using flow cytometry and IncuCyte as well as in a mouse model of AML.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>ADAPT-NK cells were &gt;90% pure with a homogeneous expression of a single self-HLA specific KIR and expanded a median of 470-fold. The ADAPT-NK cells largely retained their adaptive transcriptional signature with activation of effector programs without signs of exhaustion. ADAPT-NK cells showed high degranulation capacity and efficient killing of HLA-C\/KIR mismatched tumor cell lines as well as primary leukemic blasts from AML patients. Finally, the expanded adaptive NK cells had preserved robust antibody-dependent cellular cytotoxicity potential and combination of ADAPT-NK cells with an anti-CD16\/IL-15\/anti-CD33 tri-specific engager led to near-complete killing of resistant CD45<jats:sup>dim<\/jats:sup> blast subtypes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>These preclinical data demonstrate the feasibility of off-the-shelf therapy with a non-engineered, yet highly specific, NK cell population with full missing-self recognition capability.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2022-005577","type":"journal-article","created":{"date-parts":[[2022,11,1]],"date-time":"2022-11-01T11:01:37Z","timestamp":1667300497000},"page":"e005577","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":59,"title":["Adaptive single-KIR<sup>+<\/sup>NKG2C<sup>+<\/sup> NK cells expanded from select superdonors show potent missing-self reactivity and efficiently control HLA-mismatched acute myeloid leukemia"],"prefix":"10.1136","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4557-3606","authenticated-orcid":false,"given":"Alvaro","family":"Haroun-Izquierdo","sequence":"first","affiliation":[{"name":"Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5361-0185","authenticated-orcid":false,"given":"Marianna","family":"Vincenti","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital and University of Oslo, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3081-9581","authenticated-orcid":false,"given":"Herman","family":"Netskar","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital and University of Oslo, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"van Ooijen","sequence":"additional","affiliation":[{"name":"Department of Applied Physics, Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Zhang","sequence":"additional","affiliation":[{"name":"University of Minnesota, Masonic Cancer Center, Minneapolis, Minnesota, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Bendzick","sequence":"additional","affiliation":[{"name":"University of Minnesota, Masonic Cancer Center, Minneapolis, Minnesota, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0035-8657","authenticated-orcid":false,"given":"Minoru","family":"Kanaya","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital and University of Oslo, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pouria","family":"Momayyezi","sequence":"additional","affiliation":[{"name":"Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuo","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital and University of Oslo, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merete Thune","family":"Wiiger","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital and University of Oslo, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna Julie","family":"Hoel","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital and University of Oslo, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silje Zandstra","family":"Krokeide","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital and University of Oslo, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronika","family":"Kremer","sequence":"additional","affiliation":[{"name":"Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geir","family":"Tjonnfjord","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oslo University Hospital and K.G. 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