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• W4308018584 endingPage "e005577" @default.
• W4308018584 startingPage "e005577" @default.
• W4308018584 abstract "Background 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) + NKG2C + adaptive NK cells to maximize missing-self reactivity. Methods 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. Results ADAPT-NK cells were >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 dim blast subtypes. Conclusions 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." @default.
• W4308018584 created "2022-11-07" @default.
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• W4308018584 date "2022-11-01" @default.
• W4308018584 modified "2023-10-16" @default.
• W4308018584 title "Adaptive single-KIR⁺NKG2C⁺NK cells expanded from select superdonors show potent missing-self reactivity and efficiently control HLA-mismatched acute myeloid leukemia" @default.
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• W4308018584 doi "https://doi.org/10.1136/jitc-2022-005577" @default.
• W4308018584 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/36319065" @default.
• W4308018584 hasPublicationYear "2022" @default.
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