Adaptive single-KIR+NKG2C+ NK cells expanded from select superdonors show potent missing-self reactivity and efficiently control HLA-mismatched acute myeloid leukemia. Issue 11 (1st November 2022)

• Record Type: Journal Article
• Authors: Haroun-Izquierdo, Alvaro; Vincenti, Marianna; Netskar, Herman; van Ooijen, Hanna; Zhang, Bin; Bendzick, Laura; Kanaya, Minoru; Momayyezi, Pouria; Li, Shuo; Wiiger, Merete Thune; Hoel, Hanna Julie; Krokeide, Silje Zandstra; Kremer, Veronika; Tjonnfjord, Geir; Berggren, Stéphanie; Wikström, Kristina; Blomberg, Pontus; Alici, Evren; Felices, Martin; Önfelt, Björn; Höglund, Petter; Valamehr, Bahram; Ljunggren, Hans-Gustaf; Björklund, Andreas; Hammer, Quirin; Kveberg, Lise; Cichocki, Frank; Miller, Jeffrey S; Malmberg, Karl-Johan; Sohlberg, Ebba
• Is Part Of: Journal for immunotherapy of cancer. Volume 10:Issue 11(2022)
• Publication Date: 2022-11-01
• Subjects: killer cells, natural -- immunotherapy, adoptive -- immunity, innate; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2022-005577
• Languages: English
• ISSNs: 2051-1426

Abstract

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.