Adaptive single-KIR

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)

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

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.

Informations de copyright

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.

Déclaration de conflit d'intérêts

Competing interests: K-JM is a consultant with ownership interests at Fate Therapeutics and Vycellix and has research funding from Fate Therapeutics. He has a Royalty agreement with FATE Therapeutics through licensing of IP. K-JM has received honoraria from Oncopeptides, Cytovia and has research funding from Oncopeptides and Merck. ES is a paid consultant at Fate Therapeutics. H-GL is a founder and serves on the board of XNK Therapeutics and Vycellix. He has a Royalty agreement with FATE Therapeutics through licensing of IP. EA is a founder of XNK therapeutics, Vycellix, VyGenBio and Fuse therapeutics. EA also serves as an advisor to Artiva, Avectas, Virocell, and Sorrento therapeutics. All relationships have been reviewed and managed by Oslo University Hospital and Karolinska Institute in accordance with its conflict-of-interest policies. BV is an employee of Fate Therapeutics. BÖ is a consultant and has ownership interests at Vycellix and has research funding from Affimed. FC and JSM are paid consultants to, and receive research funds from, Fate Therapeutics. JSM serves on the Scientific Advisory Board of OnkImmune, Nektar, Magenta and is a paid consultant consult for GT BioPharma and Vycellix.