ArticleJournal for immunotherapy of cancer2025
Single-chain variable fragment affinity tuning can optimize anti-AML CAR-NK cell functionality.
Article in Journal for immunotherapy of cancer, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Induced Pluripotent Stem Cell-Derived NK Cells as an Off-the-Shelf Platform for Cancer Immunotherapy: Opportunities, Challenges, and Clinical Translation.Stem cell reviews and reports · 2026Review
- Rapid CAR screening and circRNA-driven CAR-NK cells for persistent shed-resistant immunotherapy.Signal transduction and targeted therapy · 2026Article
- CAR-NK cell therapy for hematologic malignancies: advances, challenges and optimization strategies.Molecular cancer · 2026Review
- A framework integrating multiscale in silico modeling and experimental data predicts CAR-NK cell cytotoxicity across target cell types.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- A new era in CAR-NK cell therapy: from technological innovations to clinical applications.World journal of pediatrics : WJP · 2026Review
- Review
- CD123-targeting immunotherapeutic approaches in acute myeloid leukaemia.British journal of haematology · 2025Review
- CAR-NK's balancing act: when scFv affinity is not too tight, not too loose… but just right?Journal for immunotherapy of cancer · 2025Article
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Authors and funding
16 authors.
Funding
Abstract
backgroundNatural Killer (NK) cells have intrinsic anticancer activity that can be redirected toward acute myeloid leukemia (AML) with chimeric antigen receptor (CAR) engineering. Here, we study the functional consequences of CAR binding affinity and targeted epitope on CAR-NK cell activation, cytolytic synapse formation, and antitumor activity.
methodsWe characterized NK-92 and primary NK cell populations expressing variant affinity AML-specific CARs containing single-chain variable fragments (scFvs, 26292 or 7G3) targeting two epitopes on CD123. 26292 affinity variants were discovered through directed evolution of an error-prone mutagenic library, while 7G3 affinity variants were previously reported. The resulting CAR-NK cell panel was studied with in vitro binding, activation, and cytotoxicity studies and in mouse xenograft models.
results26292 and 7G3 CARs of variable CD123 binding affinities were highly expressed in NK cells and conferred antigen-specific activation in vitro. High-resolution imaging demonstrated greater clustering of high-affinity 7G3 CAR-NK cells and consequent AML target cell death in a short-term time lapse. Low-affinity 7G3 CAR-NK cells exhibited enhanced antigen density discrimination with greater membrane-proximal signaling, cytokine production, and cytotoxicity. In longer-term assays, low-affinity 7G3 CAR-NK cells demonstrated more sustained killing of AML cells. In vivo testing highlighted greater expansion of low-affinity 7G3 CAR-NK cells in two xenograft models.
conclusionsExpression of 26292 and 7G3 CARs with a range of CD123 binding affinities in NK cells leads to antigen-specific activation and cytotoxicity against AML. Affinity-based differences in functional activation and antitumor activity are dependent on time course and are scFv/epitope specific.
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