CML paper summary - April 2025

High-throughput drug screening identifies SMAC mimetics as enhancers of NK cell cytotoxicity in chronic myeloid leukemia

Nygren P. et al. Blood, January 2025

Link to full paper: https://doi.org/10.1182/blood.2024025286

Summary

This study explored how natural killer (NK) cells, a type of immune cell known for targeting cancer cells, could be more effective against chronic myeloid leukemia (CML) when supported by specific drugs. Using a high-throughput drug screening of over 500 small-molecule compounds, the researchers evaluated the impact of oncological drugs on NK cell-mediated cytotoxicity against CML cells.

Introduction

CML is a myeloproliferative disorder driven by the BCR::ABL1 fusion gene. Although tyrosine kinase inhibitors (TKIs) have revolutionized treatment, many patients fail to achieve long-term treatment-free remission, often due to the persistence of leukemic stem cells. NK cells have the potential to control residual disease and achieve remission. However, the efficacy of NK cell-based immunotherapy in CML has not been demonstrated. This study was conducted to identify drugs that enhance NK cell cytotoxicity and better understand the molecular mechanisms behind NK cell-mediated anti-leukemia activity.

Study methods

The researchers employed a high-throughput drug screening approach using a library of 527 oncological compounds. The screening involved co-culturing NK cells with K562 leukemia cells, with target cell viability assessed via a luciferase-based assay. Differential drug sensitivity scores (dDSS) were calculated to quantify the effects of each drug on NK cell-mediated killing.

Subsequent experiments validated top hits using flow cytometry and colony-forming assays on both cell lines and primary CML patient samples. The researchers also utilized single-cell RNA sequencing to profile drug-induced transcriptomic changes in NK and target CML cells, identifying shifts in activation states and gene expression pathways.

Key findings

• SMAC mimetics identified as enhancers: SMAC mimetics birinapant and NVP-LCL161 significantly increased NK cell cytotoxicity in both cell lines and patient-derived CML samples.

• Negative impact of certain drugs: Glucocorticoids (e.g., dexamethasone) and some TKIs (e.g., dasatinib) suppressed NK cell activity and IFN-γ production.

• Single-cell insights: Drug-induced changes in NK and CML cell transcriptomes revealed enhanced NF-κB signalling with SMAC mimetics and inhibition of activation markers with suppressive drugs.

• Clinical implications: The findings support the potential of SMAC mimetics in combination NK cell immunotherapy, especially for advanced-phase CML or TKI-resistant cases.

Conclusions

This research presents a promising strategy for enhancing NK cell-based immunotherapy in CML. The identification of SMAC mimetics as potent enhancers of NK cell cytotoxicity offers a foundation for clinical studies and suggests broader applications in other malignancies. Further preclinical and clinical studies are needed to assess safety, efficacy, and optimal treatment combinations.

Further commentary:

SMAC mimetics in action in chronic myeloid leukemia
Ali G. Turhan. Blood, April 2025
https://doi.org/10.1182/blood.2024027994