CML paper summary #4 - 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

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