Enhancing AML Treatment with Dual-Targeted CAR NK Cells: A Strategic Approach to Overcoming Heterogeneity

The abstract discusses the ongoing challenge of relapse in acute myeloid leukemia (AML) treatment, despite advancements. It highlights the potential of natural killer (NK) cells in immunotherapy to treat AML without the associated risks of graft-versus-host disease or cytokine release syndrome. The study reports that haploidentical NK cells, combined with high-dose chemotherapy and cytokine support, can lead to significant remissions in AML patients.

The text emphasizes the role of stress ligands like MICA/B, which interact with the NK cell receptor NKG2D, triggering NK cell activity against abnormal cells. It mentions clinical trials that have shown promise by developing NK cells with a NKG2D chimeric antigen receptor (CAR). However, it also notes the issue of tumor cells evading NK cell detection by shedding the distal domains of MICA/B.

Researchers have identified the membrane-proximal α3 domain of MICA/B as a potential target for cancer immunotherapy. Given the heterogeneity of AML, the study suggests that dual-targeting strategies could improve clinical outcomes. The researchers have developed a Tri-specific Killer Engager (TriKE) that targets CD33, a marker present on over 80% of AML cells, alongside IL-15 to enhance NK cell response.

The study introduces a multiplexed-gene edited NK cell product derived from induced pluripotent stem cells (iPSCs). These cells express a high-affinity version of CD16, a membrane-bound IL-15 fusion receptor, and a CAR targeting the α3 domain of MICA/B. The product also includes CD38 knockout to improve metabolic fitness.

Experiments showed that the iNK cells were effective against the AML cell line HL60, with enhanced activity when combined with the anti-CD33 TriKE. The α3 domain of MICA/B was confirmed as a target on AML cells, even after protease treatment. Dual-targeting with the α3 MICA/B CAR and anti-CD33 TriKE resulted in rapid and sustained killing of AML cells under both standard and stress conditions.

The abstract concludes that the combination of CAR NK cells targeting the α3 domain of MICA/B and antigen-specific TriKE targeting CD33 is a promising clinical approach to enhance the effectiveness and longevity of AML treatment. Ongoing studies are exploring the effects of drugs known to increase NKG2D ligands in AML.