Feasibility and Safety of IL-15-Activated CD56+ Cell Therapy in High-Risk Acute Myeloid Leukemia after Hematopoietic Stem Cell Transplantation: Phase I Clinical Trial.

Abstract

Objective: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the most effective treatment for patients with high-risk acute myeloid leukemia (AML), but relapse remains a major challenge. Immunotherapy is considered a promising approach for reducing the risk of relapse. Natural killer (NK) cells exert cytotoxic effects against malignant cells, and their activation with interleukin-15 (IL-15) enhances anti-leukemic immune responses. This study evaluated the safety and feasibility of in vitro IL-15 activation of CD56⁺ cells and assessed the safety of their infusion in AML patients following allo-HSCT.

Materials and methods: In this phase I clinical trial study, CD56⁺ cells were isolated from non-mobilized donors using a one-step CD56 enrichment protocol to obtain NK and NKT cells. CD56⁺ cells were activated by overnight incubation with IL-15. A cytotoxicity assay was performed against K562 cells. Three escalating doses of CD56⁺ cells consisting of 1×10⁶, 3×10⁶, and 5×10⁶ cells/kg of patient bodyweight were infused to the three patients on days +7, +14, and +21 post-allo-HSCT. Patients were observed during and up to 4 hours after the infusion for immediate adverse events and were monitored for 21 days to detect delayed events.

Results: Activation with IL-15 increased the expression of activating receptors, including CD25, CD69, NKp30, NKp46, and NKG2D decreased the expression of the inhibitory receptor NKG2A. The cytotoxicity of IL-15-activated CD56⁺ cells was higher than that of non-activated CD56⁺ cells. This method was safe and no intervention-related complications were observed.

Conclusion: We identified a feasible method to activate CD56⁺ cells and evaluate the safety of their infusion in patients. Despite the value of activating CD56⁺ cells with IL-15, further studies with larger sample sizes are needed to confirm and validate the current hypothesi (registration number: IRCT20230801058996N2).