Safety and Efficacy of Allogeneic NKG2D NKR-NK for Acute Myeloid Leukemia

Objective: CAR-T cells have shown significant clinical efficacy in treating acute lymphoblastic leukemia, but their effectiveness in treating patients with acute myeloid leukemia (AML) is limited, necessitating the exploration of alternative treatments. Theoretically, compared to CAR-T cells, CAR-NK cells possess more favorable toxicity profiles, particularly in mitigating adverse effects such as cytokine release syndrome and graft-versus-host disease. However, issues regarding the in vivo proliferation and long-term survival of CAR-NK cells remain unresolved, typically requiring large-dose infusions. Our study tested the safety of infusing high-dose NKG2D NKR-NK cells into AML patients.

Methods: NK cells from healthy donors were transduced into NKG2D NKR-NK cells and expanded in vitro. The cytotoxicity of NKG2D NKR-NK cells against peripheral blood progenitor cells from AML patients was validated in vitro. The safety and antitumor efficacy were further confirmed in severely immunodeficient NCG mice and in xenograft AML mouse models. Additionally, NKG2D NKR-NK cells were intravenously infused into clinical trial participants to observe their in vivo antitumor activity and safety, using a dose-escalation approach to determine the maximum safe dose.

Results: NKG2D NKR-NK cells exhibited high cytotoxicity against AML-targeted cells in vitro (90% killing rate for K562 cells, 60% for HL-60 cells, and 8% for KG-1 cells). In the xenograft AML mouse model, NKG2D NKR-NK cells significantly reduced tumor burden, demonstrating strong antitumor effects. Intravenous infusion of NKG2D NKR-NK cells into AML patients did not result in any observable severe adverse effects, confirming the safety of NKG2D NKR-NK cells in the treatment of four patients at the current maximum single dose of 3.1×10⁹ cells.

Conclusion: Our data indicate that NKG2D NKR-NK cells are effective and safe in vitro and in mouse models, and are safe in four AML patients.

No relevant conflicts of interest to declare.