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Transient regulatory T-cell (Treg) depletion with IL-2 diphtheria toxin fusion protein enhances clearance of acute myeloid leukemia by haploidentical natural killer (NK) cells

Adoptive transfer of haploidentical natural killer (NK) cells can induce remissions in patients with AML. Despite lymphodepleting chemotherapy failure may result from suppression by host regulatory T cells (Treg). We report outcomes of 57 refractory AML patients treated with cyclophosphamide and fludarabine followed by haploidentical NK cells and exogenous IL-2 to facilitate NK proliferation. We augmented Treg lymphodepletion with IL-2-Diphteria toxin fusion protein (IL2DT) in 15 subjects. NK cell-enriched product characteristics are described for three production methods. Day 14 blood donor NK expansion rates were 10% (no IL2DT) versus 30% (with IL2DT) and day 28 leukemia clearance were 25% versus 53% (with IL2DT; p=0.06), suggesting clinical efficacy of IL2DT strategy. Host Treg depletion at day 7 after IL2DT (mean 1% [range 0-4.7%]) correlated with donor NK cell expansion (p=0.01). The only factor correlating with AML clearance was donor chimerism detectable a week after NK cell infusion (mean 49.5%). In vitro, Tregs co-incubated with NK cells exhausted added IL-2 (0.25ng/ml) and suppressed NK cells proliferation. Higher amounts of IL-2 (10ng/ml l) or IL15 (0.5ng/ml ) lead to unaltered NK cell proliferation in vitro even at high NK:Tregs ratios. Future clinical improvements in adoptive cell therapy might include alternate methods of Treg depletion and the use of IL-15 to augment NK cell expansion.

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Correspondence to Veronika Bachanova.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • Natural Killer
  • Natural Killer Cell
  • Acute Myeloid Leukemia
  • Fludarabine
  • Adoptive Cell Therapy