Advertisement

Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein

Veronika Bachanova, Sarah Cooley, Todd E. Defor, Michael R. Verneris, Bin Zhang, David H. McKenna, Julie Curtsinger, Angela Panoskaltsis-Mortari, Dixie Lewis, Keli Hippen, Philip McGlave, Daniel J. Weisdorf, Bruce R. Blazar and Jeffrey S. Miller

Key points

  • Depletion of host regulatory T cells with IL2DT improves efficacy of haploidentical NK cell therapy for refractory acute myeloid leukemia.

  • Depletion of Treg and persistence of NK cells for at least 7 days after NK cell adoptive transfer predicts beneficial clinical responses.

Abstract

Haploidentical natural killer (NK) cell infusions can induce remissions in some patients with AML but regulatory T-cell (Treg) suppression may reduce efficacy. We treated 57 refractory AML patients with lymphodepleting cyclophosphamide and fludarabine followed by NK cell infusion and interleukin (IL)-2 administration. In 42 patients, donor NK cell expansion was detected in 10%, whereas in 15 patients receiving host Treg depletion with the IL-2-diphtheria fusion protein (IL2DT) the rate was 27%, with a median absolute count of 1000 NK cells/µL blood. IL2DT was associated with improved complete remission rates at day 28 (53% versus 21%; P=0.02) and disease-free survival at 6 months (33% versus 5%; P<0.01). In the IL2DT cohort, NK cell expansion correlated with higher post-chemotherapy serum IL-15 levels (P=0.002), effective peripheral blood Treg depletion (< 5%) at day 7 (P<0.01) and decreased IL-35 levels at day 14 (P=0.02). In vitro assays demonstrated that Tregs co-cultured with NK cells inhibit their proliferation by competition for IL-2, but not for IL-15. Together with our clinical observations this supports the need to optimize the in vivo cytokine milieu where adoptively transferred NK cells compete with other lymphocytes to improve clinical efficacy in patients with refractory AML. This study is registered at clinicaltrials.gov, identifiers: NCT00274846 and NCT01106950.

  • Submitted October 15, 2013.
  • Accepted March 27, 2014.