Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein.
Haploidentical natural killer (NK) cell infusions can induce remissions in some patients with acute myeloid leukemia (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% vs 21%; P = .02) and disease-free survival at 6 months (33% vs 5%; P < .01). In the IL2DT cohort, NK cell expansion correlated with higher postchemotherapy serum IL-15 levels (P = .002), effective peripheral blood Treg depletion (<5%) at day 7 (P < .01), and decreased IL-35 levels at day 14 (P = .02). In vitro assays demonstrated that Tregs cocultured 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.
Department of Medicine.
Veronika
V
Bachanova
Department of Medicine.
Sarah
S
Cooley
Department of Pediatrics.
Todd E
TE
Defor
Laboratory Medicine and Pathology.
Michael R
MR
Verneris
Department of Medicine.
Bin
B
Zhang
Masonic Cancer Center, and Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, MN.
David H
DH
McKenna
Masonic Cancer Center, and Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, MN.
Julie
J
Curtsinger
Laboratory Medicine and Pathology.
Angela
A
Panoskaltsis-Mortari
Department of Pediatrics.
Dixie
D
Lewis
Laboratory Medicine and Pathology.
Keli
K
Hippen
Department of Medicine.
Philip
P
McGlave
Department of Medicine.
Daniel J
DJ
Weisdorf
Laboratory Medicine and Pathology.
Bruce R
BR
Blazar
Department of Medicine.
Jeffrey S
JS
Miller
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000276:immunology / Q000627:therapeutic use; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D018920:Coculture Techniques; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D004167:Diphtheria Toxin / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology / Q000637:transplantation*; D007951:Leukemia, Myeloid / Q000473:pathology / Q000628:therapy*; D008212:Lymphocyte Depletion / Q000379:methods; D008297:Male; D008875:Middle Aged; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use; D012074:Remission Induction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives; D055815:Young Adult
D004167:Diphtheria Toxin; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; C062518:interleukin 2-diphtheria toxin; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine