Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer.
We previously demonstrated that autologous natural killer (NK)-cell therapy after hematopoietic cell transplantation (HCT) is safe but does not provide an antitumor effect. We hypothesize that this is due to a lack of NK-cell inhibitory receptor mismatching with autologous tumor cells, which may be overcome by allogeneic NK-cell infusions. Here, we test haploidentical, related-donor NK-cell infusions in a nontransplantation setting to determine safety and in vivo NK-cell expansion. Two lower intensity outpatient immune suppressive regimens were tested: (1) low-dose cyclophosphamide and methylprednisolone and (2) fludarabine. A higher intensity inpatient regimen of high-dose cyclophosphamide and fludarabine (Hi-Cy/Flu) was tested in patients with poor-prognosis acute myeloid leukemia (AML). All patients received subcutaneous interleukin 2 (IL-2) after infusions. Patients who received lower intensity regimens showed transient persistence but no in vivo expansion of donor cells. In contrast, infusions after the more intense Hi-Cy/Flu resulted in a marked rise in endogenous IL-15, expansion of donor NK cells, and induction of complete hematologic remission in 5 of 19 poor-prognosis patients with AML. These findings suggest that haploidentical NK cells can persist and expand in vivo and may have a role in the treatment of selected malignancies used alone or as an adjunct to HCT.
Miller
Jeffrey S
JS
Division Medical and Pediatric Hematology-Oncology, University of Minnesota Cancer Center, Minneapolis, MN 55455, USA. mille011@umn.edu
Soignier
Yvette
Y
Panoskaltsis-Mortari
Angela
A
McNearney
Sarah A
SA
Yun
Gong H
GH
Fautsch
Susan K
SK
McKenna
David
D
Le
Chap
C
Defor
Todd E
TE
Burns
Linda J
LJ
Orchard
Paul J
PJ
Blazar
Bruce R
BR
Wagner
John E
JE
Slungaard
Arne
A
Weisdorf
Daniel J
DJ
Okazaki
Ian J
IJ
McGlave
Philip B
PB
D000208:Acute Disease; D019264:Adoptive Transfer; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000628:therapy; D002455:Cell Division / Q000276:immunology; D006238:Haploidy; D006689:Hodgkin Disease / Q000276:immunology / Q000628:therapy; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007680:Kidney Neoplasms / Q000276:immunology / Q000628:therapy; D007694:Killer Cells, Natural / Q000166:cytology / Q000637:transplantation*; D007951:Leukemia, Myeloid / Q000276:immunology / Q000628:therapy*; D008545:Melanoma / Q000276:immunology / Q000628:therapy; D012878:Skin Neoplasms / Q000276:immunology / Q000628:therapy; D016896:Treatment Outcome