title: Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer.
abstract: 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.
authors.affiliation: Division Medical and Pediatric Hematology-Oncology, University of Minnesota Cancer Center, Minneapolis, MN 55455, USA. mille011@umn.edu
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Miller
authors.forename: Yvette
authors.initials: Y
authors.lastname: Soignier
authors.forename: Angela
authors.initials: A
authors.lastname: Panoskaltsis-Mortari
authors.forename: Sarah A
authors.initials: SA
authors.lastname: McNearney
authors.forename: Gong H
authors.initials: GH
authors.lastname: Yun
authors.forename: Susan K
authors.initials: SK
authors.lastname: Fautsch
authors.forename: David
authors.initials: D
authors.lastname: McKenna
authors.forename: Chap
authors.initials: C
authors.lastname: Le
authors.forename: Todd E
authors.initials: TE
authors.lastname: Defor
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Burns
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Orchard
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: John E
authors.initials: JE
authors.lastname: Wagner
authors.forename: Arne
authors.initials: A
authors.lastname: Slungaard
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weisdorf
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Okazaki
authors.forename: Philip B
authors.initials: PB
authors.lastname: McGlave
mesh_terms: 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