title: A phase II study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer.
abstract: BACKGROUND
  Natural killer (NK) cells derived from patients with cancer exhibit diminished cytotoxicity compared with NK cells from healthy individuals. We evaluated the tumor response and in vivo expansion of allogeneic NK cells in recurrent ovarian and breast cancer.
  
  
  METHODS
  Patients underwent a lymphodepleting preparative regimen: fludarabine 25 mg/m(2) × 5 doses, cyclophosphamide 60 mg/kg × 2 doses, and, in seven patients, 200 cGy total body irradiation (TBI) to increase host immune suppression. An NK cell product, from a haplo-identical related donor, was incubated overnight in 1000 U/mL interleukin (IL)-2 prior to infusion. Subcutaneous IL-2 (10 MU) was given three times/week × 6 doses after NK cell infusion to promote expansion, defined as detection of ≥100 donor-derived NK cells/μL blood 14 days after infusion, based on molecular chimerism and flow cytometry.
  
  
  RESULTS
  Twenty (14 ovarian, 6 breast) patients were enrolled. The median age was 52 (range 30-65) years. Mean NK cell dose was 2.16 × 10(7)cells/kg. Donor DNA was detected 7 days after NK cell infusion in 9/13 (69%) patients without TBI and 6/7 (85%) with TBI. T-regulatory cells (Treg) were elevated at day +14 compared with pre-chemotherapy (P = 0.03). Serum IL-15 levels increased after the preparative regimen (P = <0.001). Patients receiving TBI had delayed hematologic recovery (P = 0.014). One patient who was not evaluable had successful in vivo NK cell expansion.
  
  
  CONCLUSIONS
  Adoptive transfer of haplo-identical NK cells after lymphodepleting chemotherapy is associated with transient donor chimerism and may be limited by reconstituting recipient Treg cells. Strategies to augment in vivo NK cell persistence and expansion are needed.
authors.affiliation: Obstetrics and Gynecology, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Geller
authors.forename: Sarah
authors.initials: S
authors.lastname: Cooley
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Judson
authors.forename: Rahel
authors.initials: R
authors.lastname: Ghebre
authors.forename: Linda F
authors.initials: LF
authors.lastname: Carson
authors.forename: Peter A
authors.initials: PA
authors.lastname: Argenta
authors.forename: Amy L
authors.initials: AL
authors.lastname: Jonson
authors.forename: Angela
authors.initials: A
authors.lastname: Panoskaltsis-Mortari
authors.forename: Julie
authors.initials: J
authors.lastname: Curtsinger
authors.forename: David
authors.initials: D
authors.lastname: McKenna
authors.forename: Kathryn
authors.initials: K
authors.lastname: Dusenbery
authors.forename: Robin
authors.initials: R
authors.lastname: Bliss
authors.forename: Levi S
authors.initials: LS
authors.lastname: Downs
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Miller
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy / Q000276:immunology* / Q000628:therapy*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007262:Infusions, Intravenous; D019409:Interleukin-15 / Q000097:blood; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation*; D008212:Lymphocyte Depletion; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000276:immunology / Q000628:therapy*; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy / Q000276:immunology* / Q000628:therapy*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation / Q000009:adverse effects
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D019409:Interleukin-15