title: Intraperitoneal delivery of human natural killer cells for treatment of ovarian cancer in a mouse xenograft model.
abstract: OBJECTIVE
  There is an urgent need for novel therapeutic strategies for relapsed ovarian cancer. Dramatic clinical anti-tumor effects have been observed with interleukin (IL)-2 activated natural killer (NK) cells; however, intravenous delivery of NK cells in patients with ovarian cancer has not been successful in ameliorating disease. We investigated in vivo engraftment of intraperitoneally (IP) delivered NK cells in an ovarian cancer xenograft model to determine if delivery mode can affect tumor cell killing and circumvent lack of NK cell expansion.
  
  
  METHODS
  An ovarian cancer xenograft mouse model was established to evaluate efficacy of IP-delivered NK cells. Tumor burden was monitored by bioluminescent imaging of luciferase-expressing ovarian cancer cells. NK cell persistence, tumor burden and NK cell trafficking were evaluated. Transplanted NK cells were evaluated by flow cytometry and cytotoxicity assays.
  
  
  RESULTS
  IP delivery of human NK cells plus cytokines led to high levels of circulating NK and was effective in clearing intraperitoneal ovarian cancer burden in xenografted mice. NK cells remained within the peritoneal cavity 54 days after injection and had markers of maturation. Additionally, surviving NK cells were able to kill ovarian cancer cells at a rate similar to pre-infusion levels, supporting that in vivo functionality of human NK cells can be maintained after IP infusion.
  
  
  CONCLUSIONS
  IP delivery of NK cells leads to stable engraftment and antitumor response in an ovarian cancer xenograft model. These data support further pre-clinical and clinical evaluation of IP delivery of allogeneic NK cells in ovarian cancer.
authors.affiliation: Department of Obstetrics, Gynecology, and Women's Health Division of Gynecologic Oncology, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Geller
authors.forename: David A
authors.initials: DA
authors.lastname: Knorr
authors.forename: David A
authors.initials: DA
authors.lastname: Hermanson
authors.forename: Lee
authors.initials: L
authors.lastname: Pribyl
authors.forename: Laura
authors.initials: L
authors.lastname: Bendzick
authors.forename: Valarie
authors.initials: V
authors.lastname: McCullar
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Miller
authors.forename: Dan S
authors.initials: DS
authors.lastname: Kaufman
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000628:therapy*; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D019496:Cancer Vaccines; D049109:Cell Proliferation; D002470:Cell Survival; D003602:Cytotoxicity, Immunologic; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007274:Injections, Intraperitoneal; D007376:Interleukin-2 / Q000276:immunology; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology / Q000637:transplantation*; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D010051:Ovarian Neoplasms / Q000276:immunology / Q000628:therapy*; D010529:Peritoneal Cavity / Q000473:pathology*; D012008:Recurrence; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D000943:Antigens, Differentiation; D019496:Cancer Vaccines; D007376:Interleukin-2
keywords: bioluminescent imaging; immunotherapy; natural killer (NK) cells; ovarian cancer