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Intraperitoneal delivery of human natural killer cells for treatment of ovarian cancer in a mouse xenograft model
Authors:Melissa A Geller  David A Knorr  David A Hermanson  Lee Pribyl  Laura Bendzick  Valarie Mccullar  Jeffrey S Miller  Dan S Kaufman
Institution:1. Department of Obstetrics, Gynecology, and Women''s Health (Division of Gynecologic Oncology), University of Minnesota, Minneapolis, Minnesota, USA;2. Department of Medicine (Hematology, Oncology, and Transplant), University of Minnesota, Minneapolis, Minnesota, USA;3. Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota, USA;1. Abramson Cancer Center and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;2. Translational Research Laboratory, Institut d''Investigació Biomèdica de Bellvitge–Institut Català d''Oncologia, Barcelona, Spain;3. Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY;4. Stanford Research Institute International, Biosciences Division, Menlo Park, CA;5. Computer Science Department, Courant Institute of Mathematical Sciences, New York University, New York, NY;1. Centre d’Immunologie de Marseille-Luminy, Aix Marseille Université, Inserm, CNRS, Marseille, France;2. Service d’Immunologie, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille, Marseille, France;1. Department of Hematology, The Myeloma and Lymphoma Center, Changzheng Hospital, The Second Military Medical University, 415 Fengyang Rd, Shanghai 200003, China;2. Institute of Biotechnology and Clinical Immunology, Research Laboratory of Jiangsu Province, Soochow University, Suzhou 215007, China;3. Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong Special Administrative Region;4. Department of Lymphoma/Myeloma, Division of Cancer Medicine, and Center for Cancer Immunology Research, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA;1. Lorraine University, CNRS UMR 7365, Team 6, Campus Santé, Vandoeuvre-les-Nancy, France;2. CHRU Nancy, Cell Therapy and Tissue Bank Unit, Vandoeuvre-Les-Nancy, France;3. Lorraine University, CNRS UMR7039, Team BioSIS, Campus Santé, Vandoeuvre-Les-Nancy, France;1. Blood and Marrow Transplant Program, Department of Medicine, Minneapolis, Minnesota;2. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas;3. Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota;4. Molecular & Cellular Therapeutics, University of Minnesota, Saint Paul, Minnesota;1. Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;2. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children’s Hospital, Houston, TX 77030, USA
Abstract:Background aimsThere 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.MethodsAn 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.ResultsIP 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.ConclusionsIP 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.
Keywords:bioluminescent imaging  immunotherapy  natural killer (NK) cells  ovarian cancer
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