title: Genetically re-engineered K562 cells significantly expand and functionally activate cord blood natural killer cells: Potential for adoptive cellular immunotherapy.
abstract: Natural killer (NK) cells play a significant role in reducing relapse in patients with hematological malignancies after allogeneic stem cell transplantation, but NK cell number and naturally occurring inhibitory signals limit their capability. Interleukin-15 (IL-15) and 4-1BBL are important modulators of NK expansion and functional activation. To overcome these limitations, cord blood mononuclear cells (CB MNCs) were ex vivo expanded for 7 days with genetically modified K562-mbIL15-41BBL (MODK562) or wild-type K562 (WTK562). NK cell expansion; expression of lysosome-associated membrane protein-1 (LAMP-1), granzyme B, and perforin; and in vitro and in vivo cytotoxicity against B-cell non-Hodgkin lymphoma (B-NHL) were evaluated. In vivo tumor growth in B-NHL-xenografted nonobese diabetic severe combined immune deficient (NOD-scid) gamma (NSG) mice was monitored by tumor volume, cell number, and survival. CB MNCs cultured with MODK562 compared with WTK562 demonstrated significantly increased NK expansion (thirty-fivefold, p < 0.05); LAMP-1 (p < 0.05), granzyme B, and perforin expression (p < 0.001); and in vitro cytotoxicity against B-NHL (p < 0.01). Xenografted mice treated with MODK562 CB experienced significantly decreased B-NHL tumor volume (p = 0.0086) and B-NHL cell numbers (p < 0.01) at 5 weeks and significantly increased survival (p < 0.001) at 10 weeks compared with WTK562. In summary, MODK562 significantly enhanced CB NK expansion and cytotoxicity, enhanced survival in a human Burkitt's lymphoma xenograft NSG model, and could be used in the future as adoptive cellular immunotherapy after umbilical CB transplantation. Future directions include expanding anti-CD20 chimeric receptor-modified CB NK cells to enhance B-NHL targeting in vitro and in vivo.
authors.affiliation: Department of Pediatrics, New York Medical College, Valhalla, NY, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Ayello
authors.affiliation: Department of Pediatrics, New York Medical College, Valhalla, NY, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Hochberg
authors.affiliation: Department of Pediatrics, New York Medical College, Valhalla, NY, USA.
authors.forename: Allyson
authors.initials: A
authors.lastname: Flower
authors.affiliation: Department of Pediatrics, New York Medical College, Valhalla, NY, USA.
authors.forename: Yaya
authors.initials: Y
authors.lastname: Chu
authors.affiliation: Department of Obstetrics and Gynecology, New York University Langone Medical Center, New York, NY, USA.
authors.forename: Laxmi V
authors.initials: LV
authors.lastname: Baxi
authors.affiliation: Department of Pediatrics, New York Medical College, Valhalla, NY, USA.
authors.forename: William
authors.initials: W
authors.lastname: Quish
authors.affiliation: Department of Pediatrics, New York Medical College, Valhalla, NY, USA.
authors.forename: Carmella
authors.initials: C
authors.lastname: van de Ven
authors.affiliation: Department of Pediatrics, New York Medical College, Valhalla, NY, USA; Department of Medicine, New York Medical College, Valhalla, NY, USA; Department of Pathology, New York Medical College, Valhalla, NY, USA; Department of Microbiology and Immunology, New York Medical College, Valhalla, NY, USA; Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, USA. Electronic address: mitchell_cairo@nymc.edu.
authors.forename: Mitchell S
authors.initials: MS
authors.lastname: Cairo
mesh_terms: D000818:Animals; D015415:Biomarkers; D002450:Cell Communication; D018929:Cell Culture Techniques; D060846:Cell Engineering; D045744:Cell Line, Tumor; D002470:Cell Survival; D003602:Cytotoxicity, Immunologic; D005312:Fetal Blood / Q000166:cytology*; D005818:Genetic Engineering; D053804:Granzymes / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D020014:K562 Cells / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D007963:Leukocytes, Mononuclear; D008213:Lymphocyte Activation / Q000276:immunology; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D054353:Perforin / Q000378:metabolism; D055607:Receptors, Natural Killer Cell / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D015415:Biomarkers; D052118:Lysosomal-Associated Membrane Protein 1; D055607:Receptors, Natural Killer Cell; D054353:Perforin; D053804:Granzymes