title: The IL-15-Based ALT-803 Complex Enhances FcγRIIIa-Triggered NK Cell Responses and In Vivo Clearance of B Cell Lymphomas.
abstract: OBJECTIVE
  Anti-CD20 monoclonal antibodies (mAb) are an important immunotherapy for B-cell lymphoma, and provide evidence that the immune system may be harnessed as an effective lymphoma treatment approach. ALT-803 is a superagonist IL-15 mutant and IL-15Rα-Fc fusion complex that activates the IL-15 receptor constitutively expressed on natural killer (NK) cells. We hypothesized that ALT-803 would enhance anti-CD20 mAb-directed NK-cell responses and antibody-dependent cellular cytotoxicity (ADCC).
  
  
  METHODS
  We tested this hypothesis by adding ALT-803 immunostimulation to anti-CD20 mAb triggering of NK cells in vitro and in vivo. Cell lines and primary human lymphoma cells were utilized as targets for primary human NK cells. Two complementary in vivo mouse models were used, which included human NK-cell xenografts in NOD/SCID-γc (-/-) mice.
  
  
  RESULTS
  We demonstrate that short-term ALT-803 stimulation significantly increased degranulation, IFNγ production, and ADCC by human NK cells against B-cell lymphoma cell lines or primary follicular lymphoma cells. ALT-803 augmented cytotoxicity and the expression of granzyme B and perforin, providing one potential mechanism for this enhanced functionality. Moreover, in two distinct in vivo B-cell lymphoma models, the addition of ALT-803 to anti-CD20 mAb therapy resulted in significantly reduced tumor cell burden and increased survival. Long-term ALT-803 stimulation of human NK cells induced proliferation and NK-cell subset changes with preserved ADCC.
  
  
  CONCLUSIONS
  ALT-803 represents a novel immunostimulatory drug that enhances NK-cell antilymphoma responses in vitro and in vivo, thereby supporting the clinical investigation of ALT-803 plus anti-CD20 mAbs in patients with indolent B-cell lymphoma.
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri. Department of Pathology/Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Maximillian
authors.initials: M
authors.lastname: Rosario
authors.affiliation: Altor BioScience Corporation, Miramar, Florida.
authors.forename: Bai
authors.initials: B
authors.lastname: Liu
authors.affiliation: Altor BioScience Corporation, Miramar, Florida.
authors.forename: Lin
authors.initials: L
authors.lastname: Kong
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Lynne I
authors.initials: LI
authors.lastname: Collins
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Schneider
authors.affiliation: Altor BioScience Corporation, Miramar, Florida.
authors.forename: Xiaoyue
authors.initials: X
authors.lastname: Chen
authors.affiliation: Altor BioScience Corporation, Miramar, Florida.
authors.forename: Kaiping
authors.initials: K
authors.lastname: Han
authors.affiliation: Altor BioScience Corporation, Miramar, Florida.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Jeng
authors.affiliation: Altor BioScience Corporation, Miramar, Florida.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Rhode
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Leong
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Timothy
authors.initials: T
authors.lastname: Schappe
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Brea A
authors.initials: BA
authors.lastname: Jewell
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Catherine R
authors.initials: CR
authors.lastname: Keppel
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Keval
authors.initials: K
authors.lastname: Shah
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Brian
authors.initials: B
authors.lastname: Hess
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Rizwan
authors.initials: R
authors.lastname: Romee
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri. Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: David R
authors.initials: DR
authors.lastname: Piwnica-Worms
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Amanda F
authors.initials: AF
authors.lastname: Cashen
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Bartlett
authors.affiliation: Altor BioScience Corporation, Miramar, Florida.
authors.forename: Hing C
authors.initials: HC
authors.lastname: Wong
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri. tfehnige@wustl.edu.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Fehniger
mesh_terms: D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053804:Granzymes / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D054353:Perforin / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000494:pharmacology*; D017452:Receptors, IgG / Q000378:metabolism*; D011993:Recombinant Fusion Proteins; D000069283:Rituximab / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C582303:ALT-803; D000970:Antineoplastic Agents; C496124:FCGR3A protein, human; D011506:Proteins; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D054353:Perforin; D000069283:Rituximab; D007371:Interferon-gamma; D053804:Granzymes