title: The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody.
abstract: T-cell expression of programmed death receptor-1 (PD-1) down-regulates the immune response against malignancy by interacting with cognate ligands (eg, PD-L1) on tumor cells; however, little is known regarding PD-1 and natural killer (NK) cells. NK cells exert cytotoxicity against multiple myeloma (MM), an effect enhanced through novel therapies. We show that NK cells from MM patients express PD-1 whereas normal NK cells do not and confirm PD-L1 on primary MM cells. Engagement of PD-1 with PD-L1 should down-modulate the NK-cell versus MM effect. We demonstrate that CT-011, a novel anti-PD-1 antibody, enhances human NK-cell function against autologous, primary MM cells, seemingly through effects on NK-cell trafficking, immune complex formation with MM cells, and cytotoxicity specifically toward PD-L1(+) MM tumor cells but not normal cells. We show that lenalidomide down-regulates PD-L1 on primary MM cells and may augment CT-011's enhancement of NK-cell function against MM. We demonstrate a role for the PD-1/PD-L1 signaling axis in the NK-cell immune response against MM and a role for CT-011 in enhancing the NK-cell versus MM effect. A phase 2 clinical trial of CT-011 in combination with lenalidomide for patients with MM should be considered.
authors.affiliation: Division of Hematology/Oncology, The Ohio State University Medical Center, Columbus, OH, USA.
authors.forename: Don M
authors.initials: DM
authors.lastname: Benson
authors.forename: Courtney E
authors.initials: CE
authors.lastname: Bakan
authors.forename: Anjali
authors.initials: A
authors.lastname: Mishra
authors.forename: Craig C
authors.initials: CC
authors.lastname: Hofmeister
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Efebera
authors.forename: Brian
authors.initials: B
authors.lastname: Becknell
authors.forename: Robert A
authors.initials: RA
authors.lastname: Baiocchi
authors.forename: Jianying
authors.initials: J
authors.lastname: Zhang
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.forename: Megan K
authors.initials: MK
authors.lastname: Smith
authors.forename: Carli N
authors.initials: CN
authors.lastname: Greenfield
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Porcu
authors.forename: Steven M
authors.initials: SM
authors.lastname: Devine
authors.forename: Rinat
authors.initials: R
authors.lastname: Rotem-Yehudar
authors.forename: Gerard
authors.initials: G
authors.lastname: Lozanski
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D000936:Antigen-Antibody Complex / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000008:administration & dosage; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D060890:B7-H1 Antigen; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology*; D000077269:Lenalidomide; D009101:Multiple Myeloma / Q000276:immunology* / Q000628:therapy*; D061026:Programmed Cell Death 1 Receptor; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D015703:Antigens, CD; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D019718:Receptors, CXCR4; D013792:Thalidomide; D007371:Interferon-gamma; D000077269:Lenalidomide
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