title: Anti-KIR antibody enhancement of anti-lymphoma activity of natural killer cells as monotherapy and in combination with anti-CD20 antibodies.
abstract: Natural killer (NK) cells mediate antilymphoma activity by spontaneous cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) when triggered by rituximab, an anti-CD20 monoclonal antibody (mAb) used to treat patients with B-cell lymphomas. The balance of inhibitory and activating signals determines the magnitude of the efficacy of NK cells by spontaneous cytotoxicity. Here, using a killer-cell immunoglobulin-like receptor (KIR) transgenic murine model, we show that blockade of the interface of inhibitory KIRs with major histocompatibility complex (MHC) class I antigens on lymphoma cells by anti-KIR antibodies prevents a tolerogenic interaction and augments NK-cell spontaneous cytotoxicity. In combination with anti-CD20 mAbs, anti-KIR treatment induces enhanced NK-cell-mediated, rituximab-dependent cytotoxicity against lymphoma in vitro and in vivo in KIR transgenic and syngeneic murine lymphoma models. These results support a therapeutic strategy of combination rituximab and KIR blockade through lirilumab, illustrating the potential efficacy of combining a tumor-targeting therapy with an NK-cell agonist, thus stimulating the postrituximab antilymphoma immune response.
authors: Department of Medicine, Division of Oncology, Stanford University, Stanford, CA;
authors: Holbrook E
authors: HE
authors: Kohrt
authors: Ariane
authors: A
authors: Thielens
authors: Aurelien
authors: A
authors: Marabelle
authors: Idit
authors: I
authors: Sagiv-Barfi
authors: Caroline
authors: C
authors: Sola
authors: Fabien
authors: F
authors: Chanuc
authors: Nicolas
authors: N
authors: Fuseri
authors: Cécile
authors: C
authors: Bonnafous
authors: Debra
authors: D
authors: Czerwinski
authors: Amanda
authors: A
authors: Rajapaksa
authors: Erin
authors: E
authors: Waller
authors: Sophie
authors: S
authors: Ugolini
authors: Eric
authors: E
authors: Vivier
authors: François
authors: F
authors: Romagné
authors: Ronald
authors: R
authors: Levy
authors: Mathieu
authors: M
authors: Bléry
authors: Pascale
authors: P
authors: André
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived / Q000276:immunology / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity; D018951:Antigens, CD20 / Q000276:immunology*; D002460:Cell Line; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008223:Lymphoma / Q000276:immunology / Q000628:therapy*; D008297:Male; D051379:Mice; D054340:Receptors, KIR / Q000276:immunology*; D000069283:Rituximab
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D015395:Histocompatibility Antigens Class I; D054340:Receptors, KIR; D000069283:Rituximab