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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

2010; Elsevier BV; Volume: 116; Issue: 13 Linguagem: Inglês

10.1182/blood-2010-02-271874

1528-0020

Don M. Benson, Courtney E. Bakan, Anjali Mishra, Craig C. Hofmeister, Yvonne A. Efebera, Brian Becknell, Robert A. Baiocchi, Jianying Zhang, Jianhua Yu, Megan Smith, Carli N Greenfield, Pierluigi Porcu, Steven M. Devine, Rinat Rotem‐Yehudar, Gerard Lozanski, John C. Byrd, Michael A. Caligiuri,

Cancer Immunotherapy and Biomarkers

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.