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

DM Benson Jr, CE Bakan, A Mishra… - Blood, The Journal …, 2010 - ashpublications.org
DM Benson Jr, CE Bakan, A Mishra, CC Hofmeister, Y Efebera, B Becknell, RA Baiocchi…
Blood, The Journal of the American Society of Hematology, 2010ashpublications.org
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 …
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.
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