Checkpoint Inhibition of KIR2D with the Monoclonal Antibody IPH2101 Induces Contraction and Hyporesponsiveness of NK Cells in Patients with Myeloma.
OBJECTIVE
Immune checkpoint inhibitors have recently revolutionized cancer immunotherapy. On the basis of data showing KIR-ligand mismatched natural killer (NK) cells reduce the risk of leukemia and multiple myeloma relapse following allogeneic hematopoietic stem cell transplantation, investigators have developed a checkpoint inhibition antibody that blocks KIR on NK cells. Although in vitro studies suggest the KIR2D-specific antibody IPH2101 induces KIR-ligand mismatched tumor killing by NK cells, our single-arm phase II clinical trial in patients with smoldering multiple myeloma was prematurely terminated due to lack of clinical efficacy. This study aimed at unveiling the underlying mechanisms behind the lack of clinical efficacy.


METHODS
Treatment-naïve patients received an intravenous infusion of 1 mg/kg IPH2101 every other month for up to a year. Peripheral blood was collected at baseline and 24 hours after first infusion, followed by weekly samples for the first month and monthly samples thereafter. NK cell phenotype and function was analyzed using high-resolution flow cytometry.


RESULTS
Unexpectedly, infusion of IPH2101 resulted in rapid reduction in both NK cell responsiveness and KIR2D expression on the NK cell surface. In vitro assays revealed KIR2D molecules are removed from the surface of IPH2101-treated NK cells by trogocytosis, with reductions in NK cell function directly correlating with loss of free KIR2D surface molecules. Although IPH2101 marginally augmented the antimyeloma cytotoxicity of remaining KIR2Ddullpatient NK cells, the overall response was diminished by significant contraction and reduced function of KIR2D-expressing NK cells.


CONCLUSIONS
These data raise concerns that the unexpected biological events reported in this study could compromise antibody-based strategies designed at augmenting NK cell tumor killing via checkpoint inhibition. Clin Cancer Res; 22(21); 5211-22. ©2016 AACRSee related commentary by Felices and Miller, p. 5161.
Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
Mattias
M
Carlsten
Metabolism Branch, NCI, NIH, Bethesda, Maryland.
Neha
N
Korde
Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
Ritesh
R
Kotecha
Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
Robert
R
Reger
Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
Simona
S
Bor
Metabolism Branch, NCI, NIH, Bethesda, Maryland.
Dickran
D
Kazandjian
Metabolism Branch, NCI, NIH, Bethesda, Maryland.
Ola
O
Landgren
Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland. childsr@nhlbi.nih.gov.
Richard W
RW
Childs
D000368:Aged; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000276:immunology* / Q000628:therapy*; D054340:Receptors, KIR / Q000037:antagonists & inhibitors*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D054340:Receptors, KIR; C558235:IPH-2101