A phase 1 trial of the anti-KIR antibody IPH2101 in patients with relapsed/refractory multiple myeloma

被引:189
作者
Benson, Don M., Jr. [1 ]
Hofmeister, Craig C. [1 ]
Padmanabhan, Swaminathan [2 ]
Suvannasankha, Attaya [3 ]
Jagannath, Sundar [4 ]
Abonour, Rafat [3 ]
Bakan, Courtney
Andre, Pascale [5 ]
Efebera, Yvonne [1 ]
Tiollier, Jerome [5 ]
Caligiuri, Michael A. [1 ]
Farag, Sherif S. [2 ]
机构
[1] Ohio State Univ, Ctr Comprehens Canc, Div Hematol, Columbus, OH 43210 USA
[2] Canc Treatment & Res Ctr, San Antonio, TX USA
[3] Indiana Univ, Ctr Canc, Indianapolis, IN 46204 USA
[4] Mt Sinai Med Ctr, New York, NY 10029 USA
[5] Innate Pharma, Marseille, France
关键词
NATURAL-KILLER-CELL; CLASS-I MOLECULES; BONE-MARROW; MONOCLONAL GAMMOPATHIES; TUMOR-CELLS; LENALIDOMIDE; RECEPTORS; CYTOTOXICITY; CHEMOTHERAPY; ACTIVATION;
D O I
10.1182/blood-2012-06-438028
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Natural killer (NK) cells elicit cytotoxicity against multiple myeloma (MM); however, MM cells express HLA class I molecules as ligands to NK cell inhibitory killer immunoglobulin-like receptors (KIRs) as a means of immunoevasion. KIR-ligand mismatch may improve outcomes in allogeneic transplantation for MM. Extrapolating on this concept, we conducted a phase 1 trial of IPH2101, an anti-KIR antibody, in patients with relapsed/refractory MM. IPH2101 was administered intravenously every 28 days in 7 dose-escalated cohorts (0.0003-3 mg/kg) for up to 4 cycles. Pharmacokinetic, pharmacodynamic, and correlative immunologic studies were completed. A total of 32 patients were enrolled. The biologic endpoint of full KIR2D occupancy across the dosing cycle was achieved without dose-limiting toxicity or maximally tolerated dose. One severe adverse event was noted. Pharmacokinetic and pharmacodynamic findings approximated preclinical predictions, and IPH2101 enhanced ex vivo patient-derived NK cell cytotoxicity against MM. No objective responses were seen. No evidence of autoimmunity was observed. These findings suggest that IPH2101 is safe and tolerable at doses that achieve full inhibitory KIR saturation, and this approach warrants further development in MM. This trial was registered at www.clinicaltrials.gov as #NCT00552396. (Blood. 2012;120(22):4324-4333)
引用
收藏
页码:4324 / 4333
页数:10
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