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Immune checkpoint inhibition in sepsis: a Phase 1b randomized study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of nivolumab.
- Source :
-
Intensive Care Medicine . Oct2019, Vol. 45 Issue 10, p1360-1371. 12p. 3 Charts, 2 Graphs. - Publication Year :
- 2019
-
Abstract
- <bold>Purpose: </bold>Sepsis-associated immunosuppression increases hospital-acquired infection and viral reactivation risk. A key underlying mechanism is programmed cell death protein-1 (PD-1)-mediated T-cell function impairment. This is one of the first clinical safety and pharmacokinetics (PK) assessments of the anti-PD-1 antibody nivolumab and its effect on immune biomarkers in sepsis.<bold>Methods: </bold>Randomized, double-blind, parallel-group, Phase 1b study in 31 adults at 10 US hospital ICUs with sepsis diagnosed ≥ 24 h before study treatment, ≥ 1 organ dysfunction, and absolute lymphocyte count ≤ 1.1 × 103 cells/μL. Participants received one nivolumab dose [480 mg (n = 15) or 960 mg (n = 16)]; follow-up was 90 days. Primary endpoints were safety and PK parameters.<bold>Results: </bold>Twelve deaths occurred [n = 6 per study arm; 40% (480 mg) and 37.5% (960 mg)]. Serious AEs occurred in eight participants [n = 1, 6.7% (480 mg); n = 7, 43.8% (960 mg)]. AEs considered by the investigator to be possibly drug-related and immune-mediated occurred in five participants [n = 2, 13.3% (480 mg); n = 3, 18.8% (960 mg)]. Mean ± SD terminal half-life was 14.7 ± 5.3 (480 mg) and 15.8 ± 7.9 (960 mg) days. All participants maintained > 90% receptor occupancy (RO) 28 days post-infusion. Median (Q1, Q3) mHLA-DR levels increased to 11,531 (6528, 19,495) and 11,449 (6225, 16,698) mAbs/cell in the 480- and 960-mg arms by day 14, respectively. Pro-inflammatory cytokine levels did not increase.<bold>Conclusions: </bold>In this sepsis population, nivolumab administration did not result in unexpected safety findings or indicate any 'cytokine storm'. The PK profile maintained RO > 90% for ≥ 28 days. Further efficacy and safety studies are warranted. TRIAL REGISTRATION NUMBER (CLINICALTRIALS.GOV): NCT02960854. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 03424642
- Volume :
- 45
- Issue :
- 10
- Database :
- Academic Search Index
- Journal :
- Intensive Care Medicine
- Publication Type :
- Academic Journal
- Accession number :
- 138910905
- Full Text :
- https://doi.org/10.1007/s00134-019-05704-z