Immune checkpoint inhibition in sepsis: a Phase 1b randomized study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of nivolumab

• Published in: Intensive care medicine Vol. 45; no. 10; pp. 1360 - 1371
• Main Authors: Hotchkiss, Richard S., Colston, Elizabeth, Yende, Sachin, Crouser, Elliott D., Martin, Greg S., Albertson, Timothy, Bartz, Raquel R., Brakenridge, Scott C., Delano, Matthew J., Park, Pauline K., Donnino, Michael W., Tidswell, Mark, Mayr, Florian B., Angus, Derek C., Coopersmith, Craig M., Moldawer, Lyle L., Catlett, Ian M., Girgis, Ihab G., Ye, June, Grasela, Dennis M.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.10.2019; Springer; Springer Nature B.V
• Subjects: Activation; Adult; Aged; Anesthesiology; Antibodies; Apoptosis; Biomarkers; Biomarkers - analysis; Cell death; Cell number; Clinical trials; Critical Care Medicine; Cytokines; Diagnosis; Double-Blind Method; Emergency Medicine; ESICM Lives Clinical Trials; Female; Health aspects; Health risks; HLA-DR Antigens - analysis; HLA-DR Antigens - blood; Humans; Immune checkpoint inhibitors; Immunologic Factors - pharmacokinetics; Immunologic Factors - pharmacology; Immunologic Factors - therapeutic use; Immunosuppression; Immunotherapy; Infection; Inflammation; Intensive; Intensive care; Lymphocytes; Lymphocytes T; Male; Medicine; Medicine & Public Health; Middle Aged; Monoclonal antibodies; Nivolumab - pharmacokinetics; Nivolumab - pharmacology; Nivolumab - therapeutic use; Occupancy; Original; Pain Medicine; PD-1 protein; Pediatrics; Pharmacodynamics; Pharmacokinetics; Pharmacology; Pneumology/Respiratory System; Programmed Cell Death 1 Receptor - analysis; Programmed Cell Death 1 Receptor - blood; Randomization; Safety; Sepsis; Sepsis - drug therapy; Sepsis - immunology; Sepsis - physiopathology; T cells; Viral antibodies; Sepsis; Immunosuppression; Immune checkpoint inhibition; Anti-PD-1; Phase 1; Nivolumab
• ISSN: 0342-4642; 1432-1238
• DOI: 10.1007/s00134-019-05704-z

Purpose 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. Methods 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 × 10 3 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. Results 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. Conclusions 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.