Immune Checkpoint Inhibition in Sepsis: A Phase 1b Randomized, Placebo-Controlled, Single Ascending Dose Study of Antiprogrammed Cell Death-Ligand 1 Antibody (BMS-936559).
Crit Care Med
; 47(5): 632-642, 2019 05.
Article
in En
| MEDLINE
| ID: mdl-30747773
ABSTRACT
OBJECTIVES:
To assess for the first time the safety and pharmacokinetics of an antiprogrammed cell death-ligand 1 immune checkpoint inhibitor (BMS-936559; Bristol-Myers Squibb, Princeton, NJ) and its effect on immune biomarkers in participants with sepsis-associated immunosuppression.DESIGN:
Randomized, placebo-controlled, dose-escalation.SETTING:
Seven U.S. hospital ICUs. STUDY POPULATION Twenty-four participants with sepsis, organ dysfunction (hypotension, acute respiratory failure, and/or acute renal injury), and absolute lymphocyte count less than or equal to 1,100 cells/µL.INTERVENTIONS:
Participants received single-dose BMS-936559 (10-900 mg; n = 20) or placebo (n = 4) infusions. Primary endpoints were death and adverse events; key secondary endpoints included receptor occupancy and monocyte human leukocyte antigen-DR levels. MEASUREMENTS AND MAINRESULTS:
The treated group was older (median 62 yr treated pooled vs 46 yr placebo), and a greater percentage had more than 2 organ dysfunctions (55% treated pooled vs 25% placebo); other baseline characteristics were comparable. Overall mortality was 25% (10 mg dose 2/4; 30 mg 2/4; 100 mg 1/4; 300 mg 1/4; 900 mg 0/4; placebo 0/4). All participants had adverse events (75% grade 1-2). Seventeen percent had a serious adverse event (3/20 treated pooled, 1/4 placebo), with none deemed drug-related. Adverse events that were potentially immune-related occurred in 54% of participants; most were grade 1-2, none required corticosteroids, and none were deemed drug-related. No significant changes in cytokine levels were observed. Full receptor occupancy was achieved for 28 days after BMS-936559 (900 mg). At the two highest doses, an apparent increase in monocyte human leukocyte antigen-DR expression (> 5,000 monoclonal antibodies/cell) was observed and persisted beyond 28 days.CONCLUSIONS:
In this first clinical evaluation of programmed cell death protein-1/programmed cell death-ligand 1 pathway inhibition in sepsis, BMS-936559 was well tolerated, with no evidence of drug-induced hypercytokinemia or cytokine storm, and at higher doses, some indication of restored immune status over 28 days. Further randomized trials on programmed cell death protein-1/programmed cell death-ligand 1 pathway inhibition are needed to evaluate its clinical safety and efficacy in patients with sepsis.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Sepsis
/
Antibodies, Monoclonal, Humanized
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Programmed Cell Death 1 Receptor
/
Antineoplastic Agents, Immunological
/
Antibodies, Monoclonal
Type of study:
Clinical_trials
Limits:
Aged
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Female
/
Humans
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Male
/
Middle aged
Language:
En
Journal:
Crit Care Med
Year:
2019
Type:
Article
Affiliation country:
Macao