Immune Checkpoint Inhibition in Sepsis: A Phase 1b Randomized, Placebo-Controlled, Single Ascending Dose Study of Antiprogrammed Cell Death-Ligand 1 (BMS-936559)

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 Main Results: 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. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://bit.ly/29S62lw). Supported by Bristol-Myers Squibb. Drs. Hotchkiss's, Yende's, Angus's, Moldawer's, Crouser's, Martin's, Coopersmith's, Brakenridge's, Mayr's, and Park's institution received funding from Bristol-Myers Squibb. Drs. Hotchkiss, Colston, Yende, Angus, and Moldawer received support for article research from Bristol-Myers Squibb. Drs. Hotchkiss, Colston, Moldawer, Crouser, Martin, Coopersmith, Brakenridge, Mayr, Park, Catlett, and Grasela disclosed off-label product use of antiprogrammed cell death-ligand 1 inhibitor (BMS-936559) for the treatment of immune suppression in the context of severe sepsis. Drs. Colston and Grasela disclosed they are shareholders of Bristol-Myers Squibb. Dr. Hotchkiss receives research grant support and serves on advisory boards to Bristol-Myers Squibb. Dr. Yende received grant support from Bristol-Myers Squibb for the design of this study. Dr. Angus received consulting fees from Bristol-Myers Squibb for advice on study design. Dr. Martin's institution received funding from the National Institutes of Health. Dr. Coopersmith's institution received funding from the Society of Critical Care Medicine (president in 2015). Dr. Park's institution received funding from the National Institutes of Health, and she received other support from the U.S. Food and Drug Administration/Biomedical Advanced Research and Development Authority and Atox Bio. Drs. Colston, Ye, Catlett, Girgis, and Grasela disclosed that they are employees of Bristol-Myers Squibb. Study registration number (ClinicalTrials.gov): NCT02576457. Data sharing: BMS policy on data sharing may be found at http://bit.ly/2WXXv40. For information regarding this article, E-mail: richardshotchkiss@wustl.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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