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

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Abstract

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 × 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.

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.

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Acknowledgements

The authors would like to thank the clinical study teams who participated in this study and the participants and their families who made the study possible. The authors would also like to thank Lisa Patti-Diaz (Bristol-Myers Squibb) for flow cytometry support and Ying Li (Bristol-Myers Squibb) for help with data visualizations. Medical writing support was provided by Geraint Owens, PhD, of Chameleon Communications International Ltd., with funding from Bristol-Myers Squibb.

Funding

Financial support for this work was provided by Bristol-Myers Squibb.

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Correspondence to Richard S. Hotchkiss.

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Conflicts of interest

EC, JY, IMC, IGG, and DMG are Bristol-Myers Squibb employees; EC, IMC, and DMG are Bristol-Myers Squibb shareholders. RSH receives research grant support and serves on advisory boards for Bristol-Myers Squibb. SY received grant support from Bristol-Myers Squibb for the design of this study. GSM reports grant support provided to Emory University from Bristol Myers Squibb for the conduct of the study. PKP’s institution received funding from the National Institutes of Health (NIH) and other support from the U.S. Food and Drug Administration/Biomedical Advanced Research and Development Authority, Atox Bio, and the Marcus Foundation. MWD receives funding from the NIH, American Heart Association, Open Philanthropy Project, General Electric, and Kaneka. DCA received consulting fees from Bristol-Myers Squibb for advice on study design. The remaining authors (LLM, EDC, TA, CMC, SCB, MT, FBM, RRB, and MJD) declare that they have no conflict of interest.

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Hotchkiss, R.S., Colston, E., Yende, S. et al. Immune checkpoint inhibition in sepsis: a Phase 1b randomized study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of nivolumab. Intensive Care Med 45, 1360–1371 (2019). https://doi.org/10.1007/s00134-019-05704-z

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