Table 2.

Recent clinical studies that target immunosuppression in sepsis*

Immune augmentation agent	Mechanism of action	Study population	Primary outcome	Results	Author, year of publication or NCT number
GM-CSF	Increased monocytic HLA-DR expression Increased monocytic production of TLR2/4-induced cytokines	n = 98, septic shock	Difference in the number of patients presenting ≥ 1 ICU-acquired infection at day 28 or ICU discharge	No significant difference; terminated due to insufficient recruitment	Vacheron et al. 2023 [78]
		n = 400, children with sepsis-induced multiple-organ dysfunction syndrome (MODS)	Cumulative 28-day Pediatric Logistic Organ Dysfunction (PELOD)-2 score	Recruiting	NCT05266001(GRACE2)
IFNγ	Primary activator of macrophages, neutrophils, and natural killer cells	n = 273, sepsis and septic shock	28-day mortality	No significant difference	Leventogiannis et al. 2022 [84]
		n = 280, sepsis (< 72 h)	Comparative decrease of the mean total Sequential Organ Failure Assessment (SOFA) score by at least 1.4 points by day 9 from randomization	Recruiting	Kotsaki et al. 2022 NCT04990232 (ImmunoSep) [85]
Thymosin alpha	Stimulates endogenous IFNy secretion and regulates T cell subsets	n = 1106, sepsis	28-day mortality	Pending	NCT02867267
		sepsis patients discharged after completing TESTS trial	3-year mortality	Pending	NCT04901104
Immunoglobulins (IgM-enriched)	Enhancement of pathogen recognition and clearance, scavenging of toxins and complement, neutralization of inflammatory cytokines	n = 200, sepsis or septic shock	Improvement of the mean multiple-organ failure score on day 7	Pending	NCT03334006
Mesenchymal stem cells (MSC)	Augmentation of bacterial clearance, limitation of apoptosis, injury repair enhancement	n = 9, septic shock	Safety, tolerability	Well tolerated, no infusion-associated, and serious adverse events	McIntyre et al. 2018 [101]
		n = 15, septic shock	Safety, tolerability	Well tolerated, no infusion-associated, and serious adverse events	He et al. 2018 [102]
		n = 114, sepsis and septic shock	Reduction in days on mechanical ventilation, or renal replacement therapy, or vasopressors; safety and tolerability	Pending	NCT03369275 (CISS2)
		n = 66, septic shock (≥ 2 organ failures other than hemodynamic)	Sofa score on day 7	Pending	NCT02883803 (CHOCMSC)
		n = 21, septic shock	Safety, tolerability	Pending	NCT04961658 (AMETHYST)
Immune checkpoint inhibitor nivolumab	Anti-programmed cell death (PD)-1 monoclonal antibody	n = 13, sepsis	Safety, tolerability, pharmakokinetics	Safe, well tolerated, increase in lymphocyte count and mHLA-DR expression	Watanabe et al. 2020 [114]
		n = 31, sepsis diagnosed ≥ 24 h before treatment, ≥ 1 organ dysfunction, and absolute lymphocyte count ≤ 1.1 × 103 cells/μL	Safety, tolerability and pharmacokinetics over 90d	Safe, no cytokine release syndrome	Hotchkiss et al. 2019 [115]

*A summary of clinical studies over last past 5 years