ABSTRACT
Advances in understanding the physiologic functions of the tumor necrosis factor superfamily (TNFSF) of ligands, receptors, and signaling networks are providing deeper insight into pathogenesis of infectious and autoimmune diseases and cancer. LIGHT (TNFSF14) has emerged as an important modulator of critical innate and adaptive immune responses. LIGHT and its signaling receptors, herpesvirus entry mediator (TNFRSF14), and lymphotoxin ß receptor, form an immune regulatory network with two co-receptors of herpesvirus entry mediator, checkpoint inhibitor B and T lymphocyte attenuator, and CD160. Deciphering the fundamental features of this network reveals new understanding to guide therapeutic development. Accumulating evidence from infectious diseases points to the dysregulation of the LIGHT network as a disease-driving mechanism in autoimmune and inflammatory reactions in barrier organs, including coronavirus disease 2019 pneumonia and inflammatory bowel diseases. Recent clinical results warrant further investigation of the LIGHT regulatory network and application of target-modifying therapeutics for disease intervention.
Subject(s)
COVID-19 , Receptors, Tumor Necrosis Factor, Member 14 , Humans , Inflammation , Signal Transduction , T-LymphocytesABSTRACT
BACKGROUNDSevere coronavirus disease 2019 (COVID-19) is associated with a dysregulated immune response, which can result in cytokine-release syndrome and acute respiratory distress syndrome (ARDS). Patients with COVID-19-associated ARDS have elevated free serum levels of the cytokine lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry on T cells (LIGHT; also known as TNFSF14). Such patients may benefit from LIGHT-neutralization therapy.METHODSThis randomized, double-blind, multicenter, proof-of-concept trial enrolled adults hospitalized with COVID-19-associated pneumonia and mild to moderate ARDS. Patients received standard of care plus a single dose of a human LIGHT-neutralizing antibody (CERC-002) or placebo. The primary endpoint was the proportion of patients receiving CERC-002 who remained alive and free of respiratory failure through day 28. Safety was assessed via adverse event monitoring.RESULTSFor most of the 83 enrolled patients, standard of care included systemic corticosteroids (88.0%) or remdesivir (57.8%). A higher proportion of patients remained alive and free of respiratory failure through day 28 after receiving CERC-002 (83.9%) versus placebo (64.5%; P = 0.044), including in patients 60 years of age or older (76.5% vs. 47.1%, respectively; P = 0.042). Mortality rates were 7.7% (CERC-002) and 14.3% (placebo) on day 28 and 10.8% and 22.5%, respectively, on day 60. Treatment-emergent adverse events were less frequent with CERC-002 than placebo.CONCLUSIONFor patients with COVID-19-associated ARDS, adding CERC-002 to standard-of-care treatment reduces LIGHT levels and might reduce the risk of respiratory failure and death.TRIAL REGISTRATIONClinicalTrials.gov NCT04412057.FUNDINGAvalo Therapeutics.
Subject(s)
Antibodies, Monoclonal/administration & dosage , COVID-19 Drug Treatment , Cytokine Release Syndrome/drug therapy , Respiratory Distress Syndrome/drug therapy , SARS-CoV-2/metabolism , Tumor Necrosis Factor Ligand Superfamily Member 14/antagonists & inhibitors , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/analogs & derivatives , Adrenal Cortex Hormones/administration & dosage , Adult , Alanine/administration & dosage , Alanine/analogs & derivatives , COVID-19/blood , COVID-19/mortality , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/mortality , Disease-Free Survival , Double-Blind Method , Female , Humans , Male , Middle Aged , Respiratory Distress Syndrome/blood , Respiratory Distress Syndrome/mortality , Survival Rate , Tumor Necrosis Factor Ligand Superfamily Member 14/bloodABSTRACT
Many coronavirus disease 2019 (COVID-19) patients demonstrate lethal respiratory complications caused by cytokine release syndrome (CRS). Multiple cytokines have been implicated in CRS, but levels of tumor necrosis factor superfamily 14 (TNFSF14) (LIGHT) have not been previously measured in this setting. In this study, we observed significantly elevated serum LIGHT levels in hospitalized COVID-19 patients compared to healthy age- and gender-matched control patients. The assay detected bioavailable LIGHT unbound to the inhibitor Decoy receptor-3 (DcR3). Bioavailable LIGHT levels were elevated in patients both on and off ventilatory support, with a trend toward higher levels in patients requiring mechanical ventilation. In hospitalized patients over the age of 60, who exhibited a mortality rate of 82%, LIGHT levels were significantly higher (P = 0.0209) in those who died than in survivors. As previously reported, interleukin 6 (IL-6) levels were also elevated in these patients, with significantly (P = 0.0076) higher levels observed in patients who died than in survivors, paralleling the LIGHT levels. Although attempts to block IL-6 binding to its receptor have shown limited success in COVID-19 CRS, neutralization of LIGHT may prove to be more effective owing to its more central role in regulating antiviral immune responses. The findings presented here demonstrate that LIGHT is a cytokine which may play an important role in COVID-19 patients presenting with acute respiratory distress syndrome (ARDS) and CRS and suggest that LIGHT neutralization may be beneficial to COVID-19 patients.