title: Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412.
abstract: Six healthy young male volunteers at a contract research organization were enrolled in the first phase 1 clinical trial of TGN1412, a novel superagonist anti-CD28 monoclonal antibody that directly stimulates T cells. Within 90 minutes after receiving a single intravenous dose of the drug, all six volunteers had a systemic inflammatory response characterized by a rapid induction of proinflammatory cytokines and accompanied by headache, myalgias, nausea, diarrhea, erythema, vasodilatation, and hypotension. Within 12 to 16 hours after infusion, they became critically ill, with pulmonary infiltrates and lung injury, renal failure, and disseminated intravascular coagulation. Severe and unexpected depletion of lymphocytes and monocytes occurred within 24 hours after infusion. All six patients were transferred to the care of the authors at an intensive care unit at a public hospital, where they received intensive cardiopulmonary support (including dialysis), high-dose methylprednisolone, and an anti-interleukin-2 receptor antagonist antibody. Prolonged cardiovascular shock and acute respiratory distress syndrome developed in two patients, who required intensive organ support for 8 and 16 days. Despite evidence of the multiple cytokine-release syndrome, all six patients survived. Documentation of the clinical course occurring over the 30 days after infusion offers insight into the systemic inflammatory response syndrome in the absence of contaminating pathogens, endotoxin, or underlying disease.
authors.affiliation: Department of Intensive Care Medicine, Northwick Park and St. Mark's Hospital, Harrow, London, United Kingdom. ganesh.suntharalingam@nwlh.nhs.uk
authors.forename: Ganesh
authors.initials: G
authors.lastname: Suntharalingam
authors.forename: Meghan R
authors.initials: MR
authors.lastname: Perry
authors.forename: Stephen
authors.initials: S
authors.lastname: Ward
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Brett
authors.forename: Andrew
authors.initials: A
authors.lastname: Castello-Cortes
authors.forename: Michael D
authors.initials: MD
authors.lastname: Brunner
authors.forename: Nicki
authors.initials: N
authors.lastname: Panoskaltsis
mesh_terms: D018806:APACHE; D000328:Adult; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D002097:C-Reactive Protein / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology*; D003422:Critical Care; D016207:Cytokines / Q000097:blood*; D018450:Disease Progression; D004311:Double-Blind Method; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007022:Hypotension / Q000139:chemically induced; D007262:Infusions, Intravenous; D007970:Leukopenia / Q000139:chemically induced*; D008297:Male; D009102:Multiple Organ Failure / Q000139:chemically induced* / Q000276:immunology / Q000628:therapy; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018106:CD28 Antigens; D016207:Cytokines; D002097:C-Reactive Protein; C509303:TGN-1412