Cytokine Storm in a Phase 1 Trial of the Anti-CD28 Monoclonal Antibody TGN1412
Ganesh Suntharalingam, F.R.C.A., Meghan R. Perry, M.R.C.P., Stephen Ward, F.R.C.A., Stephen J. Brett, M.D., Andrew Castello-Cortes, F.R.C.A., Michael D. Brunner, F.R.C.A., and Nicki Panoskaltsis, M.D., Ph.D.
Six healthy young male volunteers at a contract research organizationwere enrolled in the first phase 1 clinical trial of TGN1412,a novel superagonist anti-CD28 monoclonal antibody that directlystimulates T cells. Within 90 minutes after receiving a singleintravenous dose of the drug, all six volunteers had a systemicinflammatory response characterized by a rapid induction ofproinflammatory cytokines and accompanied by headache, myalgias,nausea, diarrhea, erythema, vasodilatation, and hypotension.Within 12 to 16 hours after infusion, they became criticallyill, with pulmonary infiltrates and lung injury, renal failure,and disseminated intravascular coagulation. Severe and unexpecteddepletion of lymphocytes and monocytes occurred within 24 hoursafter infusion. All six patients were transferred to the careof the authors at an intensive care unit at a public hospital,where they received intensive cardiopulmonary support (includingdialysis), high-dose methylprednisolone, and an anti–interleukin-2receptor antagonist antibody. Prolonged cardiovascular shockand acute respiratory distress syndrome developed in two patients,who required intensive organ support for 8 and 16 days. Despiteevidence of the multiple cytokine-release syndrome, all sixpatients survived. Documentation of the clinical course occurringover the 30 days after infusion offers insight into the systemicinflammatory response syndrome in the absence of contaminatingpathogens, endotoxin, or underlying disease.
Source Information
From the Department of Intensive Care Medicine, Northwick Park and St. Mark's Hospital (G.S., M.R.P., S.W., A.C.-C., M.D.B.); the Department of Intensive Care Medicine, Hammersmith Hospital (S.J.B.); and the Department of Haematology, Imperial College London, Northwick Park and St. Mark's Campus (N.P.) — all in London. An interview with Dr. Suntharalingam can be heard at www.nejm.org. This article was published at www.nejm.org on August 14, 2006.
Address reprint requests to Dr. Suntharalingam at Rm. 4J007, Department of Intensive Care Medicine, or to Dr. Panoskaltsis at the Department of Hematology — both at Northwick Park and St. Mark's Hospital, Watford Rd., Harrow, London HA1 3UJ, United Kingdom; or at ganesh.suntharalingam{at}nwlh.nhs.uk or n.panoskaltsis{at}imperial.ac.uk.
Cytokine Storm and an Anti-CD28 Monoclonal Antibody
Gardner K., Corry D. B., Lewis D. E., Puellmann K., Beham A. W., Kaminski W. E., Garcia-Bournissen F., Boragina M., Ito S., Takita M., Matsumura T., Kami M., Castello-Cortes A., Suntharalingam G., Panoskaltsis N.
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N Engl J Med 2006;
355:2591-2594, Dec 14, 2006.
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