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.

Clinical review: Blood purification for sepsis

“…The systemic inflammatory response, though a result of innate immunity, can become deleterious when excessive or uncontrolled, leading to the development of multi-organ failure syndrome and death. At least two mechanisms are identified to explain the potential harmful effects of this host inflammatory response: cytokines have the capacity to damage the cells (cytotoxic effects) [3], and the prolonged release of inflammatory mediators leads to severely impaired immunity [4]. This 'immunoparalysis' state plays a major role in mortality because it favors severe secondary nosocomial infections.…”

Immunology: A tolerant approach

“…In 2006, an antibody-based treatment developed by the German drug company TeGenero was given to six healthy volunteers in a UK trial. Designed to quell the autoimmune response by a mechanism different from antigen-specific tolerance, it instead caused a massive immune response and multiple-organ failure 5 . The participants survived, and investigators have since implemented safer dosing protocols, but researchers know that an immune response can quickly go wrong.…”

Restoring the balance: Harnessing regulatory T cells for therapy in rheumatoid arthritis

“…A wide variety of agents have been reported to induce Treg and thereby ameliorate arthritis. Perhaps the most notorious are CD28 superagonists, which showed promise in different autoimmune diseases including arthritis but led to devastating consequences when administered to humans [4]. In contrast, anti-CD3 therapy (in a nonactivating form) has had some noted success in the translation from animal model to treatment of patients with diabetes, and is being tested in collageninduced arthritis (CIA) as well as for patients with RA.…”