New England journal report describes unique features of adverse reactions in TGN1412 trial

The healthy volunteers who took part in the clinical trial of the anti-CD28 monoclonal antibody TGN1412 had multiple organ failure similar to that seen in septic shock but with several unique features, says a report published last week by Dr Suntharalingam and his colleagues, who cared for the six men after they were transferred to the NHS (New England Journal of Medicine 2006;355:1018-28).

Within 90 minutes of receiving a single intravenous dose of TGN1412 all six volunteers had a systemic inflammatory response characterised by a rapid induction of proinflammatory cytokines and accompanied by headache, myalgia, nausea, diarrhoea, erythema, vasodilatation, and hypotension. Within 12 to 16 hours 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. The patients were given a range of treatments, including steroids.

All six patients were transferred to an intensive care unit, where they received intensive cardiopulmonary support (including dialysis), high dose methylprednisolone, and an anti-interleukin 2 receptor antagonist antibody. Two patients developed prolonged cardiovascular shock and acute respiratory distress syndrome and needed intensive organ support for eight and 16 days. One developed peripheral ischaemia in a “glove and stocking” distribution, which slowly resolved, apart from patches of necrosis on his fingers and toes.

The responses to TGN1412 were initially similar to reactions to other immunomodulatory agents, including rapid increases in concentrations of tumour necrosis factor α, then in levels of interferon γ and interleukin 6, followed by cardiovascular instability and disseminated intravascular coagulation. However, unique features then appeared, including acute early lung injury, diffuse erythema with late desquamation, neurological sequelae, and post-illness myalgias.

The authors considered that the events provide some insight into an immune mediated cytokine storm leading to multiorgan failure in the absence of infection, contamination with endotoxin, or underlying disease.

“The TGN1412 variant of the syndrome has some features setting it apart from a typical cytokine storm, most notably early acute lung injury and marked lymphopenia,” explained Nicki Panoskaltsis, honorary consultant haematologist at Northwest London Hospitals Trust. “The drug was supposed to stimulate T cells to proliferate. But we found T cells were greatly reduced within eight hours. This was a major surprise.”

This reduction overlapped with the huge cytokine release, resulting in the cytokine storm. She said that future research into the underlying process may be helpful in understanding the mechanisms behind sepsis and in providing new targets for its treatment.

All six patients provided written informed consent to the NHS for the publication of data obtained during clinical case management.