Just when one thought in the 21st century that it is certainly safe to participate in the trial of a new and promising drug, something goes terribly wrong! On March 13, 2006, six healthy male volunteers at St. Mark’s Hospital experienced symptoms ranging from headache, nausea, diarrhea, to peripheral vasodilatation, hypotension, tachycardia, to adult respiratory distress syndrome and multiple organ failure, resulting from the administration of what was considered a low dose of a new monoclonal antibody, TGN1412 (1). The use of monoclonal antibodies in the treatment of diseases such as lymphoma is common place in medicine today (2). These antibodies are clones of a single parent B cell, specific to one antigen, and when, in production, they are fused to a substance of interest, they can be used to identify and purify that substance (4). They have thus been used in the treatment of various cancers and, recently, this monoclonal antibody was hoped to be promising in the treatment of leukemia and auto-immune diseases such as rheumatoid arthritis (2).
TGN1412, developed by TeGenero Immuno Therapeutics and tested initially on mice by Parexel, is one such humanized (as opposed to murine or mouse) monoclonal antibody (2). It is unique both because it is a “super-agonist” of the T cell surface receptor CD28 and because normally this trigger would require that the T cell were also attached to a co-stimulator antigen for significant response (3). For TGN1412 this is not the case and given a much greater expected immune system response, it would seem that this antibody would be geared towards patients with a suppressed immune system. Instead, it was found that TGN1412 preferentially activated regulatory T cells and a net suppression of the immune response. This was the thinking in utilizing the drug for patients with conditions like rheumatoid arthritis, where the immune system is hard at work attacking the body’s joints.
Many are calling what occurred in this first human trial with TGN1412 the result of a cytokine storm, characterized by, and evidenced in all six of the volunteers in this clinical trial, the presence of multiple inflammatory mediators in the patient’s serum (1). All six men also suffered early acute lung injury and lymphopenia, (low numbers of lymphocytes) which is not characteristic of cytokine storm (1). All six men survived after extensive treatment, complication, and stay, ranging from 30 to 45 days, in the Intensive Care Unit of the National Health Service hospital in London and an intensive inquiry into the events was immediately underway by the Medicines and Healthcare products Regulatory Agency in the United Kingdom (2). There remain questions related to the after-effects to the six volunteers, including lower than normal numbers of functioning T cells and the development of cancer in one participant (3). TeGenero maintains that all earlier animal testing produced dramatically different results with the clinical trial producing completely unexpected results. The clinical study was approved by the MHRA and according to their reports, protocols were followed, with no deficiencies identified in the manufacture and storage of TGN1412 (3). The conclusion remains that the outcome was the result of an “unpredicted biological action of the drug in humans” and much further monoclonal antibody research has been stunted in the UK (3). While certainly oftentimes the benefits outweigh the negatives of medical research, this example certainly does little to bolster the public’s confidence in placing their safety in our hands.
References:
(1) “Cytokine Storm in a Phase 1 Trial of the Anti-CD28 Monoclonal Antibody TGN1412.” The New England Journal of Medicine, Volume 355:1018-1028, September 7, 2006.
(2) “Catastrophic Immune Response may have caused drug trial horror.” New Scientist, 14:22, March 17, 2006.
(3) “TGN1412.” http://en.wikipedia.org/wiki/TGN1412, 10/2/2007.
(4) “Monoclonal antibodies.” http://en.wikipedia.org/wiki/Monoclonal_antibodies, 10/2/2007.
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4 comments:
While certainly the Serious Adverse Events that occured in this trial are very sobering and should prompt intense investigation by the makers of TGN1412 it needn't be viewed as researchers failing research participants. It appears that everything was done as it ought to have been. That is, that the researchers employed all the protections for human research participants that could be thought necessary given the state of knowledge prior to the trial.
One thing that I am always aware of is the by definition clinical research has unknown components and attendant risks. We can never conduct risk-free clinical research. If it were risk free it wouldn't be research.
As I understand it, all 6 volunteers were in the clinical trials unit at the same time, and all given the IV at the same time, too. So this could be something the inverstigators might have done better: treating one volunteer, watching and waiting, and then if it was uncomplicated, treating the others. Might they have been trying to save a little money? Overconfident that nothing would go wrong?
This is truly a disappointment, since it appears that the researchers were on the right track with attempting to upregulate the regulatory T-cells, since the predomination of effector T-cells over regulatory T-cells escalates the damaging inflammatory process in IBD and other disorders. Instead, it seems that this drug targeted both types of T-cells, resulting in an overall severe T-cell depletion. It seems that drug specificity might still be the issue here.
I don't know if I agree with the "one at a time" theory put out in Dr. Cohen's response. Wouldn't this cause perfectly good drugs to be ruled out because you picked that 1/10,000 person who would have a bad reaction to the drug. Do we want to risk the loss of years of research due to one persons eronious reaction to the drug. Sure, in this case, the other 5 would have been saved the pain. But, would we also have rejected lifesaving therapies (in other studies)to protect these five. There are relatively few examples of this kind of blanket adverse reaction in modern scientific research, so, let's not overreact. The system works pretty well as it is.
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