There has been a great deal of media coverage regarding the disastrous phase I safety trial of TGN1412, a candidate immune-based therapy for the treatment of autoimmune disorders and chronic lymphocytic leukemia. The Black Triangle blog in the UK has followed the story and posted excellent links to many articles, including recent updates regarding the interim report from the MHRA (the UK equivalent of the US Food & Drug Administration).
In a nutshell, TGN1412 is a monoclonal antibody (essentially a modified version of an antibody derived from a mouse) that was designed to specifically target a molecule called CD28 that is expressed on many T cells. Triggering CD28 activates T cells, meaning they begin a program of multiple divisions (generating many new T cells) and release potent immune system proteins called cytokines. Based on animal studies, the idea was that TGN1412 would not cause a damaging amount of T cell activation because it seemed to preferentially activate an unusual (and, to some immunologists, controversial) subset of T cells that have been dubbed "regulatory" T cells. In the test tube and some animal models, regulatory T cells act to suppress T cell activation, potentially limiting damaging T cell responses in situations such as autoimmune disease (when T cells can attack healthy body tissues and cause illness). There is a nice discussion of TGN1412's mechanism of action on the Hublog.
As the media reports vividly and horrifyingly describe, no such effect was evident when the first trial began in humans back in March. Instead, TGN1412 appears to have led to massive, systemic T cell activation that caused all six volunteers that received the drug to be hospitalized in intensive care. Although thankfully there are now indications that they are on the road to recovery, the most severely affected individual is likely to lose fingers and toes due to damage akin to that seen in frostbite. It is perhaps not coincidental that this individual was also the youngest study participant, since the most consistent expression of CD28 is on naive T cells and levels of naive T cells are highest in childhood and decline with age. Hopefully some lessons will be learnt from this trial; most glaringly, the almost simultaneous dosing of the participants with an antibody with potentially potent T cell activating properties was a terrible idea. A pause of just an hour or two would have made a huge difference. The company that makes TGN1412, TeGenero, has stated that no causes for concern emerged in animal studies, but this does not address the fact that they could have sought input from more immunologists with experience researching CD28. Many such immunologists, unaware of the trial at the time it was getting underway, have expressed shock that the study was not conducted more carefully given what is known about the molecule.
The study also raises many questions about the putative role of regulatory T cells in humans. If such cells indeed exist and were activated by TGN1412, they were clearly incapable of suppressing the overwhelming immune activation that occurred (which could be due to either insufficient numbers or limited potency). But it is also possible that the current conception of regulatory T cells is overly simplistic and overly reliant on in vitro findings. The immunologist Brigitta Stockinger has long urged caution when it comes to interpreting data on regulatory T cells, arguing that much of what appears to be suppressive activity in vivo can be explained by T cell homeostasis, wherein T cells endowed with good proliferative capacity are able to essentially "crowd out" potentially harmful self-reactive T cells. Although it's several years old now, the commentary published by Stockinger and colleagues in Nature Immunology may turn out to have been prescient. Since researchers continue to investigate whether regulatory T cells can be beneficially manipulated in diseases like HIV and cancer, a better understanding of how these cells work in humans is critical. To some extent, the TGN1412 story is a cautionary tale of how seemingly arcane debates among immunologists can crash into the real world of human drug trials with tragic consequences.