What does future hold for drug trial victims?
By Linda Geddes “Cancer hits drugs tester.” “Drug trial man says he has just two years to live.” Headlines along these lines this week predicted the fate confronting six men who took part in the catastrophic trial of the drug TGN1412. Not only did the volunteers suffer adverse reactions that put them in hospital for months, four of them have now been told they are at risk of cancer and serious autoimmune disease. However, just as it is still unclear exactly why the men reacted so badly to the drug (New Scientist, 25 March, p 10), their prognosis is less certain than the headlines suggest. Lawyers acting for the ill-fated volunteers commissioned immunology expert Richard Powell of Queen’s Medical Centre in Nottingham, UK, to assess the long-term health risks they face. Powell had access to four of the volunteers three months after they were given the drug in March, and took two sets of blood samples from each, three weeks apart. These showed abnormally low levels of regulatory T-cells – the cells the experimental drug was supposed to be stimulating – putting them at high risk of developing autoimmune diseases in the future, he says. However, immunologist Arne Akbar at the Royal Free and University College Medical School in London points out that low levels of regulatory T-cells in the blood do not necessarily correlate with low levels in the rest of the body. “Immune cells are often redirected to the spleen or gut at times of trauma,” Akbar says. “From what I’ve seen of the results, you can’t say with any certainty that there has been a decrease in white blood cells.” Even if the victims do have altered levels of immune cells, it is not certain they will suffer long-term harm. No such depletion of regulatory T-cells has been seen before in adult humans. What pointers there are come from mice whose T-cells have been destroyed, and from observations of children with IPEX syndrome, who lack these cells from birth. Both suffer an aggressive, usually fatal autoimmune disease, says Alexander Rudensky at the University of Washington Medical School in Seattle. The men involved in the drug trial still possess the genes for making these cells, Rudensky adds: “Six months from now, they could start pumping out large numbers of them.” Akbar suggests that regulatory T-cells could also be regenerated by a class of immune cell called memory cells, whose levels usually rise in response to infection. Bone marrow transplants could also potentially replace missing T-cells. So what of the risk of cancer? As well as detecting low levels of regulatory T-cells, Powell discovered changes in the expression of a protein called CD3 on the surface of some T-cells, which he says could be an early indication of lymphoid cancer. The drug could have expanded a pre-malignant population of lymphocytes in the course of activating all T-cells, says Ethan Shevach, an immunologist at the US National Institute of Allergy and Infectious Diseases in Bethesda, Maryland. Akbar suggests another explanation for the changes in CD3. “Such changes have also been seen in T-cells that have been overstimulated to the point where they are no longer responsive,