The TWO Study: A Phase II trial of regulatory T cells in renal transplantation - can we achieve sirolimus monotherapy?

Organ transplantation is a life-changing and in many cases, life-saving treatment for patients with end-stage organ disease, but all patients need life-long immunosuppression with powerful drugs to prevent rejection of the transplant. Although effective at controlling transplant rejection, immunosuppressive drugs are associated with significant side-effects and increase the risk of infection, malignancy, vascular disease and heart disease. A primary objective in transplantation medicine is to reduce the need for long-term drug treatment without reducing survival of the transplant. In the past thirty years transplant doctors and scientists have discovered transplant rejection is caused by the immune system that normally protects us from disease. We have more recently discovered that the immune system also contains populations of cells that can actually control rejection. The most important of the cells that have this ability are 'naturally-occurring regulatory T cells' or nTreg, and a large amount of evidence obtained in animal studies has shown that these cells can provide a route to long-term transplant survival without long-term drug treatment. Several research groups have shown that these cells can be isolated from human blood and grown in the laboratory. Importantly, using a special type of mouse called a 'humanised mouse', we in Oxford were the first to show that human nTreg can prevent the rejection of human transplants, which has opened up the possibility that it may be possible to use human nTreg to control rejection in transplant patients. We have followed up this work in Oxford by taking part in an EU-funded clinical trial to determine the safety and feasibility of growing such cells and administering them to a small number of kidney transplant recipients. This trial called The ONE Study, is almost complete and we have shown that cells can be grown and are safe to give to transplant recipients. The proposed study, which we are calling The TWO Study, builds upon the original trial but this time we will look to see if nTreg can actually control rejection. We will recruit 34 kidney transplant recipients over three years and each patient will receive conventional immunosuppressive drugs. However, after transplant, we will give to the patient a cellular therapy of nTreg isolated from their own blood and grown in a purpose-built cell facility at Guy's Hospital in London. Then, we will reduce the amount of drug-based immunosuppression and assess the function of the kidney transplants. In this way, we will look for evidence that these nTreg can play a role in protecting the transplants from damage. We already know that nTreg are vitally important in all of us for preventing autoimmune diseases such as diabetes and inflammatory bowel disease so we are very optimistic that these cells will have some effect. If the trial is successful, it will then be possible to think about using similar cell types in other areas such as paediatric transplants as well as heart, liver, lung and intestinal transplantation. This could have a huge benefit to transplant patients by making transplant survive for longer and potentially could reduce the costs of transplantation to the NHS.