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.

Transplantation is the most effective treatment for end-stage kidney disease. Yet despite major improvements in immunosuppression, long-term transplant survival rates remain poor. Excellent short-term survival rates are achievable with tacrolimus and mycophenolate mofetil (MMF) combination therapy, but this is associated with side-effects that include nephrotoxicity and neoplasia. Reducing immunosuppression is possible by incorporating alemtuzumab induction with early conversion from tacrolimus to sirolimus and combination therapy with MMF. We are currently exploring the potential benefit of combined sirolimus and MMF in the multi-centre Phase IV 3C Trial. In an earlier Phase II study we explored immunosuppression reduction through MMF cessation and sirolimus monotherapy but this strategy was abandoned due to a high rate of acute rejection when MMF was discontinued. Nevertheless, if achievable, sirolimus monotherapy would support enhanced renal function and fewer side-effects.

Regulatory T cell (Treg) therapy has shown promise in early clinical studies, and may promote conditions that allow immunosuppression reduction. We are currently leading a Phase I study in renal transplant recipients to assess the feasibility and safety of Treg therapy (the ONE Study). This dose escalation trial has demonstrated that production of clinical-grade Treg is feasible and that there are no adverse reactions following administration. There is an attractive argument for combining Treg with sirolimus monotherapy, since sirolimus may facilitate the survival of Tregs.

The study proposed is a 5-year single-arm Phase II immunosuppression minimisation trial in deceased and living donor renal transplant recipients, assessing the ability to achieve monotherapy with sirolimus with the use of adjuvant Treg therapy. The primary outcome will be the incidence of acute rejection episodes at 12 months post-transplantation. Results will be compared with matched controls from the 3C Trial.

This study has been designed to have a direct impact on the treatment of human disease.

1. Patients receiving kidney transplants: In accordance with the Declaration of Helsinki, the participants who will be recruited into this study are from a population of patients who are to benefit from the results of the trial. Immunoregulation after transplantation using cellular therapy with Treg has the potential to reduce the immunosuppression requirements of patients after transplantation, thus reducing the harmful side effects of immunosuppression and improving transplanted organ survival and function. This has the potential to benefit over 3000 patients receiving a kidney transplant in the UK each year.

2. Other patient groups: Immune regulation has a potential role in improving outcomes in other types of transplantation. Information from this trial will help direct future studies. Immune dysfunction is responsible for the pathology in a number of diseases including autoimmune diseases. Data will therefore be useful in designing trials for other diseases including but not limited to inflammatory bowel disease, diabetes, and autoimmune arthritis.

3. Researchers working in transplantation and immune regulation: Immune regulation is a highly investigated field and this study will be helpful in producing reliable efficacy data for the first time.

4. The commercial sector: This study will provide information on larger scale manufacture of Treg products under GMP conditions over an extended period. A number of companies are exploring commercialisation opportunities for cellular therapy. This will provide some information on the feasibility of such a venture.

5. Scalability: Engineering runs will explore the possibility of automation of some of the processes involved in Treg manufacture in order to reduce future cost and improve reliability of production.

6. The UK academic power: This will be the first adequately powered study of Treg efficacy in renal transplantation. The results will be anticipated by every international group working in this field. This will contribute to the academic standing of the UK in the field of transplantation.

7. The staff working on the trial: All the staff, as well as those on the committees, will benefit from the experience and skills gained over the course of running a unique clinical trial of cellular therapy, including trial management, patient recruitment, production of Treg, and patient immunomonitoring and clinical monitoring.

8. Future work: This trial is a necessary stepping stone to a future larger Phase III study in transplantation.