ThRIL;A 'first-in-human' study, evaluating the safety, tolerability with an investigation into the efficacy of Tregs in liver transplant recipients

Liver transplantation is a successful treatment for patients with severe liver disease. Despite this, the majority of patients are maintained on immunosuppressants (drugs that dampen down the immune system) life long with associated side effects, affecting the quality of life of the patient and the long term outcome. The aims of this study are, therefore, to i. determine if a new cell based therapy is safe and well tolerated in liver transplantation patients and ii. if immunosuppressive drugs can be withdrawn early after transplantation (once the patient has had this new therapy).
The general aim of this therapy is to allow the withdrawal of immunosuppressants in patients receiving a liver transplant, with the ultimate goal of complete withdrawal of immunosuppressants lifelong.

Interestingly, populations of immune cells in the recipient, called regulatory T cells, have been shown to regulate the patient's immune system and prevent against organ rejection. Our research is targeting at developing new treatments that involve increasing the number of these cells in the recipient. We will a. isolate these cells from the recipient at the time of transplant, expand them numerically and ensure they are stable in culture and then inject them back into the patient at 3 months after transplantation. Patients will be closely monitored at King's College Hospital (expertese in hepatology and liver transplantation) with assessment of safety of the injected cells.

The study's main focus is the assessment of safety of the cell based therapy and providing evidence which will support a larger study looking at the effectiveness of the therapy in the liver transplant recipients.

Liver transplantation(LT) is a successful treatment for end-stage liver disease. Despite this long-term survival remains suboptimal because of the morbidity and mortality associated with long-term use of immunosuppression(IS). However IS weaning early post LT has been largely unsuccessful, supporting the need for active tolerance induction strategies.

CD4+CD25+FOXP3+cells(Tregs) play an important role in immunoregulation. We have shown that in vitro expanded murine and human Tregs promotes transplantation tolerance in animal models. The safety of these cells has been already demonstrated in phase I trials of bone marrow transplantation. ThRIL will be the first combined phase I/II clinical trial of Treg therapy in solid organ transplantation.

The protocol we have devised involves the isolation and expansion of Tregs, harvested at time of transplantation from blood of LT recipients. We have expertise in expansion of large numbers of functionally suppressive and stable Tregs from healthy controls at GMP standard. We have obtained similar results using blood from LT recipients.

ThRIL is an open label, randomised, controlled, parallel group, single ascending dose study, investigating the safety and tolerability of Treg immunotherapy with a cohort expansion to investigate for a signal of efficacy. Patients will be treated with ATG at time of transplantation, and started on Tacrolimus. Rapamycin will be started at 2 months, with an infusion of Tregs at 3 months post transplantation. Two dose levels of Tregs will be assessed, a low (1.0x10^6cells/kg) and high (4.5x10^6cells/kg) dose (3 active:1 control). The chosen doses are comparable to what has been safely used in published clinical trials (3x10^6cells/kg). The cohort of patients receiving the dose which is safe and well tolerated will be expanded to investigate an efficacy signal, providing the evidence required to take the development of Treg immunotherapy towards a larger Phase II/III study.

In accordance to ethical principals as set out in the World Medical Association Declaration of Helsinki, the participants in this study are from a population of patients who stand to benefit from the results of the research.

Treg immunotherapy has the potential to be of great benefit to patients with liver transplantation, as this would allow the reduction, if not cessation, of immuno-suppressive therapy that has numerous side effects and their consequent morbidities.

This study will provide the safety, tolerability and some efficacy information for Treg immunotherapy in patients who have had a liver transplantation. In particular liver transplantation patients whose MELD score at transplantation is less than 25 at the time of transplantation (excluding patients with HCV, autoimmune liver disease). The majority of these patients will be undergoing liver transplantation for cirrhosis secondary to alcohol and/or for HCC in the setting of Hepatitis B, alcoholic or cryptogenic cirrhosis.

If it is shown to be safe and well tolerated this would allow the progression to trials that investigate efficacy of Treg immunotherapy and potentially lead to a new modality of treatment for these patients, which has less side effects than conventional immuno-suppressive therapy.

If Treg immunotherapy is able to generate tolerance in the setting of liver transplantation, the solution will not only benefit the patients, that will receive the Treg immunotherapy, but also those not suitable for nTreg immunotherapy but on the transplant waiting list. If Treg therapy is successful at inducing indefinite graft survival, immunosuppression can be withdrawn from patients receiving the therapy and patients ill no longer suffer the associated side effects of the immuno-suppressive regimen. Furthermore, this will also lead to less re-transplant and more organ available to be used for other patients on the transplant waiting list.

Furthermore if Treg immunotherapy is found to be efficacious in liver transplantation patients, this would be an indication that it might be of use in other solid organ transplantation, such as kidney. Therefore providing indirect evidence of a potential new modality of treatment in other solid organ transplantation.

Moreover this study will have a substantive impact in the field of transplantation, if successful it will pave the way towards a larger combined Phase II/III study and will inform other tolerance inducing protocols. However if unsuccessful it will be informative in aiding the design of future tolerance inducing strategies.