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

Lead Research Organisation: King's College London
Department Name: Transplantation Immunology & Mucosal Bio

Abstract

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 if immunosuppressive drugs can be withdrawn early after transplantation (once the patient has had this new therapy).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.

Technical Summary

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.

Planned Impact

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.

Publications

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Canavan JB (2013) Assessment of regulatory T-cell function in forthcoming clinical trials of cell therapy. in Expert review of molecular diagnostics

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Mason GM (2015) Phenotypic Complexity of the Human Regulatory T Cell Compartment Revealed by Mass Cytometry. in Journal of immunology (Baltimore, Md. : 1950)

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Putnam AL (2013) Clinical grade manufacturing of human alloantigen-reactive regulatory T cells for use in transplantation. in American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

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Romano M (2017) Treg therapy in transplantation: a general overview. in Transplant international : official journal of the European Society for Organ Transplantation

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Safinia N (2013) Promoting transplantation tolerance; adoptive regulatory T cell therapy. in Clinical and experimental immunology

 
Title Humanised mouse model 
Description Immunodeficient mice reconstituted with human blood to study human immune responses in vivo and develop strategies to interfere with them. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact Publications and future collaborations. 
 
Description Cell therapy in liver transplant patients 
Organisation University of San Francisco
Country United States 
Sector Academic/University 
PI Contribution Comparison of cell therapy using two preparations of regulatory T cells in liver transplant patients with the same clinical therapy.
Collaborator Contribution Generation of antigen-specific Tregs using B cells as antigen presenting cells.
Impact 1 publication so far.
Start Year 2011
 
Description EU Consortium 
Organisation University Hospital Regensburg
Country Germany 
Sector Hospitals 
PI Contribution Use of regulatory Tregs for the induction of tolerance in renal transplant patients
Collaborator Contribution Use of different cell type with the aim to induce tolerance in renal transplant patients
Impact Few manuscripts submitted.
Start Year 2010
 
Title ThRIL-liver transplant patients 
Description Cell therapy in liver transplant patients. Cell product in development in the GMP facility. Financed by the MRC. 
Type Therapeutic Intervention - Cellular and gene therapies
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2013
Development Status Under active development/distribution
Impact Immunosuppressive withdraw in liver transplant patients and indefinite survival of the transplant. 
 
Title The One Study-renal transplant patient 
Description Completed the pre-clinical assessment of the product in the GMP facility. Financed by the EU. 
Type Therapeutic Intervention - Cellular and gene therapies
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2013
Development Status Under active development/distribution
Impact So far in vitro the first patient will be treated with this cell product in February 2014. 
 
Description 13th World advanced Therapies and Regenerative Medicine Congress 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact • World advanced Therapies and Regenerative Medicine Congress- Speaker (16th-18th) London- Title: Clinical 13th development of regulatory T cells (Tregs) to assist solid organ transplantation
Year(s) Of Engagement Activity 2018
 
Description Co-organiser and chair person at Humanised Mouse Symposium 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Co-organised and chaired a workshop humanised mouse symposium
Year(s) Of Engagement Activity 2017
 
Description Committee Chair Member- Cost, Galway 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Chair person and participant to discussions at COST, Galway meeting
Year(s) Of Engagement Activity 2016
 
Description Committee Member- ONE Study, Regensberg 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Participant to discussions as a member of the committee and working group
Year(s) Of Engagement Activity 2016
 
Description ELRIG Research and Innovation conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Regulatory T cell therapy in organ transplantation
Year(s) Of Engagement Activity 2017
 
Description Key note speaker at a conference- 3rd International Molecular and Immunology & Immunogenetics Congress 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk entitled: "Clinical grade manufacture of Regulatory T cells to promote Transplantation Tolerance: Challenges and Achievements."
Year(s) Of Engagement Activity 2016,2017
 
Description Key note speaker at conference- CST-CNTRP-SQT Joint scientific Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Gave a talk entitled: "The use of Tregs in Kidney Transplantation."
Year(s) Of Engagement Activity 2016
 
Description Key note speaker to conference- Club de la Transplantation- Lille, France 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Gave a talk entitled: "Immunotherapy after TH, ThRIL Trial
Year(s) Of Engagement Activity 2017
 
Description Key note speaker- Inaugural UK Regenerative Medicine Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Gave a talk entitled: " Immunological characterisation of IPS-derived cells."
Year(s) Of Engagement Activity 2016
 
Description Member of committee- TWO Study meeting 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact participant of committee and to discussions at this meeting
Year(s) Of Engagement Activity 2017
 
Description NIHR in BTRU in ODT 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact interactive workshop involving academics creating a forum to present and share ideas
Year(s) Of Engagement Activity 2017
 
Description Personally asked as a key note speaker to a conference- AFACRR Management Committee and working group- Belgrade 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Gave a talk entitled: "Clinical grade manufacture of Regulatory T Cells to promote Transplantation Tolerance: Challenges and Achievements."
Year(s) Of Engagement Activity 2016
 
Description Science Museum 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact MRC-funded event at London's Science Museum to mark the Medical Research Council's Centenary, showcasing the work of 9 London MRC Centres including the research taking place in the Immunoregulation Laboratory. A total of 1,332 visitors attended the festival over the weekend. Visitors discovered what happens after a transplant and learnt about our research, which aims to help patients return to a healthy life. This was summarized into one key message: "We can improve long term quality of life for transplant patients by using their own cells to aid recovery instead of drugs".


A total of 1,332 visitors attended the festival over the weekend.
Year(s) Of Engagement Activity 2013
URL http://www.sciencemuseum.org.uk/about_us/press_and_media/press_releases/2013/06/Life%20Game.aspx
 
Description Seminar at Institute of Hepatology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Approaching clinical transplantation tolerance: a long and winding road
Year(s) Of Engagement Activity 2018
 
Description Visit of MEP and MP 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact One MEP and one MP attended to receive information about the involvement of King's in EU funding scheme.

They will report the success of Kings in gaining EU funding at parliamentary and european levels.
Year(s) Of Engagement Activity 2013
 
Description key note speaker to conference- Instituo de Medicina Molecular- Lisbon 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Gave a talk entitled: "Approaching clinical Transplantation tolerance."
Year(s) Of Engagement Activity 2017
 
Description • Histocompatibility Conference A.I.B.T- Venice, Italy 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact • Histocompatibility Conference A.I.B.T- Venice, Italy- Speaker (9-12)-Title Regulatory T cell based therapy in promoting tolerance in solid organ transplantation
Year(s) Of Engagement Activity 2018