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 if immunosuppressive drugs can be withdrawn early after transplantation (once the patient has had this new therapy).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.
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.
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.
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
Romano M
(2017)
Treg therapy in transplantation: a general overview.
in Transplant international : official journal of the European Society for Organ Transplantation
Trzonkowski P
(2015)
Hurdles in therapy with regulatory T cells.
in Science translational medicine
Whitehouse G
(2017)
IL-2 therapy restores regulatory T-cell dysfunction induced by calcineurin inhibitors.
in Proceedings of the National Academy of Sciences of the United States of America
Safinia N
(2016)
Successful expansion of functional and stable regulatory T cells for immunotherapy in liver transplantation.
in Oncotarget
Jacob J
(2021)
Spatiotemporal in vivo tracking of polyclonal human regulatory T cells (Tregs) reveals a role for innate immune cells in Treg transplant recruitment.
in Molecular therapy. Methods & clinical development
Fraser H
(2018)
A Rapamycin-Based GMP-Compatible Process for the Isolation and Expansion of Regulatory T Cells for Clinical Trials.
in Molecular therapy. Methods & clinical development
Sawitzki B
(2020)
Regulatory cell therapy in kidney transplantation (The ONE Study): a harmonised design and analysis of seven non-randomised, single-arm, phase 1/2A trials.
in Lancet (London, England)
Mason GM
(2015)
Phenotypic Complexity of the Human Regulatory T Cell Compartment Revealed by Mass Cytometry.
in Journal of immunology (Baltimore, Md. : 1950)
Scottà C
(2016)
Impact of immunosuppressive drugs on the therapeutic efficacy of ex vivo expanded human regulatory T cells.
in Haematologica
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 | Academy of Medical Sciences and Association of Physicians |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | To bring together world class speakers and leading industry experts from across European Pharma, Biotech and Academic sectors to share, discuss, collaborate and innovate. Latest scientific breakthroughs, target validation studies, innovative technologies, and new therapeutics will be discussed. |
Year(s) Of Engagement Activity | 2017 |
Description | Antigen-specific Tregs and other manipulations |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | 5th Newcastle International Therapeutic Tolerance Workshop 28th June-1st of July 2022 |
Year(s) Of Engagement Activity | 2022 |
Description | Cellular and Molecular mechanisms and new therapeutic concepts in translation |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | A 2 day symposium |
Year(s) Of Engagement Activity | 2017 |
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 | Discovery to Clinical applications of regulatory T cells in autoimmunity and transplantation; Birmingham |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Industry/Business |
Results and Impact | I was one of the speakers at this meeting |
Year(s) Of Engagement Activity | 2019 |
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 | London Immunology Group and the British Society for Immunology |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Industry/Business |
Results and Impact | Annual Symposium with debate with panel of invited speakers. |
Year(s) Of Engagement Activity | 2017 |
Description | One size does not fit all-specific challenges posed by individual donors, recipients and transplant characteristics |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Informing others about my work |
Year(s) Of Engagement Activity | 2019 |
Description | Optimising Treg therapy to establish transplantation tolerance; Melbourne Australia |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Presenting data |
Year(s) Of Engagement Activity | 2020 |
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 | Regulation of the immune response in support of hematopoietic progenitor cell and solid organ transplantation |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Industry/Business |
Results and Impact | British Society for Immunology Congress |
Year(s) Of Engagement Activity | 2017 |
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 | T Regulatory Cell-Based Therapy in Promoting Tolerance of Solid Organ Transplantation |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Divulgation of the work done in my lab in previous years published and not. Meeting of the Italian Transplantation Society, Naples 2-5 October |
Year(s) Of Engagement Activity | 2021 |
Description | Treg cell therapy: the journey from concept to clinic |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Professional Practitioners |
Results and Impact | BHF Centre Annual Symposium 17th/18th October 2022 Wellcome Collection, London |
Year(s) Of Engagement Activity | 2022 |
Description | UCB Seminar |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Industry/Business |
Results and Impact | Collaboration project |
Year(s) Of Engagement Activity | 2017 |
Description | UK Humanised Mouse Symposium |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Industry/Business |
Results and Impact | A working group |
Year(s) Of Engagement Activity | 2018 |
Description | Utilizzo delle Treg nelle malattie immunomediate |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | VIII CONGRESSO NAZIONALE GIRRCS; GRUPPO ITALIANO DI RICERCA IN REUMATOLOGIA CLINICA E SPERIMENTALE-11-13 November Palermo |
Year(s) Of Engagement Activity | 2021 |
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 |