Plain English Summary
Background and study aims
The body’s immune system is essential in fighting off infection and preventing cancers from forming. However, for kidney transplant patients, if left unchecked, the immune system will reject the transplanted kidney causing it to fail. Patients who have a kidney transplant must take daily medications to limit the immune system and prevent rejection. These medicines are very effective but long term they can have serious and life-threatening side-effects including an increased risk of infection, cancer, heart disease and diabetes. Medication side-effects can actually contribute to kidney transplants failing and reduce the life expectancy of kidney transplant patients. Finding new ways to prevent transplant rejection will reduce the amount of medication transplant patients require. This might help kidney transplants and transplant patients survive for longer. Regulatory T cells (Treg) are a group of naturally occurring white blood cells. In healthy individuals these cells help control the body’s immune system and prevent excessive immune responses that might actually be harmful. This study aims to use these Treg cells to prevent the immune response that leads to transplant rejection. Treg cells will be taken from the blood of kidney transplant patients. The number of Treg cells will be increased in a laboratory and given back to the same patient through a drip into the bloodstream. It is hoped that the increased number of Treg cells will help to prevent the immune system from rejecting a kidney transplant. If successful, this treatment will reduce the medications that kidney transplant patients need to take and with it reduce the serious side-effects listed above.
Who can participate?
Patients over the age of 18 who are due to have a kidney transplant from a living donor (typically a relative or friend who is willing to give the patient one of their kidneys)
What does the study involve?
Participants are randomly allocated to one of two groups. Patients in the control group receive normal care before and after their kidney transplant. They are asked to take the usual medications used to prevent transplant rejection. Patients in the treatment group give blood before their kidney transplant to find Treg cells in the blood and increase their number in the laboratory. 6 months after kidney transplant these patients are given an increased number of Treg cells back into the bloodstream through a drip. After the cells are given the aim is to reduce the number and dose of medications these patients are taking. All patients are asked to have a biopsy (sample) of their kidney transplant 9 months after the transplant operation to look for any signs of rejection or kidney damage. Biopsy results alongside routine and experimental blood tests are used to assess how well the Treg cell treatment is working and its effects on the immune system.
What are the possible benefits and risks of participating?
Participants may not benefit directly from this study. However, if cell therapy is successful, less medications will be needed to prevent rejection, reducing drug side-effects. The aim is to use the information provided by this study to guide future cell therapy treatments and improve the lives of patients having kidney transplants. Analysis of samples from participants in this study may allow the development of tests to predict which kidney transplant patients are at risk of rejection or medication side-effects so that doctors can intervene at an early stage. Participants need to donate blood throughout the study. There is a small risk of discomfort or bruising when the blood samples are taken and a very small risk of feeling faint or a simple faint occurring when taking this sample. For those patients who receive Treg cell infusions, there may be a reduction in the blood count after initial blood donation but this should return to normal within 4 weeks. The risk of Treg cell administration is less than a blood transfusion. There is a very small risk of an allergic reaction. Common symptoms include; a red, itchy skin rash; swelling of the hands, feet, ankles, and legs, dizziness and headaches. Any longer term risks of infusing Treg cells are unknown but early studies have shown this to be safe and have not identified any concerns to date. There is a low risk (<1%) of significant bleeding complications after a kidney transplant biopsy.
Where is the study run from?
Oxford Transplant Centre, Churchill Hospital, Oxford (UK)
When is the study starting and how long is it expected to run for?
September 2016 to July 2026
Who is funding the study?
Medical Research Council (MRC)
Who is the main contact?
1. Dr Paul Harden
2. Dr Fadi Issa
Dr Matthew Brook
Nuffield Department of Surgical Sciences
University of Oxford
John Radcliffe Hospital
Dr Fadi Issa
Nuffield Department of Surgical Sciences
University of Oxford
John Radcliffe Hospital
The TWO study: Transplantation Without Over-immunosuppression - a Phase IIb trial of regulatory T cells in renal transplantation
TWO Study: Treg Cell Therapy Trial v1.0
Patients receiving solid organ transplants must be maintained on drugs that suppress the immune system in order to prevent the immune system from rejecting the transplant. These medicines are highly efficacious, with one-year kidney transplant survival in the UK being > 95%. However, long-term outcomes are significantly limited by the serious and life-threatening side-effects of immunosuppressive drugs, which include enhanced rates of infection, malignancy and cardiovascular and metabolic disease such as heart attacks and diabetes. Long-term maintenance on immunosuppressive drugs together with treatment of the unwanted side effects is a huge burden not only for the patient but also for the healthcare system, in terms of resource allocation and expenditure. Thus a major goal of future transplantation is to find ways to reduce the amount of immunosuppressive drugs used, whilst protecting the the kidney transplant from immune system damage.
Regulatory T cells (Treg) are a subset of white blood cells that act to prevent autoimmune disease and to limit an ‘overshoot’ of normal immune responses to viruses. A promising approach is to use the regulatory ability of these cells to suppress the immune response causing rejection of the transplanted kidney. Having proven the safety and feasibility of Treg-based immunotherapy in the ONE Study (trial identifier: ONETreg1; ClinicalTrials.gov number: NCT02129881; EudraCT number: 2013-002099-42, co-sponsored by King’s College London and Guy’s and St Thomas’ NHS Foundation Trust, REC number 13/SC/0568); the TWO Study aims to demonstrate the efficacy of this treatment, with the goal of allowing reduction of immunosuppression to a single drug by 6-months post-transplantation.
Health Research Authority, South Central, Oxford A research ethics committee - approval pending
Randomised; Interventional; Design type: Treatment, Cellular, Immunotherapy
Primary study design
Secondary study design
Randomised controlled trial
Patient information sheet
Not available in web format, please use the contact details to request a patient information sheet
Specialty: Renal disorders, Primary sub-specialty: Renal disorders; UKCRC code/ Disease: Renal and Urogenital/ Other disorders of kidney and ureter
Participating living donor renal transplant recipients will be randomised on a 1:1 basis to either Treg cell infusion (intervention) or standard care (control). In the intervention arm 5 to 10xE6/kg autologous Treg cells (TR001) will be infused intravenously at 6 months post transplant. Patients receiving cell therapy will subsequently be maintained on low dose tacrolimus monotherapy. Patients in the control arm will receive standard maintenance immunosuppression consisting of tacrolimus and mycophenolate mofetil.
Primary outcome measures
Incidence of biopsy-confirmed acute rejection (BCAR) in the 6 to 18-month period post-transplantation. A 9 month protocol biopsy will be performed in all participants including the control arm to allow a histological comparison of the impact of Treg therapy in the treatment arm. Any other biopsies performed during follow-up will be at the discretion of the responsible clinician and will be deemed ‘for-cause’. All biopsies will be reviewed and reported by the study pathologist using the Banff criteria.
Secondary outcome measures
Measured over 18 months and again at 5 years post-transplantation:
1. Time to first biopsy-confirmed acute rejection episode will be measured in days
2. Severity of acute rejection episodes will be based on histological scoring according to the Banff criteria and degree of renal recovery following treatment
3. Incidence of graft loss due to rejection
4. Renal transplant function will be assessed by estimated glomerular filtration rate (eFGR) using the CKD-EPI equation
5. Patient survival
6. Incidence of adverse events to include:
6.1. Incidence of drug-related adverse events
6.2. Incidence of identified serious and/or opportunistic infections (including CMV, EBV and polyoma (BK) virus)
6.3. Incidence of neoplasia
6.4. Incidence of autoimmune disorders
6.5. Incidence of anaemia, cytopaenia and biochemical disturbances unrelated to kidney function
7. Total immunosuppression burden at 18 months post-transplantation will be defined by number of immunosuppressive agents, dose of immunosuppressive agents and serum tacrolimus level (measured in nanograms per ml). This will include assessment of the proportion of patients taking tacrolimus monotherapy
8. Chronic allograft nephropathy on renal transplant biopsies will be measured by the degree of interstitial fibrosis and tubular atrophy (IF/TA) as assessed by the study pathologist on protocol biopsies taken at 9 months post-transplant
9. Exploratory outcomes will be assessed at 2 weeks pre-transplant and 4, 12, 24, 30, 38, 44, 52 and 78 weeks post-transplant. Patients in the treatment arm will also be analysed at 22, 26, 27 and 28 weeks post-transplant. Outcomes will include:
9.1. Cell phenotype analysis of peripheral blood
9.2. T cell functional assays against donor and third-party antigens
9.3. Serum cytokine analysis and third-party antigen analysis
9.4. Gene expression and RNA sequencing analysis to include Treg-Specific demethylated region and T-cell receptor sequencing
Overall trial start date
Overall trial end date
Participant inclusion criteria
Kidney recipient inclusion criteria:
1. Chronic renal insufficiency necessitating kidney transplantation and approved to receive a kidney allograft from a living donor
2. Willing and able to give informed consent for participation in the trial
3. Aged 18 years or above
4. In the Investigator’s opinion, is able and willing to comply with all trial requirements
5. Able to commence the immunosuppressive regimen at the protocol-specified time point
6. Female participants of child bearing potential and male participants whose partner is of childbearing potential must be willing to ensure that they or their partner use highly effective contraception during the trial
7. Willing to allow his or her General Practitioner and consultant, if appropriate, to be notified of participation in the trial
Kidney donor inclusion criteria:
1. Eligible for live kidney donation
2. Aged at least 18 years
3. ABO blood group compatible with the organ recipient
4. Willing to provide personal, medical and biological data for the trial analysis
5. Willing and able to provide a blood sample for the immune monitoring assays
6. Willing and able to give informed consent for participation in the trial
Target number of participants
Planned Sample Size: 136; UK Sample Size: 136
Participant exclusion criteria
Kidney recipient exclusion criteria:
1. Patient has previously received any tissue or organ transplant
2. Known contraindication to the protocol-specified treatments or medications
3. ABO blood group incompatible with donor
4. Calculated reaction frequency (CRF) of >40% within 6 months prior to transplant
5. Previous treatment with any desensitisation procedure (with or without IVIg)
6. Concomitant malignancy or history of malignancy within 5 years prior to planned study entry (excluding successfully treated non-metastatic basal or squamous cell carcinomas of the skin)
7. Serologically positive for anti-HIV-1/2 Ab, HbsAg, anti-HBcAb, antiHCV Ab, anti-HTLV-1/2 Ab or syphilis (treponema palladium)
8. Significant liver disease, defined as persistently elevated ALT levels >3 x upper limit of normal range (ULN)
9. Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant’s ability to participate in the trial
10. Participation in another clinical trial during the study or within 28 days prior to planned study entry
11. Female participant who is pregnant, lactating or planning pregnancy during the course of the trial
12. Psychological, familial, sociological, or geographical factors potentially hampering compliance with the study protocol and follow-up visit schedule
13. Any form of substance abuse, psychiatric disorder, or other condition that, in the opinion of the investigator, may invalidate communication with the investigator and/or designated personnel
Kidney donor exclusion criteria:
1. Exposure to any investigational agents at the time of kidney donation, or within 28 days prior to kidney donation
2. Any form of substance abuse, psychiatric disorder, or other condition that, in the opinion of the Investigator, may invalidate communication with the Investigator designated personnel
3. Is a paired exchange donor
4. Is an altruistic donor
Recruitment start date
Recruitment end date
Countries of recruitment
Trial participating centre
Oxford Transplant Centre
Churchill Hospital Old Road Headington
Medical Research Council; Grant Codes: MR/N027930/1
Funding Body Type
Funding Body Subtype
Results and Publications
Publication and dissemination plan
The results from the TWO Study will be published in peer-reviewed scientific/medical journals and presented at scientific/clinical symposia and congresses.
IPD sharing statement
The data sharing plans for the current study are unknown and will be made available at a later date.
Intention to publish date
Participant level data
To be made available at a later date
Results - basic reporting