Donor Regulatory T Cells Infusion in Patients With Chronic Graft-versus-host Disease (GVHD)

NCT01903473 | Terminated Phase 2

• 1 other identifier: TJB1117
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 2

Brief Summary

The immune system has offensive and defensive capacities. In bone marrow transplantation, offensive cells in the donor grafts may attack host's organs, leading to a complication known as Graft versus Host Disease (GVDH). At present, patients receive steroid treatment to combat this tricky situation. Nevertheless, some patients do not respond to this therapy. Recently, it has been shown that immune system cells having defensive capacities can help in preventing the occurrence of a GVDH. This study aims to evaluate if these protective cells together with a non-standard immunosuppressor can improve the clinical condition and suppress the activity of the offensive cells in the graft.

Conditions

Chronic Graft-Versus-Host Disease; Acute Graft-Versus-Host Disease; Steroid Refractory Graft-Versus-Host Disease

Keywords

Allogeneic hematopoietic cell transplantation; GVHD; Regulatory T cells; Steroid refractory; Rapamycin; Immune recovery; Infusion; HLA-identical sibling; HLA-matched unrelated donor; IL-2

Outcome Measures

Primary Outcomes (1)

• To assess the safety of a combination of rapa administration, donor Treg infusion and low-dose IL-2 in patients with steroid-refractory chronic GVHD.

  To assess the immunological changes (including Treg number/phenotype) occurring after donor Treg infusion and rapamycin administration. Treg will be defined as CD4+CD25+FoxP3+ T cells. Treg phenotype will include CD127, CD45RA, CCR4, CCR7 and KI67. Treg will also be assessed by an analysis of the methylation status of CpG dinucleotides located in a conserved region of FoxP3 intron 1.

  12 months after inclusion

Secondary Outcomes (9)

• To assess the efficiency of Treg selection with the Clinimacs procedure.

  1 month after Treg selection

• To assess the response rate of chronic GVHD (defined using the NIH criteria as defined by Lee et al.41) to donor Treg infusion + low-dose IL-2 + rapa at 1, 2, 3, 6 and 12 months after rapa onset.

  at 1, 2, 3, 6 and 12 months after rapamycin onset

• To compare response rate of chronic GVHD in patients given Treg infusion + low-dose IL-2 + rapa (DTI arm) versus in those given rapa without Treg infusion (control arm; vide infra).

  at 1, 2, 3, 6 and 12 months after rapamycin onset

• To compare the incidence of viral, bacterial, fungal and parasital infection in patients given Treg infusion + low-dose IL-2 + rapa (DTI arm) versus in those given rapa without Treg infusion (control arm; vide infra).

  over the 12 months of the trial

• To compare overall relapse incidence in patients given Treg infusion + low-dose IL-2 + rapa (DTI arm) versus in those given rapa without Treg infusion (control arm; vide infra).

  1 year after rapamycin onset

Study Arms (2)

Donor Treg infusion arm

EXPERIMENTAL

Condition:Patients treated with steroids for a chronic GVHD occurring after allogeneic cell transplantation. Patients who have refractory chronic GVHD will be eligible. Patients in this arm will be first treated with Rapamycin while CNI (if any) will be discontinued and infused whith Treg cells 60-90 days after.

Other: T regulatory cells

Control

ACTIVE COMPARATOR

Condition:Patients treated with steroids for a chronic GVHD occurring after allogeneic cell transplantation. Patients who have refractory chronic GVHD will be eligible. Patients in this arm will be treated with Rapamycin which is an alternative immunosupression strategy allowing to fight againt GVHD and CNI (if any) will be discontinued.

Drug: Rapamycin

Interventions

Rapamycin DRUG

Rapamycin will be started within 2 weeks after inclusion. Rapamycin will be given at 2-6 mg loading dose for one day, followed by approximately 1 mg daily to achieve a target trough level of 5 to 10 ng/mL. The frequency of trough level measurements will be done according to the investigator choice; Rapamycin may be discontinued in case of resolution of chronic GVHD ≥ 3 months or in case of un-manageable side effects or progression of chronic GVHD. Calcineurin inhibitor discontinuation within 2 weeks after rapamycin initiation. No other modification of immunosuppressive drugs and in particular no decrease in the dose of steroids (unless necessary for side effects).

Also known as: Sirolimus

Control

T regulatory cells OTHER

One infusion of ≥ 0.5 x10E6 T reg cells/kg recipient at 60-90 days after first day of rapamycin administration and after calcineurin inhibitor discontinuation. The infusion procedure will take one hour. Low-dose Il-2 (1x106 IU/day) will be started the day of DTI and will be continued for a period of 2months in order to expand infused donor Tregs.

Also known as: T suppressor cells, Treg cells

Donor Treg infusion arm

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

1\. Patient criteria : Donor Treg infusion (DTI) and control arms. * Signed informed consent. * Grafts from HLA-identical siblings or HLA-matched unrelated donor (1 of 10 HLA-mismatch is allowed). * ≥ 18 years of age. * Steroid-refractory or steroid-resistant chronic GVHD defined as: * development of 1 or more new sites of disease while being treated for chronic GVHD, * progression of existing sites of disease while receiving treatment for chronic GVHD, * failure to improve despite at least 1 month of standard treatment for chronic GVHD. or severe chronic GVHD and contra-indication to the use of steroids and at least failed one prior line of treatment. * Severe chronic GVHD according to NIH definition. * No prior failure of rapamycine as treatment for chronic GVHD * No contra-indication to the use of rapamycin. * No alemtuzumab administration in the last 6 months. * GFR \> 25 mL/min. * No HIV seropositivity. * No fungal infection with radiological progression after treatment with amphotericine B or active azoles for \> 1 month. * No other uncontrolled infection. * No progression of the hematological malignancy. * Karnofsky performance score ≥ 70%. * DLCO \> 35% and no need of supplemental continuous oxygen. * No active post-transplant microangiopathy and no previous microangiopathy while on rapamycine. * No uncontrolled hypertriglyceridemia. 2 Donor criteria : DTI arm only. * Donor ≥ 18 years of age. * Written informed consent to perform apheresis from the donor (all patients) and permission from the third party donor registry (in case of unrelated donor). * Standard criteria for leukapheresis and DLI following complete work-up according to standard procedures.

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• University of Liege: lead

Study Sites (2)

Katholieke Universiteit Leuven

Leuven, Vlaams-Brabant, 3000, Belgium

Location

University Hospital Liège

Liège, 4000, Belgium

Location

MeSH Terms

Conditions

Bronchiolitis Obliterans Syndrome

Interventions

Sirolimus

Condition Hierarchy (Ancestors)

Organizing Pneumonia; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Graft vs Host Disease; Immune System Diseases

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Study Officials

• Frédéric Baron, MD, PhD

  CHU-ULg

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD

Model Details: DTI arm * 10 patients will be included in the DTI (Treg) + IL-2 arm. * Treg infusion + rapa+ IL-2 will be considered safe if no patients die because of Treg infusion, less than 4 patients die of nonrelapse causes the first 90 days after inclusion in the study, and less than 4 patients experience chronic GVHD progression within the first 90 days after inclusion. * The study will be closed at any time a fourth patient experience nonrelapse mortality within 90 days of inclusion or experience GVHD progression within 90 days of inclusion. Control arm * Up to 25 patients will be included in the control arm. * Rapa administration will be considered safe if less than 4/10, 8/20 or 10/25 patients die of nonrelapse causes the first 90 days after inclusion in the study and less than 4/10, 8/20 or 10/25 patients experienced chronic GVHD progression within the first 90 days after inclusion. * This arm of the study will be closed at any time the above criteria can no longer be met.

Study Record Dates

• First Submitted: July 10, 2013
• First Posted: July 19, 2013
• Study Start: July 1, 2013
• Primary Completion: September 12, 2022
• Study Completion: September 12, 2022
• Last Updated: September 22, 2022

Record last verified: 2022-09

Locations

BE (2)