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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.

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

RapamycinDrug

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 cellsOther

Eligibility Criteria

Age18 Years - 80 Years

Sexall

Healthy VolunteersNo

Age GroupsAdult (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.

MeSH Terms

Conditions

Bronchiolitis Obliterans Syndrome

Interventions

Sirolimus

Condition Hierarchy (Ancestors)

Organizing PneumoniaBronchiolitis ObliteransBronchiolitisBronchitisBronchial DiseasesRespiratory Tract DiseasesLung Diseases, ObstructiveLung DiseasesGraft vs Host DiseaseImmune System Diseases

Intervention Hierarchy (Ancestors)

Macrolides

Study Design

Study Type

interventional

Phase

phase 2

Allocation

NON RANDOMIZED

Masking

NONE

Purpose

PREVENTION

Intervention Model

PARALLEL

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.

Sponsor Type

OTHER

Responsible Party

PRINCIPAL INVESTIGATOR

PI Title

MD, PhD

Study Stopped

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

Brief Summary

Registry Overview

Trial Relationships

Study Timeline

Study Start

First Submitted

First Posted

Primary Completion

Study Completion

Conditions

Keywords

Outcome Measures

Primary Outcomes (1)

Secondary Outcomes (9)

Study Arms (2)

Donor Treg infusion arm

Control

Interventions

Eligibility Criteria

Sponsors & Collaborators

Study Sites (2)

MeSH Terms

Conditions

Interventions

Condition Hierarchy (Ancestors)

Intervention Hierarchy (Ancestors)

Study Officials

Enrollment

Study Design

Study Record Dates

Source record

Locations

Brief Summary

Registry Overview

Trial Relationships

Related Scientific Literature

Study Timeline

Study Start

First Submitted

First Posted

Primary Completion

Study Completion

Conditions

Keywords

Outcome Measures

Primary Outcomes (1)

Secondary Outcomes (9)

Study Arms (2)

Donor Treg infusion arm

Control

Interventions

Eligibility Criteria

Sponsors & Collaborators

Study Sites (2)

MeSH Terms

Conditions

Interventions

Condition Hierarchy (Ancestors)

Intervention Hierarchy (Ancestors)

Study Officials

Enrollment

Study Design

Study Record Dates

Source record

Locations