Treatment of Refractory cGVHD by Donor-derived Treg Cell Injection Combined With Recombinant Human Interleukin-2

Clinical Study to Evaluate the Safety and Efficacy of Donor-derived Treg Cell Injection Combined With Recombinant Human Interleukin-2 in the Treatment of Refractory cGVHD Subjects

This study is a single-arm, open-label, dose-escalation clinical trial to evaluate the safety, tolerability, changes and persistence of peripheral blood Treg cells, and pharmacodynamic characteristics of donor-derived Treg cell injection combined with recombinant human interleukin-2 in treating subjects with refractory cGVHD，and to preliminarily observe the efficacy of the study drugs in subjects with refractory cGVHD.

Study Overview

• Status: Recruiting
• Conditions: cGVHD
• Intervention / Treatment: Biological: Donor-derived Treg cell injection combined with interleukin 2

Detailed Description

This study is a single-arm, open-label, dose-escalation clinical trial to evaluate the safety, tolerability, changes and persistence of peripheral blood Treg cells, and pharmacodynamic characteristics of donor-derived Treg cell injection combined with recombinant human interleukin-2 in treating subjects with refractory cGVHD，and to preliminarily observe the efficacy of the study drugs in subjects with refractory cGVHD.In this study, rapid titration of the first dose group and a "3+3" rule design were used for dose escalation to minimize patient exposure to ineffective doses while minimizing the occurrence of risk.Three dose groups were set up: 1×10^6 Treg cells /kg dose group, 5.0×10^6 Treg cells /kg dose group and 10×10^6Treg cells /kg dose group.One infusion per dose group.

• Study Type: Interventional
• Enrollment (Estimated): 18
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: xianmin song, Doctor; Phone Number: 18616705298; Email: shongxm@139.com

Study Locations

• China
  • Shanghai, China, 200080
    • Recruiting
    • Shanghai General Hospital
    • Contact: xianmin song, Doctor; Phone Number: 18616705298; Email: shongxm@139.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Subjects aged 18-70 years old, male or female;
• The subjects had received allo-HSCT, including cord blood transplantation;

• TSubjects with moderate/severe cGVHD that meets the NIH diagnostic criteria (031) for steroid dependence or resistance, meeting one of the following:

  1. There was no improvement in cGVHD in initial treatment patients treated with > 0.5mg/kg/ day or 1 mg/kg/ day every other day for at least 4 weeks;
  2. Steroid dependence: predtisone dose > 0.25 mg/kg/d or > 0.5 mg/kg/qod cGVHD relapse or progression; cGVHD recurred after two attempts to gradually reduce prednisone dose at an interval of at least 8 weeks, with prednisone dose > 0.25 mg/kg/day to be maintained.
• Prednisone dose > 0.25 mg/kg/d for more than 4 weeks; Subjects must maintain a stable prednisone dose for 4 weeks prior to the first Treg cell infusion and not increase or discontinue other immunosuppressants (including cyclosporine, tacrolimus, and sirolimus);
• The ECOG score of the subjects was 0-2;
• the expected survival of the subject is more than 3 months;

• Liver, kidney, heart and lung function meet the following requirements (except liver and kidney dysfunction caused by cGVHD) :

  1. Creatinine clearance (calculated by Cockcroft Gault formula) ≥60 mL/min;
  2. Cardiac ejection fraction greater than 50%, no clinically significant electrocardiogram changes;
  3. Forced expiratory volume (FEV1) in the first second of baseline lung function ≥50%, and FEV1 decline caused by cGVHD could be included;
  4. Total bilirubin ≤2.0ULN; ALT and AST≤3ULN, ALT and AST increases caused by cGVHD could be included in the group.
• Hematopoietic function: neutrophils >1×10^9/L, platelets >25×10^9/L; Supportive treatments such as platelet transfusion and other cytokines are excluded.
• The subject or the subject's guardian can understand this experiment and has signed the informed consent.
• Donor age 14-70 years old, male or female;
• The ECOG score of the donor is 0-1;
• The donor must be a hematopoietic stem cell donor who underwent allo-HSCT prior to the subject;
• Female donors must test negative for serum or urine beta-human chorionic gonadotropin (HCG) within 3 weeks of blood collection;
• The donor can establish the necessary venous access for collection, without the contraindication of white blood cell collection; If peripheral venous leukocyte collection is insufficient, be willing to insert a central catheter; (15) The donor agrees to donate and signs a consent form.

Exclusion Criteria:

• Subjects had a recurrence of primary malignant disease before receiving Treg treatment;
• The subjects had persistent, recurrent or delayed aGVHD;
• Continuous use of prednisone >1 mg/kg/day is required;
• The severity of the subject's cGVHD cannot be assessed by physical examination or laboratory examination;
• overlap syndrome；
• The subjects had major organ (cardio-cerebrovascular, pulmonary) dysfunction not caused by cGVHD, and had previous (within 3 months) gastrointestinal active bleeding; History of uncontrolled hypertension or hypertensive crisis or hypertensive encephalopathy, history or evidence of significant cardiovascular and cerebrovascular risk, including any of the following conditions: congestive heart failure, unstable angina pectoris, clinically significant arrhythmias (e.g., ventricular fibrillation, ventricular tachycardia, etc.); History of arterial thrombosis (such as stroke, transient ischemic attack) within the last 3 months; A history of symptomatic deep vein thrombosis, pulmonary embolism, or coronary angiogenesis, defibrillation, or any clinically relevant complication or disease within the last 6 months that could pose a risk to subject safety or interfere with study evaluation, procedure, or completion;
• The subjects are hemodialysis patients;
• The subject or donor has an active, uncontrolled bacterial, viral, or fungal infection that requires treatment；
• The subjects are pregnant or lactating women; Subjects who plan to become pregnant during the post-transfusion study, or within 1 year of completion or withdrawal from the study;
• Participants who had received IL-2 therapy or drug therapy targeting IL-2 within 4 weeks prior to enrollment；
• Received DLI treatment within 100 days before enrollment;
• Received CAR-T or similar engineered cell therapy within 100 days prior to enrollment;
• Had received new cGVHD therapies (including imatinib, BTK inhibitors, rituximab and other immunosuppressants) within 4 weeks before enrollment after transplantation;
• Have a history of microvascular diseases such as TMA, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, etc；
• Subjects with poor IL-2 treatment compliance;
• Participants who participated in other CGVHD-related clinical studies within 4 weeks prior to enrollment;
• Subjects who are known to be allergic to any component of Treg cell injection;
• Any situation that the investigator believes would compromise the safety of the subject or interfere with the study purpose, or that the investigator considers it inappropriate to participate in the study;
• Having a medical condition that affects the signing of written informed consent or the inability to follow study procedures; Unwilling or unable to comply with research requirements;
• The donor was a pregnant woman.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Donor-derived Treg cell injection combined with interleukin 2; Donor-derived Treg cell injection, injections, The first dose was 1.0× 10^6Treg cells /kg, the second dose was 5.0×10^6Treg cells /kg, and the third dose was 10.0×10^6Treg cells /kg,single-dose. Interleukin 2,1 million IU/m2/d,last 13 weeks.	Biological: Donor-derived Treg cell injection combined with interleukin 2; Subjects received Treg cell infusion at day D0, and interleukin 2 was administered subcutaneously daily from 1 week before to 12 weeks after infusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate the incidence of DLT in patients with refractory cGVHD treated with donor-derived Treg cell injection combined with low dose rhIL-2 injection	To evaluate the incidence of DLT in patients with refractory cGVHD treated with donor-derived Treg cell injection combined with low dose rhIL-2 injection。 DLT is defined as any of the following conditions related to the study drug within 28 days after the subject's infusion of Treg cell injection, despite treatment: Grade 4 or 5 cytokine release syndrome caused by Treg cell injection treatment;; Grade 3 cytokine syndrome caused by Treg cell injection treatment and no remission to grade 2 or below within 7 days;; Occurrence of grade 3 or higher neurotoxicity;; Grade 4 hematologic toxicity: caused by non-underlying disease and lasting ≥ 28 days (except for lymphopenia, neutrophil and thrombocytopenia caused by chemotherapy pretreatment);; Any unanticipated toxicity that necessitates discontinuation of treatment at the discretion of the investigator or collaborating unit.	Up to day 28
Incidence of grade 3 and above adverse reactions	Incidence of adverse events associated with the study products；Adverse events assessed according to NCI-CTCAE v5.0.	Through study completion, an average of 2 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluate the number of Treg cells in subjects' peripheral blood	Evaluate the number of Treg cells in subjects' peripheral blood after donor-derived Treg cell injection administration	An average of 1 year
Analysis of the number changes of lymphocyte subsets in peripheral blood.	Analysis of the number changes of lymphocyte subsets in peripheral blood, Including T/B/NK cells.	Through study completion, an average of 2 year
Score changes in the 36-Item Short Form Health Survey (SF-36)	Adopt 36-Item Short Form Survey (SF-36)to analyze the changes in patients' scores after medication compared with baseline.	Through study completion, an average of 2 year
Score changes in Lee Chronic Graft-versus-Host Disease Symptom Scale	Adopt 36-Item Short Form Survey (SF-36)to analyze the changes in patients' scores after medication compared with baseline.	Through study completion, an average of 2 year
Changes in cGVHD severity	Changes in cGVHD severity,according to chronic graft-versus-host disease grading system.	Through study completion, an average of 2 year
Objective Response Rate (ORR)	To evaluate the efficacy of donor-derived Treg cells combined with low-dose IL-2 in the treatment of refractory cGVHD subjects, including 12 and 24 weeks of ORR.	Through study completion, an average of 2 year
Patient-reported Outcomes	Reports directly from patients on their own health, functional status, and treatment experience, excluding explanations from health care workers or anyone else. A score of ≥7 on the Lee cGVHD Symptom Scale was associated with improved quality of life.	Through study completion, an average of 2 year
Proportion of subjects able to reduce steroid requirement to <0.25 mg/kg/ day.	Proportion of subjects able to reduce steroid requirement to <0.25 mg/kg/ day.	Through study completion, an average of 2 year
Duration of response after administration (DOR)	Duration of response after administration (DOR),Defined as the time between first remission and disease progression, new cGvHD systemic treatment, or all-cause death, whichever occurs first.	Through study completion, an average of 2 year
Failure-free survival after administration (FFS)	Failure-free survival after administration (FFS),The time from the beginning of cell reinfusion to the first disease progression, recurrence after remission, or death from any cause.	Through study completion, an average of 2 year
Overall survival	The time from cell retransfusion to death from any cause.	Through study completion, an average of 2 year

Collaborators and Investigators

• Sponsor: Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
• Investigators: Principal Investigator: xianmin song, Doctor, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): June 14, 2025
• Primary Completion (Estimated): May 15, 2027
• Study Completion (Estimated): September 15, 2027

Study Registration Dates

• First Submitted: March 19, 2025
• First Submitted That Met QC Criteria: April 2, 2025
• First Posted (Actual): April 9, 2025

Study Record Updates

• Last Update Posted (Estimated): September 30, 2025
• Last Update Submitted That Met QC Criteria: September 28, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Steroid dependence; Refractory cGVHD
• Additional Relevant MeSH Terms: Organizing Pneumonia; Immune System Diseases; Respiratory Tract Diseases; Lung Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Graft vs Host Disease; Bronchiolitis Obliterans Syndrome; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Intercellular Signaling Peptides and Proteins; Cytokines; Interleukins; Lymphokines; Interleukin-2
• Other Study ID Numbers: SHSYXY-Treg-cGVHD-2024

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No