Clinical Study of EBV-TCR-T Cells for EBV Infection After Allogenic HSCT

Study Overview
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Brief Summary
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This is a multi-center, single arm, open-label, phase I study to determine the safety and effectiveness of EBV-TCR-T cell immunotherapy in treating EBV virus infection after allogenic HSCT.

Detailed Description
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EB virus (EBV) infection after allogeneic hematopoietic stem cell transplantation (HSCT) is common and can be lethal without prompt treatment. In this prospective study, HLA-A*02:01/11:01/24:02-restricted EBV-specific T cell receptor (TCR) will be introduced into the T cells of HSCT donors by ex vivo lentiviral transduction to generate EBV-TCR-T cells. An escalated dose ranging from 3×10^5/kg to 1×10^6/kg of EBV-TCR-T cells will be infused into patients with EBV infection. The safety, efficacy, pharmacokinetics and cytokine levels of allogenic EBV-TCR-T cell therapy will be evaluated.

Official Title
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Multicenter, Open Label, Single-arm Exploratory Clinical Study of EBV-TCR-T Cells for EBV Infection After Allogenic HSCT

Conditions
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EBV Infection After Allogenic HSCT

Intervention / Treatment
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* Biological: EBV-TCR-T cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 14-75 years, gender unlimited. Diagnosed with hematologic malignancies and have undergone allogeneic hematopoietic stem cell transplantation (allo-HSCT), with EBV infection after allo-HSCT. Karnofsky Score ≥ 70(age ≥16y) or Lansky Score ≥ 50(age<16y). TCR-T cell donor inclusion criteria: 1) Age 8-70 years; 2) Understand and voluntarily sign informed consent and are willing to comply with laboratory tests and other research procedures; 3) ≥ 3/6 HLA match with TCR-T cell recipients enrolled; 4) Lymphocyte count = (0.8 4) × 10^9/L; 5) Have sufficient venous circulation, without any symptoms that do not allow blood cell isolation. Exclusion Criteria: Patients with uncontrolled active aGVHD one day before TCR-T cell infusion. Patients with severe kidney disease (Cr > 3×normal value), liver damage (TBIL >2.5×upper limit of normal value, ALT and AST > 3×upper limit of normal value) or heart failure (NYHA heart function grade IV) one week before TCR-T cell infusion. Anticipated to take immunosuppressive hormones on the day of TCR-T cell infusion. Have other malignancies. Have relapsed and uncontrolled hematologic malignancies. Serologically positive for HIV-Ab or TAP-ab. Pregnant or lactating women. Anticipated to have other cell therapies in 4 week post TCR-T cell infusion. Participated in any other clinical study of drugs and medical devices before 30 days of enrollment.

Ages Eligible for Study
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Minimum Age: 14 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EBV-TCR-T cells<br>Phase 1 trail: The patients with EBV infection after HSCT will receive one to three infusions of donor-derived EBV-TCR-T cells, with the escalated dose ranging from 5×10^5/kg to 1×10^6/kg EBV-TCR-T cells per dose. Phase 2 trail: According to the PK and response data, the dose escalation phase will be carried out. | Biological: EBV-TCR-T cells<br>* The patients with EBV infection after HSCT will receive one to three infusions of donor-derived EBV-TCR-T cells, with the escalated dose ranging from 5×10^5/kg to 1×10^6/kg EBV-TCR-T cells per dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | Percentage of participants with adverse events. | 1 year after EBV-TCR-T treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes of EBV-DNA copies number | Quantitative PCR will be used to determine viral copy numbers in peripheral blood. | 1 year after EBV-TCR-T treatment | 
| Persistence of EBV-TCR-T cells | Quantitative PCR using primers specific for the gene encoding EBV-TCR will be used to determine the number of circulating EBV-TCR-T cells in peripheral blood post infusion. | 1 year after EBV-TCR-T treatment | 
| Dose-limiting toxicity | Toxic effects considered by the investigators to be related to the EBV-TCR-T | 28 days after EBV-TCR-T treatment | 
| Maximum tolerated dose | The highest dose of DLT was seen in 1/6 of the subjects | 28 days after EBV-TCR-T treatment | 
| The proportion of EBV-DNA negative patients | The proportion of patients EBV-DNA negative after EBV-TCR-T treatment | 180 days after EBV-TCR-T treatment | 
| The time to EBV-DNA negative | The time from the start of therapy to EBV-DNA negative detected | 180 days after EBV-TCR-T treatment | 
| The time to response | The time from the start of therapy to the time when patients firstly achieve complete remission or partial remission | 180 days after EBV-TCR-T treatment | 
| The duration of response | The time from the patients firstly achieve complete remission or partial remission to progression of disease | 1 year after EBV-TCR-T treatment | 
| The incidence of EBV-PTLD | The incidence of EBV-PTLD after EBV-TCR-T treatment | 1 year after EBV-TCR-T treatment | 
| The overall response rate to EBV-TCR-T treatment | The overall response rate to EBV-TCR-T treatment | 28,90,180,365,730 days after EBV-TCR-T treatment | 
| The complete response rate to EBV-TCR-T treatment | The complete response rate to EBV-TCR-T treatment | 28,90,180,365, and 730 days after EBV-TCR-T treatment | 
| The incidence of EBV reactivation after EBV-TCR-T treatment | The incidence of EBV reactivation after EBV-TCR-T treatment | 1 year after EBV-TCR-T treatment | 
| Maximum Plasma Concentration (Cmax) of EBV-TCR-T cells | Pharmacokinetic (PK) parameters of EBV-TCR-T cells in patients with EBV reactivation | 28 days after EBV-TCR-T treatment | 
| Area under the plasma concentration versus time curve (AUC) of EBV-TCR-T cells | Pharmacokinetic (PK) parameters of EBV-TCR-T cells in patients with EBV reactivation | 28 days after EBV-TCR-T treatment | 
| Half life time (T1/2) of EBV-TCR-T cells | Pharmacokinetic (PK) parameters of EBV-TCR-T cells in patients with EBV reactivation | 28 days after EBV-TCR-T treatment | 
| Concentration levels of cytokines | Concentration levels of cytokines (IL-2, IL-6, IL-10, TNF-α, IFN-γ) | 28 days after EBV-TCR-T treatment | 
| Concentration levels of CRP | Pharmacokinetics of EBV-TCR-T cells | 28 days after EBV-TCR-T treatment | 
| Concentration levels of ferritin | Pharmacokinetics of EBV-TCR-T cells | 28 days after EBV-TCR-T treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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EBV infection, allogenic HSCT