Clinical Study of EBV-TCR-T Cells for EBV-associated Hemophagocytic Lymphohistiocytosis or EBV Infection

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-associated hemophagocytic lymphohistiocytosis (EBV-HLH) or EBV infection

Detailed Description
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Epstein-Barr virus (EBV) is a widely disseminated herpesvirus that is spread by intimate contact between susceptible persons and asymptomatic EBV shedders. The inability to control EBV infection can lead to some patients developing EBV-positive B-cell lymphomas, chronic active EBV infections, and hemophagocytic lymphohistiocytosis (HLH). 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 donors by ex vivo lentiviral transduction to generate EBV-TCR-T cells. An escalated dose ranging from 1×10^6/kg to 1×10^8/kg of EBV-TCR-T cells will be infused into patients with EBV-HLH or 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-associated Hemophagocytic Lymphohistiocytosis or EBV Infection

Conditions
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EBV-associated Hemophagocytic Lymphohistiocytosis, EBV Infection

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 1-60 years, gender unlimited. Diagnosed with EBV associated-hemophagocytic lymphohistiocytosis (HLH) or EBV infection. Fully understood and informed the study and signed the ICF. Karnofsky Score ≥ 70(age ≥16y) or Lansky Score ≥ 50(age<16y). TCRT-T cell donor inclusion criteria: 1)Age >=8 years, gender unlimited; 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 or left ventricular ejection fraction<50%) one week before TCR-T cell infusion. Anticipated to take immunosuppressive hormones on the day of TCR-T cell infusion. Use of immunosuppressive drugs or G-CSF within 2 weeks before PBMC blood collection. Have tumours, active and uncontrolled malignant diseases. Serologically positive for HIV-Ab or TAP-ab. Pregnant or lactating women. Men and their partners or women of childbearing potential refused contraception during the study period. 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 4 weeks of enrollment. Allergy to albumin. TCRT-T cell donor exclusion criteria: 1) pregnant woman; 2) Serologically positive for HBsAg, HCV-Ab, HIV-Ab or TAP-ab; 3) EBV-DNA or CMV-DNA positive; 4) other uncontrolled infection; 5) Use of immunosuppressive drugs or G-CSF within 2 weeks before PBMC blood collection.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 60 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: Experimental: EBV-TCR-T cells<br>The patients with EBV-HLH or EBV infection will receive infusions of EBV-TCR-T cells, with the escalated dose ranging from 1×10^6/kg to 1×10^8/kg EBV-TCR-T cells per dose | Biological: EBV-TCR-T cells<br>* The patients with EBV-HLH or EBV infection will receive infusions of EBV-TCR-T cells, with the escalated dose ranging from 1×10^6/kg to 1×10^8/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 |
| --- | --- | --- |
| Dose-limiting toxicity (DLT) | Toxic effects considered by the investigators to be related to the EBV-TCR-T | 28 days after EBV-TCR-T treatment | 
| Maximum tolerated dose （MTD） | The highest dose of DLT was seen in 1/6 of 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 | 
| 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 | 
| Maximum Plasma Concentration (Cmax) of EBV-TCR-T cells | Cmax of EBV-TCR-T cells in patients with EBV-HLH or EBV infection | 28 days after EBV-TCR-T treatment | 
| Area under the plasma concentration versus time curve (AUC) of EBV-TCR-T cells | AUC of EBV-TCR-T cells in patients with EBV-HLH or EBV infection | 28 days after EBV-TCR-T treatment | 
| Time to peak (Tmax) of EBV-TCR-T cells | Tmax of EBV-TCR-T cells in patients with EBV-HLH or EBV infection | 28 days after EBV-TCR-T treatment | 
| Half life time (T1/2) of EBV-TCR-T cells | T1/2 of EBV-TCR-T cells in patients with EBV-HLH or EBV infection | 28 days after EBV-TCR-T treatment |