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

Multicenter, Open Label, Single-arm Exploratory Clinical Study of EBV-TCR-T Cells for EBV-associated Hemophagocytic Lymphohistiocytosis or EBV Infection

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

Study Overview

• Status: Recruiting
• Conditions: EBV Infection; EBV-associated Hemophagocytic Lymphohistiocytosis
• Intervention / Treatment: Biological: EBV-TCR-T cells

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 9
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Liping Dou, Doctor; Phone Number: +8613681207138; Email: lipingruirui@163.com
• Study Contact Backup: Name: Daihong Liu, Doctor; Phone Number: +86 18301339032; Email: daihongrm@163.com

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100853
      • Recruiting
      • Chinese PLA General Hospital
      • Contact: Liping Dou, Doctor; Phone Number: +8613681207138; Email: lipingruirui@163.com
      • Contact: Daihong Liu, Doctor; Phone Number: +86 18301339032; Email: daihongrm@163.com

Participation Criteria

Eligibility Criteria

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

Description

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.

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: Experimental: EBV-TCR-T cells; 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; 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.

What is the study measuring?

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
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
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
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

Collaborators and Investigators

• Sponsor: Chinese PLA General Hospital
• Investigators: Principal Investigator: Daihong Liu, Doctor, Chinese PLA General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2023
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: November 12, 2023
• First Submitted That Met QC Criteria: November 12, 2023
• First Posted (Estimated): November 16, 2023

Study Record Updates

• Last Update Posted (Estimated): November 16, 2023
• Last Update Submitted That Met QC Criteria: November 12, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Virus Diseases; Lymphatic Diseases; Disease Attributes; DNA Virus Infections; Tumor Virus Infections; Herpesviridae Infections; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Infections; Communicable Diseases; Epstein-Barr Virus Infections; Lymphohistiocytosis, Hemophagocytic
• Other Study ID Numbers: S2022-381-01

Drug and device information, study documents

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