EBV-associated Hemophagocytic Lymphohistiocytosis, EBV Infection
Conditions
Brief summary
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
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.
Interventions
BIOLOGICALEBV-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.
Sponsors
Chinese PLA General Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 60 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse events | 1 year after EBV-TCR-T treatment | Percentage of participants with adverse events |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum tolerated dose （MTD） | 28 days after EBV-TCR-T treatment | The highest dose of DLT was seen in 1/6 of subjects |
| The proportion of EBV-DNA negative patients | 180 days after EBV-TCR-T treatment | The proportion of patients EBV-DNA negative after EBV-TCR-T treatment |
| The time to EBV-DNA negative | 180 days after EBV-TCR-T treatment | The time from the start of therapy to EBV-DNA negative detected |
| Changes of EBV-DNA copies number | 1 year after EBV-TCR-T treatment | Quantitative PCR will be used to determine viral copy numbers in peripheral blood. |
| Dose-limiting toxicity (DLT) | 28 days after EBV-TCR-T treatment | Toxic effects considered by the investigators to be related to the EBV-TCR-T |
| Area under the plasma concentration versus time curve (AUC) of EBV-TCR-T cells | 28 days after EBV-TCR-T treatment | AUC of EBV-TCR-T cells in patients with EBV-HLH or EBV infection |
| Time to peak (Tmax) of EBV-TCR-T cells | 28 days after EBV-TCR-T treatment | Tmax of EBV-TCR-T cells in patients with EBV-HLH or EBV infection |
| Half life time (T1/2) of EBV-TCR-T cells | 28 days after EBV-TCR-T treatment | T1/2 of EBV-TCR-T cells in patients with EBV-HLH or EBV infection |
| Maximum Plasma Concentration (Cmax) of EBV-TCR-T cells | 28 days after EBV-TCR-T treatment | Cmax of EBV-TCR-T cells in patients with EBV-HLH or EBV infection |
Countries
China
Contacts
Primary ContactDaihong Liu, Doctor
Backup ContactLiping Dou, Doctor
Outcome results
None listed