EBV-Positive Lymphoma, Epstein-Barr Virus-Associated Lymphoproliferative Disorders
Conditions
Keywords
EBV-associated lymphoproliferative disorder, EBV-positive lymphoma, Adoptive T-cell therapy, Antigen-specific T cells
Brief summary
This is an investigator-initiated, open-label, single-arm, dose-escalation exploratory study to evaluate the safety, tolerability, and preliminary efficacy of EBV-AST cell injection in adults with EBV-associated lymphoproliferative disorders, including post-transplant lymphoproliferative disease (PTLD) and EBV-positive lymphomas. Participants will receive EBV-AST cell infusions intravenously every 2 weeks for up to 3 infusions at escalating dose levels. The primary objective is to assess safety and determine a potential optimal biologically active dose. Secondary objectives include preliminary tumor response and EBV-related virologic outcomes, as well as cellular PK/PD.
Detailed description
EBV-associated lymphoproliferative disorders (LPD), including PTLD and EBV-positive lymphomas, are clinically challenging and may occur in immunocompromised or heavily treated patients. EBV-AST is a cellular immunotherapy consisting of EBV antigen-specific cytotoxic T lymphocytes generated by ex vivo stimulation and expansion of T cells using antigen peptide-loaded dendritic cells. After infusion, EBV-AST cells are expected to recognize and eliminate EBV-infected or EBV-antigen-expressing target cells and provide EBV-specific immune reconstitution. This investigator-initiated, open-label, single-arm exploratory study uses a dose-escalation design to evaluate EBV-AST cell injection in adults with EBV-associated LPD. Approximately 4-18 participants will be enrolled across three dose levels (3×10\^5, 3×10\^6, and 3×10\^7 cells/kg per infusion). EBV-AST will be administered by intravenous infusion every 2 weeks for up to three infusions, following protocol-defined escalation rules and DLT assessment within 28 days after the first infusion. Participants will be monitored for adverse events and immune-related toxicities, and assessed for preliminary efficacy (tumor response and EBV-DNA/virologic outcomes) and cellular PK/PD.
Interventions
BIOLOGICALEBV-AST Cell Injection
EBV-AST is an Epstein-Barr virus (EBV) antigen-specific cytotoxic T-lymphocyte product generated by ex vivo stimulation and expansion of T cells using peptide-loaded dendritic cells. EBV-AST is administered by intravenous infusion every 2 weeks for up to 3 infusions at escalating dose levels (3×10\^5, 3×10\^6, or 3×10\^7 cells/kg per infusion), according to the protocol-defined dose-escalation design.
Sponsors
Daihong Liu
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Able to understand and voluntarily sign written informed consent. 2. Age 18 to 75 years, inclusive. 3. HLA genotype matches at least one of the following: HLA-A02:01, HLA-A11:01, or HLA-A\*24:02. 4. Karnofsky Performance Status (KPS) ≥ 70. 5. Life expectancy ≥ 3 months. 6. Diagnosed with EBV-associated lymphoproliferative disorders, including: 7. EBV infection-associated post-transplant lymphoproliferative disorder (PTLD) that is relapsed/refractory after at least first-line standard therapy; or 8. EBV-associated lymphoma confirmed by histology and/or cytology with EBER positivity (ISH/FISH), with no standard treatment available or not suitable for standard therapy, including but not limited to: EBV-positive DLBCL, EBV-positive NK/T-cell lymphoma, EBV-positive Hodgkin lymphoma, EBV-positive Burkitt lymphoma, EBV-positive nodal TFH lymphoma (AITL type), and EBV-positive primary cutaneous T-cell lymphoma, meeting protocol-defined relapsed/refractory criteria. 9. Absolute lymphocyte count ≥ 0.8 × 10\^9/L (except for PTLD participants). 10. Adequate organ and bone marrow function per protocol-defined criteria. 11. Participants of childbearing potential agree to use highly effective contraception throughout the study; women of childbearing potential must have a negative pregnancy test at screening.
Exclusion criteria
1. Known hypersensitivity to the investigational product or its components. 2. Uncontrolled active graft-versus-host disease (GVHD) in PTLD participants. 3. Known primary immunodeficiency disorders (e.g., X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, chronic granulomatous disease, hyper-IgE syndrome). 4. Severe uncontrolled medical conditions that, in the investigator's judgment, make the participant unsuitable for enrollment. 5. Serious cardiac disease within 6 months prior to first infusion (e.g., myocardial infarction, severe/unstable angina, bypass surgery, NYHA class III-IV heart failure). 6. Chronic diseases requiring systemic immunosuppressants or systemic steroids (except local/inhaled steroids or physiologic replacement therapy). 7. History of other malignancy within the past 5 years, except carcinoma in situ (e.g., cervix, bladder, breast) or non-melanoma skin cancer. 8. Receipt of lymphocyte-based immunotherapy (e.g., CIK, DC, DC-CIK, LAK) within 3 months prior to consent. 9. Receipt of interferon or other targeted immunodeficiency drugs within 3 months prior to consent; prior high-dose IL-2 therapy. 10. Anti-cancer therapy within 14 days prior to consent (including chemotherapy or immunosuppressants/steroids); other cell therapy or live vaccines/attenuated vaccines or other investigational drugs within 28 days prior to consent; curative radiotherapy or major surgery within 4 weeks, or palliative local radiotherapy within 2 weeks prior to consent. 11. Prior immune therapy-associated ≥ Grade 3 immune-related adverse events (irAEs). 12. Unresolved toxicity from prior therapy \> Grade 1 (except alopecia any grade; peripheral sensory neuropathy ≤ Grade 2). 13. Uncontrolled psychiatric or neurologic disorders; drug abuse or alcohol dependence. 14. Positive HIV antibody; positive Treponema pallidum antibody; active hepatitis B (HBsAg and/or HBeAg positive with HBV-DNA above ULN) or active hepatitis C (HCV-Ab positive and HCV-RNA positive). 15. Uncontrolled severe active infection or contagious disease (excluding EBV infection). 16. Pregnant or breastfeeding women.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-Limiting Toxicities (DLTs) | From first infusion (Day 0) through Day 28 | Number of participants experiencing dose-limiting toxicities (DLTs) within 28 days after the first EBV-AST cell infusion, as defined by protocol-specific criteria and graded according to NCI CTCAE v5.0. |
| Safety: Incidence of Adverse Events | From first infusion (Day 0) through 12 months after first infusion | Number of participants with treatment-emergent adverse events (AEs), immune-related adverse events (irAEs), and serious adverse events (SAEs), graded according to NCI CTCAE v5.0, including clinically significant laboratory abnormalities. |
| Recommended/Optimal Biologically Active Dose (OBD) | Up to 28 days after first infusion for DLT evaluation; overall dose decision through study completion | Recommended/optimal biologically active dose (OBD) of EBV-AST, determined based on the incidence of DLTs, overall safety profile, and tolerability across dose levels. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | From first infusion (Day 0) through 12 months after first infusion | Objective response rate (ORR), defined as the proportion of participants achieving complete response (CR) or partial response (PR) according to protocol-defined response criteria. |
| Disease Control Rate (DCR) | From first infusion (Day 0) through 12 months after first infusion | Disease control rate (DCR), defined as the proportion of participants achieving complete response (CR), partial response (PR), or stable disease (SD) according to protocol-defined criteria. |
| Progression-Free Survival (PFS) | From first infusion (Day 0) through 12 months after first infusion | Progression-free survival (PFS), defined as the time from first EBV-AST infusion to documented disease progression or death from any cause. |
| Overall Survival (OS) | From first infusion (Day 0) through 12 months after first infusion | Overall survival (OS), defined as the time from first EBV-AST infusion to death from any cause. |
| Duration of Response (DOR) | From first documented response through 12 months after first infusion | Duration of response (DOR), defined as the time from first documented complete or partial response to disease progression or death. |
| EBV-DNA Negativity Rate | From first infusion (Day 0) through 12 months after first infusion | Proportion of participants achieving EBV-DNA negativity in peripheral blood as measured by quantitative polymerase chain reaction (qPCR). |
| Time to EBV-DNA Negativity | From first infusion (Day 0) through 12 months after first infusion | Time from first EBV-AST infusion to first documented EBV-DNA negativity in peripheral blood. |
| Change in EBV-DNA Level | From baseline through 12 months after first infusion | Change from baseline in EBV-DNA levels in peripheral blood over time, as measured by quantitative polymerase chain reaction (qPCR). |
| Maximum Concentration (Cmax) of EBV-AST Cells in Peripheral Blood | From first infusion (Day 0) through Day 28 | The highest measured absolute concentration of viable EBV-AST cells in peripheral blood following infusion, quantified by flow cytometry. |
| Concentration of EBV-AST Cells in Peripheral Blood (Cmax) | From baseline through Day 28 after first infusion | Maximum absolute concentration of viable EBV-AST cells in peripheral blood post-infusion, quantified by flow cytometry. Unit of Measure: viable EBV-AST cells per microliter (cells/μL). |
Countries
China
Contacts
CONTACTDaihong Liu
CONTACTLiping Dou
STUDY_CHAIRDaihong Liu
Chinese PLA General Hospital
Outcome results
None listed