A Study of the Safety and Efficacy of EBV Specific T-cell Lines

Study Overview
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Brief Summary
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This study evaluates the safety and efficacy of EBV-specific T-cell lines to treat patients suffering from high EBV viral titers not responding to standard of care therapies and to treat EBV-related lymphoma. The study will recruit 6 patients to receive autologous T cells or a T cell line derived from the patient's allogeneic donor (in the case of stem cell transplant recipients), and 6 patients to receive a T-cell line prepared from a matched or partially matched related donor.

Detailed Description
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Epstein-Barr virus (EBV) is a member of the herpes virus family and infects up to 95% of individuals over their lifetime. Most initial infections occur in childhood and after a brief flu-like illness, the virus enters a phase of latency. Patients who receive a bone marrow transplant or an organ transplant take medications drugs that weaken their immune systems. In these contexts, the virus can reactivate and cause very serious problems, such as lymphoma. For unknown reasons, people with a normal immune system can also develop lymphoma due to EBV. The purpose of this study is to test the safety and efficacy of immune cells (T lymphocytes) that are specifically taught to recognize the virus-infected cells and to eliminate them. This education occurs is done over during a 2 weeks period (approximately), in the research laboratory. The cells are then transfused into the patient.

Official Title
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A Phase I/II Open-label Study of the Safety and Efficacy of Epstein-Barr Virus Specific T-cell Lines for the Treatment of EBV Infection or EBV-related Lymphoproliferative Diseases

Conditions
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Epstein-Barr Virus Infections, Post-Transplant Lymphoproliferative Disorder, Lymphoma

Intervention / Treatment
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* Biological: Group A
* Biological: Group B


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Capacity to provide informed consent Age ≥ 18 years old Confirmed treatment-refractory EBV reactivation or EBV-related lymphoma ECOG of 2 or less Exclusion Criteria: Medical condition requiring a corticosteroid dose greater than Prednisone 0.5mg/kg/day (or equivalent) at the time of the infusion. Patient has received T-cell depleting antibodies or stem cell transplantation in the 28 days prior to proposed date of anti-EBV T-cell line infusion Patient has received a solid organ transplant in the 3 months prior to proposed date of anti-EBV T-cell line infusion. Pregnant or nursing females Life expectancy of less than 3 months due to a condition unrelated to the EBV- related disease. Active uncontrolled GVHD Active uncontrolled SOT rejection episode DONOR ELIGIBILITY: An allogeneic donor must be a first-degree relative with at least 3/6 HLA compatibility, have consented to donate peripheral blood mononuclear cells, and fulfill the same criteria for stem cell donation according to the hospital's standard operating procedure.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Autologous or allogenic (stem cell donor) T cells<br>Subjects receive an autologous anti-EBV T-cell line or a T-cell line derived from the patient's allogeneic (stem cell transplant) donor. | Biological: Group A<br>* Peptide-stimulated T cells 2 x 10^7/m^2<br>|
| Experimental: Allogeneic third party T cells<br>Subjects receive a T-cell line from a matched or partially matched related donor. | Biological: Group B<br>* Peptide-stimulated T cells per dose-escalation protocol<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: Incidence and description of CTCAE v.4.03 adverse events related to the experimental treatment | Complications: infusional toxicity, immune-related and other | During observation period (up to 42 days post infusion) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in EBV titers (viral load) for each patient | As measured by PCR weekly until week 6, at 3 months, 6 months and 12 months | Until 12 months post infusion | 
| Immune reconstitution as measured by various laboratory assays of immune cell type and function | ELISpot on peripheral blood is assessed at the time points mentioned above | During observation period until 12 months post infusion | 
| All cause mortality | Within the 12 months observation period | At 12 months | 
| Transplant-related outcomes | Incidence/severity of graft-versus-host disease, solid organ rejection episodes, relapse | During observation period until 12 months post infusion | 
| Incidence/severity of graft-versus-host disease among patients who underwent stem cell transplantation | Based on standardized assessments done weekly until week 6 and at 3, 6 and 12 months | During observation period until 12 months post infusion | 
| Number and severity of solid organ rejection episodes per patient among those who underwent solid organ transplant | Based on standardized assessments done weekly until week 6 and at 3, 6 and 12 months | During observation period until 12 months post infusion | 
| Incidence of primary disease relapse among patients who underwent stem cell transplantation | Based on standardized assessments done weekly until week 6 and at 3, 6 and 12 months | During observation period until 12 months post infusion | 
| Malignancy staging for patients with lymphoma, per internationally-accepted guidelines for the different specific lymphomas | As clinically indicated by the investigators and/or primary physician | During observation period until 12 months post infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Allogeneic Transplantation, T cell, Epstein-Barr Virus