EBV-Tscm Cytotoxic T Cells (CTLs) for EBV- Driven Lymphomas/ Diseases

Study Overview
=================
Brief Summary
-----------------
In this multi-center open-label, non-randomized phase I/II intervention study three consecutive doses of donor-derived EBV Tscm-CTLs will be administered to 10 patients with treatment-refractory EBV lymphoma, diseases or PTLDs. EBV Tscm-CTLs will derive from hematopoietic cell transplant (HCT) or third-party donors.

Detailed Description
-----------------
Epstein Barr virus (EBV)-driven lymphomas and diseases are associated with poor prognosis. EBV proteins are recognized by T cells providing opportunities for EBV-specific T-cell therapy. Recent findings show that early differentiated T cells (T memory stem cells, Tscm) improve the prognosis in chronic viral diseases and are associated with effective tumor cell killing in melanoma patients. Tscm might be superior to highly differentiated T cells because of their longevity, robust proliferative potential, and capacity to reconstitute a wide T-cell receptor (TCR) diversity. This project will test the hypothesis that Tscm are efficacious for EBV-specific T-cell therapy. Clinical-grade enriched EBV-specific Tscm-CTLs will be prepared and used to treat patients with primary EBV lymphomas, diseases or post-transplant lymphoproliferative disease (PTLD) with limited other treatment options.

Official Title
-----------------
Epstein-Barr Virus (EBV) -Specific T Memory Stem Cell (Tscm) Therapy to Treat EBV- Driven Lymphomas/ Diseases

Conditions
-----------------
EBV Lymphoma, Post-transplant Lymphoproliferative Disease (PTLD)

Intervention / Treatment
-----------------
* Drug: Donor-derived ex-vivo expanded EBV Tscm CTL


Participation Criteria
=================
Eligibility Criteria
-----------------
Patients' inclusion criteria: Group A: Patients with EBV driven lymphomas (e.g., NK/T-cell lymphoma), with EBV complications (e.g. HLH, CAEBV) or patients with primary immunodeficiency disorders with high risk for EBV complications (e.g. SCID) with planned allogeneic HCT Group B: EBV-driven PTLD that develop after a HCT or SOT For both groups: All age groups Negative pregnancy test in female patients of childbearing potential. Signed written informed consent of patient or/and parents Patients' exclusion criteria: Patients receiving anti-thymocyte globulin or Campath within 28 days of infusion Patients with active, acute GvHD grades III-IV Previous severe reaction to dimethylsulfoxide (DMSO) Donors' inclusion criteria: EBV positive serology (VCA and Epstein-Barr nuclear antigen (EBNA) immunoglobulin G (IgG) positive) Detectable interferon (IFN)-y-secreting T cells (>100 SFC/10e6 PBMC) measured by Elispot to the EBV consensus peptide pool Suitability for blood or HCT donation meeting requirements of local institutional guidelines An informed consent for EBV Tscm CTL manufacturing Age > 18 years Donors' exclusion criteria: Detectable IFN-y-secreting T-cells <100 spot-forming cell (SFC)/10e6 PBMC measured by Elispot to EBV select Unwilling and/or unable to donate, according to the donor center
Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multi-center open-label, non-randomized phase I/II study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: patients who undergo allogeneic HCT<br>Patients with EBV driven lymphomas (e.g., natural killer (NK)/T-cell lymphoma), with EBV complications (e.g. haemophagocytic lymphohistiocytosis (HLH), CAEBV) or patients with primary immunodeficiency disorders with high risk for EBV complications (e.g. SCID) with planned allogeneic HCT. | Drug: Donor-derived ex-vivo expanded EBV Tscm CTL<br>* Cryopreserved cells will be thawed and infused at three time points. Dosing will be 2x10e6 EBV CTLs per kg of body weight. No prior lymphodepletion will be performed.<br>|
| Experimental: Group B: patients after HCT or SOT<br>EBV-driven PTLD that develop after a HCT or solid organ transplantation (SOT) and show decreased response to rituximab. | Drug: Donor-derived ex-vivo expanded EBV Tscm CTL<br>* Cryopreserved cells will be thawed and infused at three time points. Dosing will be 2x10e6 EBV CTLs per kg of body weight. No prior lymphodepletion will be performed.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of feasibility to expand Tscm-enriched EBV CTLs | Feasibility is defined as meeting the release criteria of EBV Tscm-CTL endproduct. Release criteria for the EBV Tscm-CTL follow Swissmedic Investigational Medicinal Product Dossier (IMPD). This includes viability of cluster of differentiation 3 (CD3)+ >70%, absolute CD3 count per kg of body weight per dose (≤2x10e6/kg), and a purity of CD3+ >90%. These criteria will be assessed before cryopreservation. A negative culture for bacteria and fungi for at least 7 days, endotoxin testing ≤5 EU/ml and negative result for Mycoplasma is required. | one time assessment on day 9-11 of expansion before cryopreservation (plus at least 7 days for microbiological culture) | 
| Safety of EBV Tscm-CTL infusion assessed by number of early infusion-related events | Number of early infusion-related events (early infusion-related events are clinically significant alterations of vital signs) | up to 12 hours after first dose of EBV Tscm-CTL infusion | 
| Safety of EBV Tscm-CTL infusion assessed by number of late clinical reaction to EBV Tscm-CTLs | Late clinical reaction to EBV Tscm-CTLs are signs of acute graft-versus-host disease (GvHD). Acute GVHD will be graded according to the modified Glucksberg criteria. | from 12 hours after first dose until 3 months after the last dose of EBV CTLs | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
EBV-driven Lymphomas, EBV disease, Epstein-Barr Virus (EBV), Memory Stem Cell Therapy, Epstein-Barr Virus-specific T Memory Stem Cell Therapy (EBV-Tscm), cytotoxic T-cell line (CTL), T memory stem cells (Tscm), T-cell receptor (TCR), post-transplant lymphoproliferative disease (PTLD), Wnt-β-catenin inhibition, hematopoietic cell transplantation (HCT), Hematopoietic stem cell transplantation (HSCT)