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

Sponsor

University Hospital, Basel, Switzerland (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05688241

Collaborator

(none)

Enrollment

Locations

Arms

Anticipated Duration (Months)

1.3

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
EBV Lymphoma Post-transplant Lymphoproliferative Disease (PTLD)	Drug: Donor-derived ex-vivo expanded EBV Tscm CTL	Phase 1/Phase 2

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

10 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Multi-center open-label, non-randomized phase I/II study.Multi-center open-label, non-randomized phase I/II study.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Feb 1, 2023

Anticipated Primary Completion Date :

Dec 1, 2025

Anticipated Study Completion Date :

Dec 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group A: patients who undergo allogeneic HCT 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 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.
Experimental: Group B: patients after HCT or SOT 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 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.

Arm

Intervention/Treatment

Experimental: Group A: patients who undergo allogeneic HCT

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

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.

Experimental: Group B: patients after HCT or SOT

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

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.

Outcome Measures

Primary Outcome Measures

Assessment of feasibility to expand Tscm-enriched EBV CTLs [one time assessment on day 9-11 of expansion before cryopreservation (plus at least 7 days for microbiological culture)]
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.
Safety of EBV Tscm-CTL infusion assessed by number of early infusion-related events [up to 12 hours after first dose of EBV Tscm-CTL infusion]
Number of early infusion-related events (early infusion-related events are clinically significant alterations of vital signs)
Safety of EBV Tscm-CTL infusion assessed by number of late clinical reaction to EBV Tscm-CTLs [from 12 hours after first dose until 3 months after the last dose of EBV 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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	University Hospital Basel, Klinik für Infektiologie und Spitalhygiene	Basel	Switzerland	4031
2	Universitäts-Kinderspital beider Basel (UKBB)	Basel	Switzerland	4056
3	Universitätsspital Bern, Klinik für Infektiologie	Bern	Switzerland	3010
4	Hôpitaux Universitaires de Genève, Hôpital des Enfants	Genève	Switzerland	1205
5	Hôpitaux Universitaires de Genève, Service d'Hématologie	Genève	Switzerland	1211
6	Centre hospitalier universitaire vaudois, Service et Laboratoire central d'hématologie	Lausanne	Switzerland	1011
7	Kinderspital Zürich	Zürich	Switzerland	8032
8	University Hospital Zurich, Hämatologie	Zürich	Switzerland	8091