Preventative/Preemptive Adoptive Transfer of Peptide Stimulated CMV/EBV Specific T-cells in Patients After Allogeneic Stem Cell Transplantation

Prospective, Open, Randomized, Two-arm, Controlled, Multicenter Clinical Phase I/IIa Trial to Evaluate the Safety and Efficacy of Adoptive Immunotherapy With Allogeneic CMV/EBV Specific, Peptide Stimulated T-cells (CD3+) for Prevention or Preemptive Therapy of Reactivation of CMV and/or EBV in Patients After Allogeneic, HLA Identical Stem Cell Transplantation

In patients after allogeneic stem cell transplantation reactivation of latent herpesviruses such as Cytomegalovirus (CMV) and Epstein Barr Virus (EBV) is a frequent and life threatening complication requiring antiviral treatment. The underlying problem is a severe suppression of the donors immune system after transplantation into the patient. Herpesviruses such as CMV and EBV persist after primary infection life long in the host and therefore require constant immunological control. This control is largely provided by the T-cell compartment of the immune system. After allogeneic stem cell transplantation the T-cell compartment requires a long time for its reconstitution since only a small fraction of the donor T-cells are transplanted. During this time Herpesviruses can reoccur due to the lack of effective T-cell control.

This study therefore aims at reconstituting the T-cell compartment with CMV and EBV specific T-cells at an early time point after allogeneic stem cell transplantation. It is mainly a phase I study to demonstrate that these in vitro generated T-cells can be applied safely in this patient population. The study also aims at demonstrating the efficacy of CMV/EBV specific T-cells by monitoring viral reactivation and use of antiviral drugs. The hypothesis is, that CMV/EBV specific T-cell can be applied safely and do not result in graft versus host disease and that they successfully prevent reactivation of CMV and EBV after adoptive transfer in patients after allogeneic stem cell transplantation.

Study Overview

• Status: Completed
• Conditions: Patients Undergoing Allogeneic Stem Cell Transplantation
• Intervention / Treatment: Biological: CMV/EBV specific T-cell

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Germany
  • Augsburg, Germany, 86156
    • Medical Center Augsburg
  • Berlin, Germany, 13353
    • Charité University Hospital Berlin
  • Erlangen, Germany, 91054
    • Universitiy Hospital Erlangen
  • Mainz, Germany, 55131
    • University of Mainz
  • Munich, Germany, 81377
    • University of Munich LMU
  • Regensburg, Germany, 93053
    • University of Regensburg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Indication for allogeneic stem cell transplantation
• HLA identical donor, related or unrelated, 10/10 match
• Stem cell source: G-SCF mobilized peripheral blood stem cells
• Presence of at least one HLA allele: A0101, A0201, B0702, B0801, B3501, C0702
• Positive EBV serology of the donor
• Positive CMV serology of the donor
• Adequate contraception

Exclusion Criteria:

• Donor CMV seronegative
• Donor EBV seronegative
• Stem cell source: bone marrow or cord blood
• Alemtuzumab for conditioning
• Sorror Score >3
• Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Adoptive transfer of CMV/EBV specific T-cells; Repetitive adoptive T-cell transfer starting at day 30 after allogeneic stem cell transplantation.	Biological: CMV/EBV specific T-cell; Peptide stimulated allogeneic T-cells with dual specificity for CMV and EBV; Other Names: T cell
No Intervention: Control; Observation only.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity of adoptive transfer of CMV/EBV specific T-cells	Assessment of acute transfusion toxicity within 24 hours after adoptive T-cell transfer. Assessment of the development of acute transfusion associated acute graft versus host disease (GvHD) within 28 days after adoptive T-cell transfer	1-28 days after adoptive T-cell transfer

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Influence of preventative/preemptive adoptive transfer of CMV/EBV specific T-cells on virus reactivation	Incidence of reactivation of CMV and/or EBV during the observation period assessed by virus specific PCR of peripheral blood.	During observation period until day 204 post transplantation
Influence of preventative/preemptive adoptive transfer of CMV/EBV specific T-cells on the use of antiviral therapy	Cumulative dose of Ganciclovir, Valganciclovir, Foscarnet, Cidofovir	During observation period until day 204 post transplantation
Influence of preventative/preemptive adoptive transfer of CMV/EBV specific T-cells on the use of Rituximab	Cumulative dose of Rituximab.	During observation period until day 204 post transplantation
Influence of preventative/preemptive adoptive transfer of CMV/EBV specific T-cells on T-cell reconstitution	Immunomonitoring of peripheral blood by flow cytometry.	During observation period until day 204 post transplantation

Collaborators and Investigators

• Sponsor: University of Erlangen-Nürnberg Medical School
• Collaborators: German Research Foundation; Charite University, Berlin, Germany; Ludwig-Maximilians - University of Munich; Johannes Gutenberg University Mainz; University of Regensburg; University Hospital Augsburg; BayImmuNet Bavarian Immunotherapy Network
• Investigators: Study Director: Armin H Gerbitz, MD, PhD, Charite University, Berlin, Germany; Principal Investigator: Bernd Spriewald, MD, PhD, University Hospital Erlangen; Principal Investigator: Anita Kremer, MD,PhD, University Hospital Erlangen; Principal Investigator: Katja San Niccolo, MD, University Hospital Erlangen

Publications and helpful links

Helpful Links

• Dept. of Medicine 5, Hematology/Oncology, University of Erlangen

Study record dates

Study Major Dates

• Study Start: October 1, 2014
• Primary Completion (Actual): October 1, 2016
• Study Completion (Actual): March 1, 2017

Study Registration Dates

• First Submitted: August 26, 2014
• First Submitted That Met QC Criteria: August 27, 2014
• First Posted (Estimate): August 28, 2014

Study Record Updates

• Last Update Posted (Actual): December 14, 2020
• Last Update Submitted That Met QC Criteria: December 10, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: transplantation; Cytomegalovirus; CMV; Epstein Barr Virus; EBV; virus; T cell; allogeneic; adoptive transfer
• Other Study ID Numbers: AIT-MULTIVIR-01; 2012-004240-30 (EudraCT Number)