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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Patients Undergoing Allogeneic Stem Cell Transplantation

Intervention / Treatment
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* Biological: CMV/EBV specific T-cell


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CMV, EBV, Cytomegalovirus, Epstein Barr Virus, virus, T cell, adoptive transfer, transplantation, allogeneic