Virus-specific ImmunoTherapy Following Allogeneic Stem Cell Transplantation (VISIT)

Phase I/II: Treatment of Adenovirus and Cytomegalovirus Infection Post Human Allogeneic Stem Cell Transplantation With Short-term Expanded Virus-specific T Cells

Invasive infections with CMV and Adenovirus, not responding to virostatic treatment are treated with virusspecific donor derived or autologous virusspecific T-cells.

Study Overview

• Status: Withdrawn
• Conditions: Cytomegalovirus Infection; Adenovirus Infection
• Intervention / Treatment: Biological: virus-specific T-Cells

Detailed Description

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only treatment option for several haematological diseases. In spite of substantial progress in this field, viral infections, mainly cytomegalovirus (CMV) and adenovirus (HAdV) in the context of delayed immunoreconstitution remain life threatening complications. Weekly screening of high-risk patients and preemptive virostatic treatment has become a current strategy. Unfortunately, treatment with virostatic drugs is associated with substantial nephro- and myelo-toxicity and of limited effectiveness. Human adenovirus (HAdV) and cytomegalvirus (CMV) disseminated infections are associated with mortality rates of up to 50%-60% despite virostatic treatment.

All HSCT patients at the St. Anna Children's Hospital undergo weekly viral quantitative PCR-screening for HAdV and CMV and weekly PB FACS (Fluorescence Activated Cell Sorter)-Analysis according to the local HSCT-diagnostic SOP (Standard Operating Procedure) from day -7 until day +100 Patients with HAdV or CMV viremia will receive preemptive treatment with either gancyclovir (in case of isolated CMV-viremia) or Cidofovir (in case of HAdV viremia or combined HAdV/CMV infection). In case of increasing viremia ≥ 1log despite antiviral treatment for two weeks or stable with 10E6 viral load and the absence of virus specific T-cells in the recipient, the treating physician will check, if the patient is eligible for seVirus-T-cell infusion (see inclusion criteria).

Study Design: Mononuclear Donor-Cells from peripheral blood (100 ml extra donation) will be cryopreserved at the time-point of HSCT. In case of progredient viremia these cells will be stimulated with interleukin-15 and peptides out of the virus molecule, virusspecific T-Cells are enriched for 2-3 logs-teps and potentially alloreactive cells diluted at the same time. This new approach reduces the risk of graft-versus-host-disease (GvHD) and enables the infusion of virus-specific T-cells also from haploidentical donors.

• Study Type: Interventional
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • St. Anna Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age at timepoint of HSCT ≤18 years undergoing allogeneic stem cell transplantation
• Presence of HAdV or CMV-specific T-cells in the donor or CMV-specific T-cells in the recipient pre-transplant
• Stable (≥ 10E6) or increasing viremia despite antiviral treatment post HSCT
• Absence of HAdV or CMV -specific T cells post HSCT
• Karnofsky / Lansky score >50%
• Pregnancy excluded
• Informed study participation consent is signed

Exclusion Criteria:

• Infusion of polyclonal or monoclonal T-cell directed antibodies within 28 days before seVirus T-Cell infusion
• Multiple organ failure at screening-timepoint seVirus T-Cell infusion
• History of GvHD Gr III-IV or actual GvHD Gr III-IV
• Pregnancy
• Treatment with granulocyte transfusion within the last 72 hours
• Karnofsky / Lansky score <50%
• Subject is unwilling or unable to comply with the study procedures
• High dose treatment with steroids (≥ 2mg/kg/d, methylprednisone-equivalent)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ARM 1; Patients with Adenovirus or CMV infection after HSCT and no reduction of viral disease or stable disease with 10E6 viral copies within 2 weeks of antiviral treatment will receive a single infusion of virus-specific T-Cells	Biological: virus-specific T-Cells; infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Non pre-existing Immune System Disorders i.e. Allergic reaction, Anaphylaxis, Cytokine release syndrome or Serum sickness of Grade III-IV of seVirus-T-cell infusion within 48 hours from infusion	assessment is performed according to CTCAE 4.3 Scale	48 hours
De novo acute GvHD > Gr II or increase of pre-existing GvHD more than 1 grade from 2 weeks post infusion until 8 weeks post infusion	assessment is performed according to Glucksberg Scale, modified for paediatic patients from D. Jacobsohn (publication Blood 2008)	8 weeks
Incidence of graft rejection		8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Detection of virus-specific T-cells within 8 weeks after T-cell therapy. Measurement of the viral load following the infusion of seVirus-T-cells		6 months
Correlation of the presence of virus-specific T-cells with partial reduction (>1 log viral copies /ml blood) or complete clearance of viral load		8 weeks
Tracking of the infused T-cells by NGS (Next Generation Sequencing) of the TCRs (T-Cell Receptors)-beta rearrangements	PBMCs (isolated from about 10ml of peripheral blood) will be resuspended in TRIzol, a ready to use mixture important for later DNA isolation. The samples will undergo DNA isolation using a multiplex TCR-beta PCR approach in combination with NGS of the generated amplicons and detailed bioinformatic interpretation of the generated sequence data. Current high-throughput sequencing technologies such as Illumina, (HiSeq) enable the analysis of T-cell receptor repertoires in an unprecedented depth. As every T-cell harbours a unique TCR-beta rearrangement, we will be able to track T-cell expansion even on a single cell level.	3 months

Collaborators and Investigators

• Sponsor: St. Anna Kinderkrebsforschung
• Investigators: Principal Investigator: Susanne Matthes, MD, St. Anna Kinderkrebsforschung

Study record dates

Study Major Dates

• Study Start (Actual): August 3, 2016
• Primary Completion (Actual): April 1, 2019
• Study Completion (Actual): April 1, 2019

Study Registration Dates

• First Submitted: March 1, 2016
• First Submitted That Met QC Criteria: March 3, 2016
• First Posted (Estimate): March 8, 2016

Study Record Updates

• Last Update Posted (Actual): May 9, 2019
• Last Update Submitted That Met QC Criteria: May 7, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: viral infections post HSCT, virus-specific T-cells
• Additional Relevant MeSH Terms: Pathologic Processes; Virus Diseases; Disease Attributes; DNA Virus Infections; Herpesviridae Infections; Infections; Communicable Diseases; Cytomegalovirus Infections; Adenoviridae Infections
• Other Study ID Numbers: Eudra CT2013-002492-17

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: not planned yet