CMV Specific T Cell Therapy After Allogeneic Stem Cell Transplantation.

December 19, 2022 updated by: University Hospital, Ghent

CMV Specific T Cell Therapy for the Treatment of Relapsing or Therapy Refractory CMV Infection After Allogeneic Stem Cell Transplantation With a CMV-positive Donor.

Viral infections remain an important cause of morbidity and mortality after allogeneic stem cell transplantation (SCT), especially after myelo-ablative conditioning and if the donor is antigen-mismatched or haplo-identical.. In the described setting the patient's own immune system has been destroyed by the necessary highly immuno- and myelo-ablative conditioning and all memory against infections has been deleted. Therefore, there is a high risk for several viral infections and other infectious organisms.Both primary viral infections and reactivations can occur, and patients can become refractory to antiviral treatments, or in some cases an adequate antiviral treatment is unavailable or too toxic. In this study, the investigators will target CMV, as refractory CMV infection and disease is accompanied by an extremely high mortality rate and therefore the development of new treatment approaches is required. Despite the available antiviral drugs, a considerable number of patients are facing an insufficient control of CMV reactivation after SCT. Because reconstitution of CMV-specific T cells confer protection against the development of CMV disease after SCT, attempts have been made to restore antiviral immunity by direct infusion of CMV-specific T cells. Most clinical cellular immunotherapy protocols for CMV treatment have used CMV-specific cytotoxic CD8+ T-cell lines generated by repetitive in vitro stimulation with CMV antigens with success. Despite the proven efficacy, use of cellular therapy in the clinic has been limited, because the approach is time and labor consuming and requires specialized facility allowing handling of the therapeutic cells according to good manufacturing practice. In addition, no sustained response was seen after adoptive transfer that involved only cytotoxic CD8+ T cells. This phenomenon is supported by the fact that recall responses to latent infections depend on the presence of CD4+ T cells to help cytotoxic CD8+ T cells. An alternative approach for the transfer of T-cell immunity is the isolation of Ag-specific T cells ex vivo from the blood of CMV seropositive donors, based on interferon γ (IFN-γ) secretion of T cells after in vitro stimulation with viral Ag, resulting in a combination of CD4+ T helper and cytotoxic CD8+ CMV specific T cells. Using this strategy, a short-term ex vivo protocol was developed for the isolation of pp65 (CMV immunodominant protein)-specific T cells. Since then, several centers have used this protocol in the clinic, infusing low numbers of pp65-specific T cells, that were able to restore protective T-cell immunity against CMV in a post SCT setting in patients with refractory CMV disease or viremia. For this protocol the investigators have set up and validated this method of CMV-specific T-cell generation in the Ghent University Hospital and the investigators will make it available for other Belgian transplant centers.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
1

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Belgium
      • Antwerpen, Belgium, 2060
        • ZNA Stuivenberg
      • Brugge, Belgium, 8000
        • AZ Sint-Jan Brugge
      • Brussel, Belgium, 1200
        • Cliniques Universitaires Saint Luc
      • Brussel, Belgium, 1090
        • Universitair Ziekenhuis Brussel
      • Brussel, Belgium, 1000
        • Institut Jules Bordet
      • Luik, Belgium, 4000
        • Université de Liège
      • Roeselare, Belgium, 8800
        • Heilig Hart Ziekenhuis Roeselare
    • Oost-Vlaanderen
      • Gent, Oost-Vlaanderen, Belgium, 9000
        • Universitair Ziekenhuis Gent

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

12 years to 71 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patients:

    1. All underlying diseases that form an indication for allogeneic stem cell transplantation
    2. Underwent allogeneic stem cell transplantation with a donor that fulfills the following criteria:
  • CMV-seropositive at the time of transplant and
  • Age 18-70 years 3) Having a CMV reactivation or primary infection or disease with the following characteristics: CMV PCR at least twice positive AND CMV infection relapsing after 3 successful treatment episodes with gancyclovir OR Refractory to treatment with available antiviral drugs which is defined as follows: Persistent positive CMV PCR > detection limit 14 days after initiation of antiviral treatment OR increasing CMV viral load 7 days after initiation of antiviral treatment 4) Informed consent given

  • Donor:

    1. Is identical to donor of the previous stem cell transplant
    2. The donor will be pre-screened for the presence of sufficient numbers of CMV-specific T cells:
  • IFNgamma producing T cells upon CMVpp65 stimulation are at least twice the background level (unstimulated cells)
  • At least 10 events of IFNgamma positive T cells are measured
  • IFNgamma producing T cells upon CMVpp65 stimulation are equal or higher than 0,1% of the viable CD4+ and CD8+ cell population If the donor shows sufficient number of circulating CMV-specific cells, according to the test described in 2 3) Only if the donor shows sufficient number of circulating CMV-specific cells, according to the test described in 2:
  • Donor has positive IgG serology for CMV, IgM negative or positive
  • Donor has signed informed consent for the donation of donor lymphocyte cells
  • Donor is found fit for donation by a medical doctor according to selection criteria conform KB annex II (C-2009/18414)
  • Donor is negative for infectious disease markers including HCV, HBV and HIV-NAT testing: HBs antigen, HBc/HBs antibodies, Syphilis (TPHA or equivalent), HVC and HIV antibodies.
  • Additional testing should be performed and negative when relevant: malaria, west nile virus, trypanosomiasis, HTLV conform KB annex II (C-2009/18414)
  • HCG negative within 7 days of apheresis

Exclusion Criteria:

  • Patients:

    1. HIV, HCV, HBV positive (HbSAg positivity after vaccination is allowed)
    2. Life expectancy severely limited by disease other than malignancy or viral infection
    3. Administration of cytotoxic agent(s) for cytoreduction within three weeks prior to initiation of the treatment or to be expected within 8 weeks after administration of the treatment
    4. Terminal organ failure except for renal failure (dialysis acceptable)
    5. Uncontrolled other infection than the one being treated
    6. Karnofsky performance score < 60%
    7. Patient is a fertile man or woman who is unwilling to use contraceptive techniques during and for 12 months following treatment
    8. Patient is a female who is pregnant or breastfeeding
    9. Patient with active aGVHD grade 3 or more
    10. Patient with severe chronic GVHD
    11. Patient on corticosteroids > 0.5mg/kg. Patient can still be on therapeutic doses of immunosuppressive therapy, but these will be tapered to the lowest possible dose, as is part of standard care in case of CMV reactivation.
    12. Patient that has received ATG < 1 month prior to infusion or Campath < 1 year prior to infusion
    13. Any condition not fulfilling inclusion criteria

  • Donor:

    1. Any condition not fulfilling inclusion criteria

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Treatment group
The patients for which a suitable donor product can be obtained will be included in the treatment arm of the protocol. Treatment consists of the administration of CMV-specific T-cells, administered through intravenous transfusion. Depending on response in viral load and GVHD status, a second and/or third administration is possible.
Genetic: CMV-specific T cells
Active Comparator: Control group
Patients for which the investigator can't obtain a suitable donor product, will be included in the control group consisting of standard anti-viral treatment.
Drug: Standard anti-viral therapy
Continue with the anti-viral treatment as per standard of care.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Percentage of patients for whom the investigator can manufacture a product that meets release criteria, and can therefore receive the product.
Time Frame: Within 1 year after the last follow-up visit of the last patient.
Starting from patients and donors that fulfill all inclusion criteria and do not have any exclusion criterium, and donors fulfilling all pre-apheresis criteria.
Within 1 year after the last follow-up visit of the last patient.
Safety of the administered cell product in terms of Graft-versus-Host-Disease occurence/worsening.
Time Frame: Within 1 year after the last follow-up visit of the last patient.
Evaluation of the frequency of patients who develop de novo or recurrent (with a history of (completely recovered)) acute GVHD grade 2 or more or show worsening of an existing aGVHD with at least 1 grade, or emergence of an additional organ involved.
Within 1 year after the last follow-up visit of the last patient.

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Clinical efficacy measured by change in CMV PCR or resolution of CMV disease.
Time Frame: Within 1 year after the last follow-up visit of the last patient.
Clinical efficacy has already been shown (albeit not in a randomized phase 3 trial) but as there is no alternative therapy for these patients (except for continuing the therapy they are already getting and to which they are not (longer) responding, this study is not placebo or best supportive care controlled, but is designed as a single arm study. However, by including all patients who can get the product in the treatment arm and those who can't get the product in the observational arm, the study will be able to have a control group without randomization.
Within 1 year after the last follow-up visit of the last patient.
Evaluation of infusion related adverse event as per CTCAE 4.03.
Time Frame: Within 1 year after the last follow-up visit of the last patient.
Within 1 year after the last follow-up visit of the last patient.
Explore the relationship between the presence of CMV specific T cells in the peripheral blood of the patient and the objective clinical response
Time Frame: Within 1 year after the last follow-up visit of the last patient.
Within 1 year after the last follow-up visit of the last patient.
Make the treatment of relapsing or refractory CMV infection after allogeneic stem cell transplantation with CMV-specific T cell therapy from the CMV positive donor available for patients in Belgium
Time Frame: Within 1 year after the last follow-up visit of the last patient.
Within 1 year after the last follow-up visit of the last patient.
Compare resistance to antiviral therapy in both arms (investigational vs. observational) b measuring change in CMV PCR or evaluating resolution of CMV disease.
Time Frame: Within 1 year after the last follow-up visit of the last patient.
Within 1 year after the last follow-up visit of the last patient.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University Hospital, Ghent

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Tessa Kerre, MD, PhD, University Hospital, Ghent

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
October 1, 2016

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 31, 2021

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 31, 2021

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
October 6, 2016

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 23, 2017

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
March 1, 2017

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
December 21, 2022

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 19, 2022

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
December 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • BHS-TJT1401
  • 2013-004953-26 (EudraCT Number)
  • BHS-TC13 (Other Identifier: Belgian Hematological Society)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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