Dynamics of T Cell Expression of Immune Checkpoint Molecules in Progressive Multifocal Leukoencephalopathy (ICIP)
Primary Purpose
Progressive Multifocal Leukoencephalopathy
Status
Recruiting
Phase
Not Applicable
Locations
France
Study Type
Interventional
Intervention
Collection of blood and urine
Spinal tap
Brain MRI
Neurological evaluation
Sponsored by
About this trial
This is an interventional basic science trial for Progressive Multifocal Leukoencephalopathy focused on measuring Progressive multifocal leukoencephalopathy, Pathophysiology, Immune checkpoint molecules, Immune Checkpoint Inhibitors
Eligibility Criteria
Inclusion Criteria:
- Adults ≥18 years old
- Informed consent
- Active virological PML : Recent neurological symptoms (< 3 months) with brain MRI lesions suggestive of PML and positive PCR in cerebrospinal fluid for JCV
- Affiliated or benefiting from public health insurance.
Exclusion Criteria:
- Non active PML
- Possible PML with negative JCV PCR
- Adults under guardianship or other legal protection, deprived of their liberty by judicial or administrative decision
- Pregnant and/or breastfeeding women
Sites / Locations
- CHU Bordeaux
- CHU Montpellier
- CHU Nimes
- CHU de TOULOUSERecruiting
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Patients with active PML
Arm Description
Patients with neurological symptoms (< 3 months) with brain MRI lesions suggestive of PML and positive PCR in cerebrospinal fluid for JCV
Outcomes
Primary Outcome Measures
Immune checkpoint molecules
Expression level of a broad panel of immune checkpoint molecules by T cells at PML diagnosis bu flow cytometry
Immune checkpoint molecules
Expression level of a broad panel of immune checkpoint molecules by T cells at PML diagnosis bu flow cytometry
Immune checkpoint molecules
Expression level of a broad panel of immune checkpoint molecules by T cells at PML diagnosis bu flow cytometry
JC viral load
JC viral load in cerebrospinal fluid, blood and urine by ultra-sensitive PCR at PML diagnosis
JC viral load
JC viral load in cerebrospinal fluid, blood and urine by ultra-sensitive PCR at PML diagnosis
JC viral load
JC viral load in cerebrospinal fluid, blood and urine by ultra-sensitive PCR at PML diagnosis
Detection of immune responses against a JCV peptide library
Detection of specific immune responses against a JCV peptide library at PML diagnosis by flow cytometry
Detection of immune responses against a JCV peptide library
Detection of specific immune responses against a JCV peptide library at PML diagnosis by flow cytometry
Detection of immune responses against a JCV peptide library
Detection of specific immune responses against a JCV peptide library at PML diagnosis by flow cytometry
Secondary Outcome Measures
Differential impact of immune checkpoint inhibition
Differential impact of immune checkpoint inhibition in vitro on detection of specific immune responses at PML diagnosis by flow cytometry
Clinical outcome with Performance status
Clinical outcome using validated scales such as Performance status at PML diagnosis
Clinical outcome with NIHSS
Clinical outcome using validated scales such as NIHSS (National Institute of Health Stroke Score) at PML diagnosis
Clinical outcome with Rankin
Clinical outcome using validated scales such as Rankin at PML diagnosis
Neuroradiological monitoring
Neuroradiological monitoring by brain MRI at PML diagnosis
JC virus genotyping
JC virus genotyping in blood, cerebrospinal fluid (CSF) and urine by ultra-sensitive PCR at PML diagnosis
Full Information
NCT ID
NCT04453917
First Posted
June 3, 2020
Last Updated
July 27, 2023
Sponsor
University Hospital, Toulouse
1. Study Identification
Unique Protocol Identification Number
NCT04453917
Brief Title
Dynamics of T Cell Expression of Immune Checkpoint Molecules in Progressive Multifocal Leukoencephalopathy
Acronym
ICIP
Official Title
Dynamics of T Cell Expression of Immune Checkpoint Molecules in Progressive Multifocal Leukoencephalopathy
Study Type
Interventional
2. Study Status
Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
February 23, 2021 (Actual)
Primary Completion Date
December 31, 2023 (Anticipated)
Study Completion Date
December 31, 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Toulouse
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
5. Study Description
Brief Summary
Progressive multifocal leukoencephalopathy (PML) is a rare viral infection of the central nervous system (CNS) occurring in immunocompromised patients. Recovery of JC virus (JCV) specific T cell immune responses is the only available therapeutic option. JCV may use immune checkpoint inhibitory pathways to evade immune responses. The aim of this project is to determine whether T cell expression of immune checkpoint molecules is correlated to antiviral T cell responses, control of JCV replication and PML outcome. Immune checkpoint blockade by reversing T cell exhaustion may represent a therapeutic perspective for PML.
Detailed Description
PML is a devastating orphan disease of the CNS due to the reactivation of JCV in immunocompromised patients. Given the lack of drugs controlling JCV replication, initiation of antiretroviral therapy in HIV-infected patients or cessation of immunosuppressive therapies in others, and subsequent recovery of JCV-specific T cell immune responses remains to date the only available therapeutic option. Promoting antiviral immune responses may improve the control of viral replication and the outcome of this severe disease. Immune checkpoint molecules such as PD-1 are inhibitory receptors expressed on T cells that trigger inhibitory signaling pathways, limiting effector immune responses in cancer and chronic infections. Immune checkpoint inhibitory pathways implicated in evading immune responses may be at play in PML. Immune checkpoint blockade using monoclonal antibodies targeting PD-1, by reversing T cell exhaustion, has been suggested as a therapeutic perspective for PML. More insights in the dynamics of immune checkpoint molecules expressed by T cells in PML patients are needed to pave the way for a therapeutic study.
The aim here is to determine whether T cell expression of a broad range of immune checkpoint molecules, and its dynamics, correlates with the generation of antiviral of immune responses, the control of JCV replication and PML outcome.
To this end the investigators will recruit 15 PML patients from 4 teaching hospitals in the South West of France and assess at PML diagnosis and 1, 3 and 6 months after, the expression of immune checkpoint molecules on circulating T cells, ex vivo specific immune responses against a JCV peptide library, JC viral load in cerebrospinal fluid, blood and urine, and clinical and neuroradiological outcomes.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Progressive Multifocal Leukoencephalopathy
Keywords
Progressive multifocal leukoencephalopathy, Pathophysiology, Immune checkpoint molecules, Immune Checkpoint Inhibitors
7. Study Design
Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Model Description
Patients with neurological symptoms (< 3 months) with brain MRI lesions suggestive of PML and positive PCR in cerebrospinal fluid for JCV
Masking
None (Open Label)
Allocation
N/A
Enrollment
15 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Patients with active PML
Arm Type
Experimental
Arm Description
Patients with neurological symptoms (< 3 months) with brain MRI lesions suggestive of PML and positive PCR in cerebrospinal fluid for JCV
Intervention Type
Biological
Intervention Name(s)
Collection of blood and urine
Intervention Description
Collection of blood (47 mL) and urine (5 mL) at PML diagnosis and 1, 3 and 6 months after, for analysis of immune checkpoint molecules expression, detection of antiviral immune responses and virological analyses.
Intervention Type
Biological
Intervention Name(s)
Spinal tap
Intervention Description
Spinal tap for monitoring of JC viral load at PML diagnosis and 1, 3 and 6 months after, and collection of CSF (2 mL) for virological analyses.
Intervention Type
Diagnostic Test
Intervention Name(s)
Brain MRI
Intervention Description
Brain MRI at at PML diagnosis and 3 and 6 months after
Intervention Type
Biological
Intervention Name(s)
Neurological evaluation
Intervention Description
Neurological evaluation at PML diagnosis and 1, 3 and 6 months after
Primary Outcome Measure Information:
Title
Immune checkpoint molecules
Description
Expression level of a broad panel of immune checkpoint molecules by T cells at PML diagnosis bu flow cytometry
Time Frame
1 month
Title
Immune checkpoint molecules
Description
Expression level of a broad panel of immune checkpoint molecules by T cells at PML diagnosis bu flow cytometry
Time Frame
3 months
Title
Immune checkpoint molecules
Description
Expression level of a broad panel of immune checkpoint molecules by T cells at PML diagnosis bu flow cytometry
Time Frame
6 months
Title
JC viral load
Description
JC viral load in cerebrospinal fluid, blood and urine by ultra-sensitive PCR at PML diagnosis
Time Frame
1 month
Title
JC viral load
Description
JC viral load in cerebrospinal fluid, blood and urine by ultra-sensitive PCR at PML diagnosis
Time Frame
3 months
Title
JC viral load
Description
JC viral load in cerebrospinal fluid, blood and urine by ultra-sensitive PCR at PML diagnosis
Time Frame
6 months
Title
Detection of immune responses against a JCV peptide library
Description
Detection of specific immune responses against a JCV peptide library at PML diagnosis by flow cytometry
Time Frame
1 month
Title
Detection of immune responses against a JCV peptide library
Description
Detection of specific immune responses against a JCV peptide library at PML diagnosis by flow cytometry
Time Frame
3 months
Title
Detection of immune responses against a JCV peptide library
Description
Detection of specific immune responses against a JCV peptide library at PML diagnosis by flow cytometry
Time Frame
6 months
Secondary Outcome Measure Information:
Title
Differential impact of immune checkpoint inhibition
Description
Differential impact of immune checkpoint inhibition in vitro on detection of specific immune responses at PML diagnosis by flow cytometry
Time Frame
1 month, 3 months and 6 months
Title
Clinical outcome with Performance status
Description
Clinical outcome using validated scales such as Performance status at PML diagnosis
Time Frame
1 month, 3 months and 6 months
Title
Clinical outcome with NIHSS
Description
Clinical outcome using validated scales such as NIHSS (National Institute of Health Stroke Score) at PML diagnosis
Time Frame
1 month, 3 months and 6 months
Title
Clinical outcome with Rankin
Description
Clinical outcome using validated scales such as Rankin at PML diagnosis
Time Frame
1 month, 3 months and 6 months
Title
Neuroradiological monitoring
Description
Neuroradiological monitoring by brain MRI at PML diagnosis
Time Frame
3 months and 6 months
Title
JC virus genotyping
Description
JC virus genotyping in blood, cerebrospinal fluid (CSF) and urine by ultra-sensitive PCR at PML diagnosis
Time Frame
1 month, 3 months and 6 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Adults ≥18 years old
Informed consent
Active virological PML : Recent neurological symptoms (< 3 months) with brain MRI lesions suggestive of PML and positive PCR in cerebrospinal fluid for JCV
Affiliated or benefiting from public health insurance.
Exclusion Criteria:
Non active PML
Possible PML with negative JCV PCR
Adults under guardianship or other legal protection, deprived of their liberty by judicial or administrative decision
Pregnant and/or breastfeeding women
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Guillaume MARTIN-BLONDEL
Phone
5 61 77 96 99
Ext
33
Email
martin-blondel.g@chu-toulouse.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Guillaume MARTIN-BLONDEL
Organizational Affiliation
CHU Toulouse
Official's Role
Principal Investigator
Facility Information:
Facility Name
CHU Bordeaux
City
Bordeaux
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Charles CAZANAVE
Facility Name
CHU Montpellier
City
Montpellier
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Vincent LE MOING
Facility Name
CHU Nimes
City
Nîmes
ZIP/Postal Code
30029
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Albert SOTTO
Facility Name
CHU de TOULOUSE
City
Toulouse
ZIP/Postal Code
31000
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Charline Daguzan, PhD
Phone
561778490
Ext
33
Email
daguzan.c@chu-toulouse.fr
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Dynamics of T Cell Expression of Immune Checkpoint Molecules in Progressive Multifocal Leukoencephalopathy
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