Dynamics of T Cell Expression of Immune Checkpoint Molecules in Progressive Multifocal Leukoencephalopathy

Progressive Multifocal Leukoencephalopathy Clinical Trial

— ICIP  

Official title:

Dynamics of T Cell Expression of Immune Checkpoint Molecules in Progressive Multifocal Leukoencephalopathy

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04453917
• Other study ID #: RC31/19/0506
• Status: Recruiting
• Phase: N/A
• Start date: February 23, 2021
• Est. completion date: December 31, 2023

Study information

• Verified date: July 2023
• Source: University Hospital, Toulouse
• Contact: Guillaume MARTIN-BLONDEL
• Phone: 5 61 77 96 99
• Email: martin-blondel.g[@]chu-toulouse.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 15
• Est. completion date: December 31, 2023
• Est. primary completion date: December 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Leukoencephalopathies
• Leukoencephalopathy, Progressive Multifocal
• Progressive Multifocal Leukoencephalopathy

Intervention

Biological:
• Collection of blood and urine
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.
• Spinal tap
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.

Diagnostic Test:
• Brain MRI
Brain MRI at at PML diagnosis and 3 and 6 months after

Biological:
• Neurological evaluation
Neurological evaluation at PML diagnosis and 1, 3 and 6 months after

Locations

Country	Name	City	State
France	CHU Bordeaux	Bordeaux
France	CHU Montpellier	Montpellier
France	CHU Nimes	Nîmes
France	CHU de TOULOUSE	Toulouse

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Toulouse

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Immune checkpoint molecules	Expression level of a broad panel of immune checkpoint molecules by T cells at PML diagnosis bu flow cytometry	1 month
Primary	Immune checkpoint molecules	Expression level of a broad panel of immune checkpoint molecules by T cells at PML diagnosis bu flow cytometry	3 months
Primary	Immune checkpoint molecules	Expression level of a broad panel of immune checkpoint molecules by T cells at PML diagnosis bu flow cytometry	6 months
Primary	JC viral load	JC viral load in cerebrospinal fluid, blood and urine by ultra-sensitive PCR at PML diagnosis	1 month
Primary	JC viral load	JC viral load in cerebrospinal fluid, blood and urine by ultra-sensitive PCR at PML diagnosis	3 months
Primary	JC viral load	JC viral load in cerebrospinal fluid, blood and urine by ultra-sensitive PCR at PML diagnosis	6 months
Primary	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	1 month
Primary	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	3 months
Primary	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	6 months
Secondary	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	1 month, 3 months and 6 months
Secondary	Clinical outcome with Performance status	Clinical outcome using validated scales such as Performance status at PML diagnosis	1 month, 3 months and 6 months
Secondary	Clinical outcome with NIHSS	Clinical outcome using validated scales such as NIHSS (National Institute of Health Stroke Score) at PML diagnosis	1 month, 3 months and 6 months
Secondary	Clinical outcome with Rankin	Clinical outcome using validated scales such as Rankin at PML diagnosis	1 month, 3 months and 6 months
Secondary	Neuroradiological monitoring	Neuroradiological monitoring by brain MRI at PML diagnosis	3 months and 6 months
Secondary	JC virus genotyping	JC virus genotyping in blood, cerebrospinal fluid (CSF) and urine by ultra-sensitive PCR at PML diagnosis	1 month, 3 months and 6 months