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

NCT ID: NCT04453917

Last Updated: 2025-12-31

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 22 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-02-23
• Study Completion Date: 2024-07-12

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.

Conditions

Progressive Multifocal Leukoencephalopathy

Keywords

Progressive multifocal leukoencephalopathy; Pathophysiology; Immune checkpoint molecules; Immune Checkpoint Inhibitors

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Patients with active PML

Patients with neurological symptoms (\< 3 months) with brain MRI lesions suggestive of PML and positive PCR in cerebrospinal fluid for JCV

Group Type: EXPERIMENTAL

Collection of blood and urine

Intervention Type: BIOLOGICAL

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

Intervention Type: BIOLOGICAL

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.

Brain MRI

Intervention Type: DIAGNOSTIC_TEST

Brain MRI at at PML diagnosis and 3 and 6 months after

Neurological evaluation

Intervention Type: BIOLOGICAL

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

Interventions

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.

Intervention Type: BIOLOGICAL

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.

Intervention Type: BIOLOGICAL

Brain MRI

Brain MRI at at PML diagnosis and 3 and 6 months after

Intervention Type: DIAGNOSTIC_TEST

Neurological evaluation

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

Intervention Type: BIOLOGICAL

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Hospital, Toulouse

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Guillaume MARTIN-BLONDEL

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Toulouse

Locations

CHU Bordeaux

Bordeaux, , France

CHU Montpellier

Montpellier, , France

CHU de TOULOUSE

Toulouse, , France

Countries

France

Other Identifiers

RC31/19/0506

Identifier Type: -

Identifier Source: org_study_id