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

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.

Study Overview

• Status: Recruiting
• Conditions: Progressive Multifocal Leukoencephalopathy
• Intervention / Treatment: Biological: Collection of blood and urine; Biological: Spinal tap; Diagnostic test: Brain MRI; Biological: Neurological evaluation

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.

• Study Type: Interventional
• Enrollment (Estimated): 15
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Guillaume MARTIN-BLONDEL; Phone Number: 33 5 61 77 96 99; Email: martin-blondel.g@chu-toulouse.fr

Study Locations

• France
  • Bordeaux, France
    • Not yet recruiting
    • CHU Bordeaux
    • Contact: Charles Cazanave
  • Montpellier, France
    • Not yet recruiting
    • CHU Montpellier
    • Contact: Vincent LE MOING
  • Nîmes, France, 30029
    • Not yet recruiting
    • CHU Nîmes
    • Contact: Albert SOTTO
  • Toulouse, France, 31000
    • Recruiting
    • CHU de Toulouse
    • Contact: Charline Daguzan, PhD; Phone Number: 33 561778490; Email: daguzan.c@chu-toulouse.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• 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: 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

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.; 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.; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immune checkpoint molecules	Expression level of a broad panel of immune checkpoint molecules by T cells at PML diagnosis bu flow cytometry	1 month
Immune checkpoint molecules	Expression level of a broad panel of immune checkpoint molecules by T cells at PML diagnosis bu flow cytometry	3 months
Immune checkpoint molecules	Expression level of a broad panel of immune checkpoint molecules by T cells at PML diagnosis bu flow cytometry	6 months
JC viral load	JC viral load in cerebrospinal fluid, blood and urine by ultra-sensitive PCR at PML diagnosis	1 month
JC viral load	JC viral load in cerebrospinal fluid, blood and urine by ultra-sensitive PCR at PML diagnosis	3 months
JC viral load	JC viral load in cerebrospinal fluid, blood and urine by ultra-sensitive PCR at PML diagnosis	6 months
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
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
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Clinical outcome with Performance status	Clinical outcome using validated scales such as Performance status at PML diagnosis	1 month, 3 months and 6 months
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
Clinical outcome with Rankin	Clinical outcome using validated scales such as Rankin at PML diagnosis	1 month, 3 months and 6 months
Neuroradiological monitoring	Neuroradiological monitoring by brain MRI at PML diagnosis	3 months and 6 months
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

Collaborators and Investigators

• Sponsor: University Hospital, Toulouse
• Investigators: Principal Investigator: Guillaume MARTIN-BLONDEL, CHU Toulouse

Study record dates

Study Major Dates

• Study Start (Actual): February 23, 2021
• Primary Completion (Estimated): December 31, 2023
• Study Completion (Estimated): December 31, 2023

Study Registration Dates

• First Submitted: June 3, 2020
• First Submitted That Met QC Criteria: June 26, 2020
• First Posted (Actual): July 1, 2020

Study Record Updates

• Last Update Posted (Actual): July 28, 2023
• Last Update Submitted That Met QC Criteria: July 27, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Immune Checkpoint Inhibitors; Pathophysiology; Progressive multifocal leukoencephalopathy; Immune checkpoint molecules
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Virus Diseases; Infections; Demyelinating Diseases; Encephalitis, Viral; Central Nervous System Viral Diseases; Central Nervous System Infections; Infectious Encephalitis; DNA Virus Infections; Slow Virus Diseases; Encephalitis; Polyomavirus Infections; Neuroinflammatory Diseases; Leukoencephalopathy, Progressive Multifocal; Leukoencephalopathies
• Other Study ID Numbers: RC31/19/0506

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No