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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Progressive Multifocal Leukoencephalopathy

Intervention / Treatment
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* Biological: Collection of blood and urine
* Biological: Spinal tap
* Diagnostic Test: Brain MRI
* Biological: Neurological evaluation


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patients with active PML<br>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<br>* 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.<br>Biological: Spinal tap<br>* 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.<br>Diagnostic Test: Brain MRI<br>* Brain MRI at at PML diagnosis and 3 and 6 months after<br>Biological: Neurological evaluation<br>* Neurological evaluation at PML diagnosis and 1, 3 and 6 months after<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Progressive multifocal leukoencephalopathy, Pathophysiology, Immune checkpoint molecules, Immune Checkpoint Inhibitors