Clinical trial NCT04453917: Dynamics of T Cell Expression of Immune Checkpoint Molecules in Progressive Multifocal Leukoencephalopathy
Official title: Dynamics of T Cell Expression of Immune Checkpoint Molecules in Progressive Multifocal Leukoencephalopathy
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Progressive Multifocal Leukoencephalopathy
Keywords: Progressive multifocal leukoencephalopathy
Pathophysiology
Immune checkpoint molecules
Immune Checkpoint Inhibitors
Lead sponsor: University Hospital, Toulouse
Sponsor class: OTHER
First posted: 2020-07-01
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Patients with neurological symptoms (\< 3 months) with brain MRI lesions suggestive of PML and positive PCR in cerebrospinal fluid for JCV
Primary purpose: BASIC_SCIENCE

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.

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

Primary outcomes:
measure: Immune checkpoint molecules
timeFrame: 1 month
measure: Immune checkpoint molecules
timeFrame: 3 months
measure: Immune checkpoint molecules
timeFrame: 6 months
measure: JC viral load
timeFrame: 1 month
measure: JC viral load
timeFrame: 3 months
measure: JC viral load
timeFrame: 6 months
measure: Detection of immune responses against a JCV peptide library
timeFrame: 1 month
measure: Detection of immune responses against a JCV peptide library
timeFrame: 3 months
measure: Detection of immune responses against a JCV peptide library
timeFrame: 6 months
Secondary outcomes:
measure: Differential impact of immune checkpoint inhibition
timeFrame: 1 month, 3 months and 6 months
measure: Clinical outcome with Performance status
timeFrame: 1 month, 3 months and 6 months
measure: Clinical outcome with NIHSS
timeFrame: 1 month, 3 months and 6 months
measure: Clinical outcome with Rankin
timeFrame: 1 month, 3 months and 6 months
measure: Neuroradiological monitoring
timeFrame: 3 months and 6 months
measure: JC virus genotyping
timeFrame: 1 month, 3 months and 6 months
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: CHU Bordeaux
city: Montpellier
country: France
facility: CHU Montpellier
city: Nîmes
country: France
facility: CHU Nimes
city: Toulouse
country: France
facility: CHU de TOULOUSE
Study officials:
affiliation: CHU Toulouse
name: Guillaume MARTIN-BLONDEL
role: PRINCIPAL_INVESTIGATOR
References: