Translational Studies in Progressive Multifocal Leukoencephalopathy

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications & trials

Abstract

The NINDS Experimental Immunotherapeutics Unit (EIU) was established in April 2021. Since that time, progress has been made toward establishing the infrastructure of the unit and toward accomplishing the Specific Aims. Aim 1 is primarily addressed through the EIU PML Natural History Study (NCT01730131). This study enrolls patients with confirmed or suspected PML, as well as disease controls and healthy volunteers. Participants follow scheduled collection of clinical, radiological, immunological and virological outcomes with the purpose of defining the natural history of JCV infection and PML, and of developing and validating biomarkers of disease and recovery. In collaboration with the Translational Neuroradiology Section (TNS), in FY21 our longitudinal MRI data enabled the development of an automated method for segmentation of PML lesions and estimation of lesion burden; this tool was subsequently used for MRI analysis of our pilot study of adoptive immunotherapy. Also under Aim 1, we have begun work in establishing a PML brain bank, which, coupled with post-mortem imaging being pursued in collaboration with the Quantitative MRI Core Facility, will provide the unique ability to investigate radiological-histological-molecular characterization with correlation to clinical outcomes. For Aim 2, our underlying hypothesis is that immune reconstitution strategies are a viable treatment approach for PML. Our previous experience using checkpoint inhibition as a strategy for reinvigorating anti-viral immune responses supported this hypothesis, but also highlighted the highly heterogenous nature of underlying immune suppression across patients with PML. Indeed, for many patients with underlying systemic autoimmune disease, general immune reconstitution strategies represent a serious risk of exacerbating immune-mediated disease in vital organs, which can similarly be life-threatening. For others, with severely depressed or dysfunctional immune systems, immune reconstitution strategies that rely on reinvigoration or expansion of existing immune cells, are simply ineffective. Thus it is expected it will be necessary to tailor such treatment strategies to increase possibility of benefit and minimize risk. During FY21 we published results of our pilot study of adoptive immunotherapy for the treatment of PML using anti-viral T cells generated from haploidentical 1st degree relatives, conducted with the NINDS Neuroimmunology Clinic, NHLBI Hematology Branch, and the NIH Center for Cellular Engineering (NCT02694783). We further developed and opened enrolment for a new interventional study using long-acting recombinant IL-7 as a strategy to reconstitute severely lymphopenic patients with PML (NCT04781309). IL-7 is a naturally occurring cytokine involved in maintaining T cell homeostasis; pharmacologically, this molecule can reconstitute lymphopenic patients, re-establishing healthy repertoire diversity. Isolated reports suggest benefit of treatment with IL-7 in PML. For Aim 3, in collaboration with the Viral Immunology Section, we have established in-vitro assays for characterization of JCV antiviral immune response, now being routinely used in our natural history cohort and as exploratory outcomes in our interventional patient cohorts.