Wattjes, Department of Diagnostic and Interventional Radiology, Hannover Medical School, Hannover, Germany. Ortwin Adams, Department of Virology, University or college Hospital Dsseldorf, Dsseldorf, Germany. Sandra Nay, Department of Neurology, Hannover Medical School, Hannover, Germany. Daria Tkachenko, Department of Neurology, Hannover Medical School, Hannover, Germany. Friederike Salge, Department of Neurology, Hannover Medical School, Hannover, Germany. Johanne Heine, Department of Neurology, Hannover Medical School, Hannover, Germany. Kaweh Pars, Department of Neurology, Western Medical School, University or college Oldenburg, Oldenburg, Germany. Gnter H?glinger, Department of Neurology, Hannover Medical School, Hannover, Germany. Gesine Respondek, Department of Neurology, Hannover Medical School, Hannover, Germany. Martin Stangel, Department of Neurology, Hannover Medical School, Hannover, Germany. Thomas Skripuletz, Department of Neurology, Hannover Medical School, Hannover, Germany. Roland Jacobs, Department of Rheumatology & Clinical Immunology, Hannover Medical School, Hannover, Germany. Kurt-Wolfram Shs, Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. restored, PML progresses rapidly and often ends fatally within months. Recently, some evidence for positive response has been reported in patients treated with immune checkpoint inhibitor therapy. Here, we provide a case series of three PML patients with underlying hematological malignancies who were treated with anti-PD-1-antibody pembrolizumab at Hannover Medical School. All patients received an extensive diagnostic follow-up Rabbit Polyclonal to FOXO1/3/4-pan (phospho-Thr24/32) including cerebrospinal fluid analysis, brain imaging, and lymphocyte-phenotyping circulation cytometry. Our patients had very different outcomes, with the only patient showing a specific anti-JCPyV immune response in the sense of an increased JCPyV antibody index clearly benefiting most from the treatment. Our results partly support the hypothesis that anti-PD-1 therapy may represent AEZS-108 a encouraging treatment option for patients with PML. However, there is a current lack of pre-therapeutic stratification regarding the therapeutic response rates. Before larger studies can be initiated to further evaluate the efficacy of anti-PD-1 antibodies in PML, it is imperative to develop a reliable strategy for selecting suitable patients. Keywords: circulation cytometry, immune checkpoint inhibitor, Progressive multifocal leukencephalopathy, PD-1 Introduction Progressive multifocal leukoencephalopathy (PML) is an opportunistic contamination of the brain caused by reactivation of human JC polyoma computer virus (JCPyV) leading to a lytic contamination of oligodendrocytes and neuronal cells.1 Typically, PML presents with multifocal areas of demyelination particularly in the deep and juxtacortical white matter.2 It is assumed that the computer virus establishes low-level persistent or latent infections in the kidney and in bone marrow-derived cells largely due to inefficient viral replication in these cell types.3 The major tropism of JCPyV for human glial cells is not fully understood, but host cell- and species-specific transcription and replication factors seem to be responsible for contributing to strong viral replication in this cell type.4 PML and other JCPyV related diseases such as granule cell neuronopathy and JCPyV encephalopathy almost exclusively occur in immunocompromised patients. The spectrum of immunosuppressive conditions related to PML is usually broad and heterogenous. In general, PML is usually a relatively rare disease, but it represents the most frequent opportunistic contamination of the brain in therapy-related immunosuppression.5 The clinical outcome in terms of mortality and long-term neurologic morbidity depends on the underlying immunosuppressive condition and the possibility to reverse this, that is, whether immunosuppressive treatments can be stopped or the immune deficiency be counterbalanced. In general, post-transplantation PML seems to have a higher case fatality rate compared with PML in HIV patients on highly-active antiretroviral therapy or in multiple sclerosis patients treated with natalizumab.6 The diagnosis of PML is AEZS-108 based on the clinical presentation, imaging findings, and the detection of JCPyV DNA in the cerebrospinal fluid (CSF).7,8 There is no efficient therapy available. Several approaches such as treatment with mirtazapine or mefloquine have been examined with poor results.9 Survival depends on the ability to accomplish timely immune reconstitution. Thus, withdrawal of immunosuppressive drugs or, rather, provision of antiretroviral therapy are the only methods to show a survival benefit so far.7 More recently, some evidence for positive response has been reported in patients treated with immune checkpoint inhibitor therapy.10C15 The blockade of checkpoint molecules such as PD-1, PD-L1, and CTLA-4, with monoclonal antibodies, has enabled the development of breakthrough therapies in oncology. Several observations suggest that the PD-1 pathway may be of relevance in PML as the percentage of PD-1 positive AEZS-108 T-cells is usually elevated in blood and CSF of PML patients compared with healthy individuals.10 Based on this observation, anti-PD-1 therapy was assumed to have the potential to activate T-cells and consecutively clear JCPyV from your central nervous system (CNS) of.