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Multifocal Electroretinograms
Published on: December 4, 2011
Pembrolizumab Treatment for Progressive Multifocal Leukoencephalopathy
Irene Cortese1, Pawel Muranski1, Yoshimi Enose-Akahata1
1From the Neuroimmunology Clinic (I.C., J.O.), the Viral Immunology Section (Y.E.-A., S.J.), the Section of Infections of the Nervous System (B.S., L.B.R., A.N.), the Laboratory of Molecular Medicine and Neuroscience (M.M., C.R., E.O.M.), and the Translational Neuroradiology Section (S.-K.H., M.K.S., E.B., D.S.R.), National Institute of Neurological Disorders and Stroke, and the Hematology Branch, National Heart, Lung, and Blood Institute (P.M.), National Institutes of Health, Bethesda, MD; and the Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York (P.M.).
Background:
Progressive multifocal leukoencephalopathy (PML) is an opportunistic brain infection that is caused by the JC virus and is typically fatal unless immune function can be restored. Programmed cell death protein 1 (PD-1) is a negative regulator of the immune response that may contribute to impaired viral clearance. Whether PD-1 blockade with pembrolizumab could reinvigorate anti-JC virus immune activity in patients with PML was unknown.
Methods:
We administered pembrolizumab at a dose of 2 mg per kilogram of body weight every 4 to 6 weeks to eight adults with PML, each with a different underlying predisposing condition. Each patient received at least one dose but no more than three doses.
Results:
Pembrolizumab induced down-regulation of PD-1 expression on lymphocytes in peripheral blood and in cerebrospinal fluid (CSF) in all eight patients. Five patients had clinical improvement or stabilization of PML accompanied by a reduction in the JC viral load in the CSF and an increase in in vitro CD4+ and CD8+ anti-JC virus activity. In the other three patients, no meaningful change was observed in the viral load or in the magnitude of antiviral cellular immune response, and there was no clinical improvement.
Conclusions:
Our findings are consistent with the hypothesis that in some patients with PML, pembrolizumab reduces JC viral load and increases CD4+ and CD8+ activity against the JC virus; clinical improvement or stabilization occurred in five of the eight patients who received pembrolizumab. Further study of immune checkpoint inhibitors in the treatment of PML is warranted. (Funded by the National Institutes of Health.).
Insights
Pembrolizumab may help treat progressive multifocal leukoencephalopathy (PML) by boosting anti-JC virus immune activity. Five of eight patients showed clinical improvement or stabilization, with reduced viral load and increased T-cell responses.
Area of Science:
- Neuroimmunology
- Viral Infections
- Oncology
Background:
- Progressive multifocal leukoencephalopathy (PML) is a fatal opportunistic brain infection caused by the JC virus.
- Programmed cell death protein 1 (PD-1) negatively regulates immune responses, potentially impairing viral clearance in PML.
- The efficacy of PD-1 blockade with pembrolizumab for anti-JC virus immunity in PML was previously unknown.
Purpose of the Study:
- To investigate whether PD-1 blockade with pembrolizumab can reinvigorate anti-JC virus immune activity in patients with PML.
- To evaluate the clinical and virological effects of pembrolizumab treatment in PML patients.
Main Methods:
- Eight adult patients with PML received pembrolizumab (2 mg/kg every 4-6 weeks) for 1-3 doses.
- PD-1 expression on lymphocytes in peripheral blood and CSF was monitored.
- JC viral load in CSF and in vitro anti-JC virus cellular immune activity (CD4+ and CD8+) were assessed.
Main Results:
- Pembrolizumab down-regulated PD-1 expression on lymphocytes in all eight patients.
- Five patients experienced clinical improvement or stabilization, with reduced JC viral load and increased anti-JC virus CD4+ and CD8+ T-cell activity.
- Three patients showed no significant changes in viral load, immune response, or clinical status.
Conclusions:
- Pembrolizumab may reduce JC viral load and enhance anti-JC virus cellular immunity in some PML patients.
- Clinical improvement or stabilization was observed in 5/8 patients treated with pembrolizumab.
- Further research into immune checkpoint inhibitors for PML treatment is warranted.
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