• Irene Cortese, Pawel Muranski, Yoshimi Enose-Akahata, Seung-Kwon Ha, Bryan Smith, MariaChiara Monaco, Caroline Ryschkewitsch, Eugene O Major, Joan Ohayon, Matthew K Schindler, Erin Beck, Lauren B Reoma, Steve Jacobson, Daniel S Reich, and Avindra Nath.
• From 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.).
• N. Engl. J. Med. 2019 Apr 25; 380 (17): 1597-1605.

BackgroundProgressive 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.MethodsWe 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.ResultsPembrolizumab 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.ConclusionsOur 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.).Copyright © 2019 Massachusetts Medical Society.

36 keywords...

hide…