Assistant Attending Neurologist, NewYork-Presbyterian Hospital; Assistant Professor of Neurology, and Feil Family Clinical Scholar in Multiple Sclerosis I, Weill Cornell Medical College
Dr. Kaunzner reports no financial relationships relevant to this field of study.
SYNOPSIS: These authors evaluated the effect of pembrolizumab, a monoclonal antibody that functions as a down-regulator of PD-1 (programmed cell death protein 1), on patients with progressive multifocal leukoencephalopathy. In five of eight treated patients, clinical stabilization or improvement was seen in association with reduced cerebrospinal fluid JC viral load. This is the first reported effective treatment for this disease with a therapeutic agent targeting the JC virus.
SOURCE: Cortese I, Muranski P, Enose-Akahata Y, et al. Pembrolizumab treatment for progressive multifocal leukoencephalopathy.
N Engl J Med 2019;390:1597-1605.
Progressive multifocal leukoencephalopathy (PML) is an opportunistic, often fatal, infection of the central nervous system (CNS) caused by the polyomavirus JC. Antibodies to the JC virus can be found in approximately 50-60% of healthy adults. In cases of immunodeficiency, the virus can transform into a neurotropic virus, causing PML, with areas of demyelination. Historically, PML was described in leukemia and lymphoma patients; however, more recently, PML has been described in patients with immune-deficiency secondary to immunosuppressant medications given for various autoimmune conditions.
Presenting symptoms can include visual impairment, cognitive dysfunction, and ataxia, but various other neurological symptoms can be associated with PML. The diagnosis of PML is based on MRI findings, the detection of the JC virus in cerebrospinal fluid (CSF), and brain biopsy, which is still the diagnostic gold standard. So far, treatment options for PML are limited, and the predominant focus has been on restoring immune function. Mortality is dependent on the underlying disease and on the degree of immune suppression.
Programmed cell death protein 1 (PD-1) is an immune checkpoint protein that is expressed on T cell surfaces, and down-regulates immune function. Increased PD-1 expression contributes to decreased immune response to viral infection. PD-1 is up-regulated on CD4 and CD8 T cells in blood and CSF of PML patients and has been shown to be increased in autopsy tissue of PML patients.
Cortese et al tested the hypothesis that blockage of the PD-1 pathway with pembrolizumab, a down-regulator of PD-1 expression, can renew anti-JC virus immune activity in patients with PML. Eight patients with PML were enrolled and all patients had different immunodeficiencies (chronic lymphocytic leukemia, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, idiopathic lymphopenia, HIV). Clinical disability ranged from two to four on the modified Rankin Scale.
Patients received pembrolizumab every four to six weeks, up to a total of three doses. After pembrolizumab administration, down-regulation of PD-1 was seen on lymphocytes in the blood and CSF of all eight patients. Five patients stabilized or showed improvement, and reduction in CSF JC viral count was seen. Four out of these five patients showed persistent reduction of JC viral load and showed clinical stabilization with no recurrence of PML 16-26 months later. MRI showed corresponding reduction in PML lesions, but no PML lesions disappeared fully. Three of eight patients had no positive response to pembrolizumab; one patient had already stabilized and two deteriorated and succumbed to PML. None of the patients developed IRIS.
This is a landmark study, since no specific medication is available for the treatment of PML, a CNS infection with a high mortality rate. Improving the underlying immunosuppressive disease (e.g., initiating treatment of HIV) is the main approach to PML treatment. For
patients on immunosuppressant medications, re-constitution of the immune system is attempted by withdrawing immune-suppressant treatment and adding plasmapheresis. Mirtazapine, a potential blocker of JC virus into cells, has been tried but no benefit on disease outcome has been demonstrated.
In this study, five out of eight patients stabilized clinically, and four out of these five patients showed a persistent reduction of their viral count, which is an impressive result, despite the small study size. An additional benefit is that none of these patients developed IRIS after their immune function improved, which was attributed to continuous low lymphocyte count in the respective patients.
As the authors noted, it would be important to know if these effects are solely secondary to pembrolizumab administration or if improvement of the underlying condition contributed to the outcome. Larger studies or clinical trials would be warranted to assess the efficacy and safety associated with pembrolizumab for different underlying immunodeficient diseases. It also would be important to determine if pembrolizumab has a positive effect on patients on immunosuppressant medications, and if it improves mortality after immune-suppressant medication has been withdrawn. Overall, this is an elegant approach to explore the blockage of PD-1 and its impact on PML, and might have the potential for a future treatment option in a disease that desperately needs treatment options.