By Stan Deresinski, MD, FACP, FIDSA

Clinical Professor of Medicine, Stanford University

Dr. Deresinski reports no financial relationships relevant to this field of study.

SYNOPSIS: Enhancing the immune response with checkpoint inhibitors may be beneficial in the management of progressive multifocal leukoencephalopathy, a viral disease previously recalcitrant to therapy.

SOURCE: Cortese I, Muranski P, Enose-Akahata Y, et al. Pembrolizumab treatment for progressive multifocal leukoencephalopathy. N Engl J Med 2019;380:1597-1605.

Progressive multifocal leukoencephalopathy (PML) is a rare infection caused by the John Cunningham virus (JCV) that is most often lethal. The authors of the studies reviewed here set out to evaluate the potential of checkpoint inhibitors in the treatment of PML. Checkpoint inhibitors are enhancers of the immune response that have been demonstrated to be effective in the treatment of some malignancies.

Cortese and colleagues administered a maximum of three doses of pembrolizumab, given at four- to six-week intervals, to eight adults with PML. Two patients had HIV infection, two had chronic lymphocytic leukemia, two had idiopathic lymphocytopenia, and one each had non-Hodgkin’s lymphoma and a remote history of Hodgkin’s lymphoma. With pembrolizumab treatment, all eight patients exhibited reduced expression of the target of the drug, programmed cell death protein 1 (PD-1), on both peripheral blood and cerebrospinal fluid (CSF) lymphocytes. Researchers observed a clinical response (improvement or stabilization) in five patients, each of whom also experienced stabilization or reduction (but not elimination) of lesions seen on brain MRI. In all five patients, clinical response was associated with increased in vitro antiviral activity directed at JCV of CD4+ and CD8+ lymphocytes in association with a reduction in JC viral load in CSF. Investigators observed no such findings in the three patients who failed to improve clinically.

The same issue of the journal contained two individual case reports: one of a patient without evident immunosuppression and one with diffuse large B-cell lymphoma, with clinical responses to nivolumab and pembrolizumab, respectively.1,2


Most adults are chronically infected with JCV. Infection with this polyomavirus ordinarily remains confined to the kidneys, and infected individuals suffer no ill consequences. However, in the presence of immunosuppressive disease or therapy, the virus may undergo genetic rearrangements in noncoding regions of its virome, which lead it to become neurotropic, potentially causing fatal brain disease. Other than reversal of the immunosuppressed state by reducing immunosuppressive therapy or by providing effective antiretroviral treatment to patients with AIDS, no therapy has demonstrated effectiveness. However, recommended treatment of PML associated with natalizumab treatment of multiple sclerosis also involves plasma exchange in addition to discontinuation of the drug.

Present on the surface of T lymphocytes, PD-1 is a negative regulator of the immune response. Blocking its expression with an inhibitor of this immune checkpoint has proven effective in treating several malignancies in which PD-1 expression is elevated. In patients with PML, PD-1 expression also is increased on both CD4+ and CD8+ T cells. This is especially the case for CD8+ T cells specifically directed at JCV.3

The experiences reviewed here raise hope that checkpoint inhibitor therapy may be effective in treating PML. However, the assessment is muddied somewhat by the complexity and variety of underlying diseases in the 10 patients described. As noted in an accompanying editorial, two of the five responders in the report by Cortese et al had HIV infection for which effective antiretroviral therapy frequently is an effective modality in dealing with PML.3 The authors of the editorial also pointed out that another of the responders may have been improving already at the time of the intervention. The editorial authors rightly called for a randomized clinical trial — not an easy task given the rarity of this disease.


  1. Rauer S, Marks R, Urbach H, et al. Treatment of progressive multifocal leukoencephalopathy with pembrolizumab. N Engl J Med 2019;380:1676-1677.
  2. Walter O, Treiner E, Bonneville F, et al; Immune Checkpoint Inhibitors in PML Study Group. Treatment of progressive multifocal leukoencephalopathy with nivolumab. N Engl J Med 2019;380:1674-1676.
  3. Koralnik IJ. Can immune checkpoint inhibitors keep JC virus in check? N Engl J Med 2019;380:1667-1668.