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Microscopic images of cerebrospinal fluid cells. a Lymphocytic pleocytosis and cell activation, May-Grünwald Giemsa stain. b Note the high amount of cytotoxic T-Zells (approx. 70%, CD8-immunoreaction in brown (magnification ×100)
Context in source publication
Context 1
... showed a clear extension of the PML lesion. A second lumbar puncture showed an inflammatory process with a lymphocytic pleocytosis and a high content of cytotoxic T-cells. Consistent with these findings, a florid infection with an increase in the JC viral load by more than two log levels to 3,500,000 copies/ml was determined by quantitative PCR (Fig. 2). In order to restore the immune function, we further escalated the therapy adding the PD1 inhibitor pembrolizumab with the aim of activating JC virusspecific T cells using the same scheme Cortese et al. described (2 mg/kg of body weight, every 4 weeks; altogether three infusions) [1]. Unfortunately, the symptoms of the patient worsened ...
Citations
... There are only 3 reported cases of pembrolizumab used in PML patients with HIV [ Table 1] [1,12]. All other PML cases with causes of immune compromise other than HIV, treated with pembrolizumab are listed in Table 2 [1,[3][4][5]7,10,11,[13][14][15][16][17]. Overall, 17 out of 28 cases had reported improvement or stabilization of neurological symptoms. ...
Progressive multifocal leukoencephalopathy (PML) is an opportunistic central nervous system (CNS) infection caused by the reactivation of John Cunningham polyomavirus (JCV) from suppression of the host immune system due to conditions such as human immunodeficiency virus causing acquired immunodeficiency syndrome (HIV/AIDS), hematological malignancies, multiple sclerosis, and use of immunosuppressant medications. Pembrolizumab is an immune checkpoint inhibitor targeting programmed cell death protein-1 (PD-1) receptors on lymphocytes. In recent years its use is expanding to treat several malignancies and it is a drug of interest for the treatment of PML. In this case report, we present a case of an HIV/AIDS patient who was given a trial of pembrolizumab for treatment of PML. We also provide a literature review of the reported cases of use of this medication in other immunocompromised states.
... A case series published in 2019 showed a positive outcome of 5 of 8 patients with PML treated with pembrolizumab(Cortese et al. 2019). Combined with following case reports, until January 2021, 14 patients with PML due to lymphoproliferative disorders were treated with pembrolizumab(Cortese et al. 2019;Dufour et al. 2020;Holmes et al. 2020;Kapadia and Ney 2020;Mahler et al. 2020;Möhn et al. 2021;Rauer et al. 2019;Stögbauer et al. 2021). Of those, 9 patients stabilized or showed clinical improvement. ...
Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the CNS caused by the human polyomavirus 2 (JCV). PML predominantly occurs in immunocompromised patients. To date, no specific antiviral treatment exists, leaving only restoration of the immune system as possible treatment. In 2019, the monoclonal antibody pembrolizumab was reported as a potential treatment option in PML in a case series. Following case reports could not thoroughly confirm a positive outcome. Pembrolizumab targets the inhibitory programmed cell death protein 1 (PD-1) receptor on lymphocytes and is associated with beneficial expansion of pre-existing virus-specific T cells. Here we describe a patient with PML who benefited from combined treatment with intravenous immunoglobulins, maraviroc, and pembrolizumab.
... To our knowledge, 31 published patients with PML have so far been treated with either pembrolizumab or nivolumab. Treatment outcomes range from moderate improvement of symptoms with stabilization to death from disease progression [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]. To date, there are no clear prognostic factors to identify patients in whom checkpoint inhibition will be able to ameliorate PML [26]. ...
... This is demonstrated by a median survival of 2 months in a case series of patients with in hematologic malignancies and stem-cell transplantation [27]. Checkpoint inhibition has been applied so far in 11 cases with nivolumab therapy and 20 cases with pembrolizumab therapy (including our previous report) with varying results [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]. Here were report on a series of 4 novel patients with PML in the context of PID or hematologic malignancy treated with pembrolizumab and follow-up data on one previously reported patient [21]. ...
... In Patient 4 disease progression could not be stopped, demonstrated by rising copy numbers of JCV-DNA in CSF and increasing lesions on MRI. Similar catastrophic clinical courses have been published previously, including a young patient who was diagnosed early after mild symptoms developed and had low copy numbers of JCV-DNA in CSF at diagnosis [10,12,18,20,22]. This challenges the concept that the disease can be controlled if treatment was commenced early and raises the question, if the underlying immunodeficiency itself is a prognostic factor. ...
Progressive multifocal leukoencephalopathy is a rare opportunistic infection of the brain by John Cunningham polyomavirus in immune-compromised patients. In cases where no overt option for immune reconstitution is available [e.g., in patients with primary immunodeficiency (PID)], the disease is lethal in the majority of patients. Immune checkpoint inhibition has been applied in recent years with mixed outcomes. We present four novel patients and the follow-up of a previously published patient suffering from progressive multifocal leukoencephalopathy (PML) due to PID and/or hematologic malignancy who were treated with the immune checkpoint inhibitor pembrolizumab. In two patients with PID, symptoms improved and stabilized. One patient died because of worsening PML another of intracranial hemorrhage which was unrelated to PML or its treatment with pembrolizumab. The fifth patient suffered from PID and died of a pre-existing immune dysregulation, possibly exacerbated by pembrolizumab. The long-term follow-up of the first patient provides support for therapeutic decisions during this therapy and is the longest published clinical course of a patient with checkpoint inhibition for PML. We conclude that pembrolizumab can control PML symptoms long term in a subgroup of patients with PID, in our cases for 21 and 36 months. However, therapy must be started early because symptoms are only partially reversible. In light of severe adverse events, application of pembrolizumab is only justified if the prognosis for the individual patient is very poor.
... In addition to the eight cases mentioned above, additional 13 individual case reports and two smaller case series (totaling 22 additional patients) were published during the course of the study on the use of PD-1 inhibitors in PML [53][54][55][56][57][58][59][60][61][62][63][64]. Eight of the 13 individual case reports described the use of pembrolizumab, and the remaining five publications used nivolumab. ...
Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral disease of the brain—caused by human polyomavirus 2. It affects patients whose immune system is compromised by a corresponding underlying disease or by drugs. Patients with an underlying lymphoproliferative disease have the worst prognosis with a mortality rate of up to 90%. Several therapeutic strategies have been proposed but failed to show any benefit so far. Therefore, the primary therapeutic strategy aims to reconstitute the impaired immune system to generate an effective endogenous antiviral response. Recently, anti-PD-1 antibodies and application of allogeneic virus-specific T cells demonstrated promising effects on the outcome in individual PML patients. This article aims to provide a detailed overview of the literature with a focus on these two treatment approaches.
... 28,32 Table (detailed in Supplementary Table 1) summarizes published studies using the anti-PD-1 antibodies nivolumab and pembrolizumab in PML patients. [32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50] Anti-PD-1 therapies have shown promising results in some cases, with documented clinical and radiological benefit. In these patients, nivolumab or pembrolizumab seem to have triggered an effector response mediated by JCV-specific CD4 + and CD8 + T cells, 32,34 as well as immune reconstitution demonstrable on brain biopsy 36 and clearance of the virus in the CSF. ...
Progressive multifocal encephalopathy (PML) is a severe demyelinating disease of the central nervous system caused by JC virus (JCV), which occurs in immunocompromised individuals. Management of PML relies on restoration of immunity within the CNS. However, when this restoration cannot be readily achieved PML has a grim prognosis. Innovative strategies have shown promises in promoting anti-JCV immune responses, and include T cell adoptive transfer or immune checkpoint inhibitor therapies. Conversely, management of immune reconstitution inflammatory syndrome, particularly in iatrogenic PML, remains a major challenge. In this paper, we review recent development in the treatment of PML.
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... We found 20 articles (14 case reports and six case series) reporting a total of 37 patients who received an ICI in order to treat PML [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. One patient was excluded from the present report because PML had already stabilized before ICI administration [3] and another patient because reported data were insufficient to determine the eventual clinical course [13]. ...
Introduction
Progressive multifocal leukoencephalopathy (PML) is an infectious brain disease caused by JC virus in immunocompromised individuals. Immune checkpoint inhibitors (ICIs) recently emerged as a therapeutic hope for these patients but identification of those likely to respond to the treatment is still an unmet need.
Method
We performed a systematic PubMed search for reports of patients treated for PML using an ICI. Clinical, biological and radiological characteristics were contrasted between patients who responded to the treatment (RP) and those who did not (NRP).
Results
35 patients were included in the present study. 21 of them reportedly benefited from the treatment. Age, blood CD4+ cells count, pre-treatment viral load in the cerebrospinal fluid (CSF), PML lesions localization, treatment delay since first PML symptoms, type of ICI used and immune-related adverse events (irAEs) occurrence did not significantly differ between RP and NRP. By contrast, a history of therapeutic immune suppression and the use of an immunosuppressive therapy at treatment initiation were significantly associated with a poor response. Besides, reaching an undetectable viral load the CSF and reduction of the lesion load on magnetic resonance imaging after ICI administration were associated with a good clinical response.
Conclusion
Current data suggest that patients with PML under immunosuppressive therapy are less likely to respond to ICIs and raise the issue of the optimal management of irAEs during ICI treatment in this setting.
