Journal of NeuroVirology

https://doi.org/10.1007/s13365-023-01180-w

Pembrolizumab for the treatment of progressive multifocal

leukoencephalopathy in China
Siyuan Fan1 · Mange Liu1 · Lin Bai1 · Sixian Chen1 · Bo Hou2 · Nan Lin1 · Jing Yuan1 · Chenhui Mao1 · Jingwen Niu1 ·
Haitao Ren1 · Yanhuan Zhao1 · Zaiqiang Zhang3 · Yicheng Zhu1 · Bin Peng1 · Hongzhi Guan1

Received: 20 June 2023 / Revised: 6 September 2023 / Accepted: 12 October 2023

© The Author(s) under exclusive licence to The Journal of NeuroVirology, Inc. 2023

Abstract
The aim of this study is to analyze the clinical characteristics and outcomes of Chinese patients with progressive multifocal
leukoencephalopathy (PML) who were treated with programmed cell death protein 1 (PD1) blockade therapies. We retro-
spectively analyzed patients who were admitted to our hospital between October 1, 2020, and October 1, 2022, diagnosed
with PML and treated with PD1 blockade therapies. Four patients with PML who were treated with PD1 blockade therapies
were identified. All patients were male, and their ages ranged from 19 to 54 years old. One patient (Case 2) exhibited mild
pleocytosis, while three patients (Cases 2–4) had markedly reduced T lymphocyte cell counts prior to treatment. The time
interval between symptom onset and treatment initiation ranged from six to 54 weeks. All patients received pembrolizumab
treatment, with a total of two to four doses administered. Three patients who responded to pembrolizumab treatment showed
clinical improvement starting around 8 weeks after the initiation of therapy. Although one patient did not show clinical
improvement, they ultimately survived until the last follow-up. None of the patients in this study exhibited immune-related
adverse events or immune reconstitution inflammatory syndrome. PD1 blockade appears to be a promising novel therapeutic
option for PML; additional prospective studies are necessary to confirm its efficacy.

Keywords Progressive multifocal leukoencephalopathy · PD1 blockade

Introduction immunodeficiency virus (HIV) infection, hematological

Progressive multifocal leukoencephalopathy (PML) is a
severe and frequently fatal infection of the central nervous
system caused by the JC virus (JCV) (Cortese et al. 2021).
Although asymptomatic JCV latent infection occurs in 60
to 80% of healthy adults, it can undergo genetic rearrange-
ments in noncoding regions and transform into a neurotropic
virus capable of infecting glial cells and causing PML in indi-
viduals with cellular immunodeficiency, including human
* Hongzhi Guan
pumchghz@126.com
1
Department of Neurology, Peking Union Medical College
Hospital, Chinese Academy of Medical Sciences and Peking
Union Medical College, 100730 Beijing, China
2
Department of Radiology, Peking Union Medical College
Hospital, Chinese Academy of Medical Sciences and Peking
Union Medical College, 100730 Beijing, China
3
Department of Neurology, Beijing Tiantan Hospital, Capital
Medical University, 100050 Beijing, China
malignancies, medication use (e.g., natalizumab), organ trans-
plantation, and primary immunodeficiency diseases (Beck
and Cortese 2020; Bennett and Fernandes 2020; Cortese
et al. 2021; Major et al. 2018). To date, there is no effective
antiviral treatment for JCV, and the prognosis is generally
poor unless immunosuppression can be reversed (Bennett
and Fernandes 2020; Cortese et al. 2021). For example, the
application of combination antiretroviral therapy (cART) to
preserve immune function in patients with HIV infection has
substantially reduced the 1-year mortality rate of patients with
HIV-associated PML from 82 cases per 100 patient-years to
38 cases per 100 patient-years (Khanna et al. 2009).
In chronic infections or tumors, persistent exposure to
antigens can result in permanent expression of programmed
cell death protein 1 (PD1), which may limit the ability of the
immune system to clear pathogens or malignant cells (Jubel
et al. 2020). PD1 blockade has emerged as an important thera-
peutic strategy for cancer in recent decades, as it can remove
inhibitory signals that prevent T cell activation, allowing
tumor-reactive T cells to overcome negative regulatory

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mechanisms and mount an effective antitumor response (Fan
et al. 2020a; Wei et al. 2018). Given the success of PD1 block-
ade in cancer therapy, targeting these pathways may also be
effective in treating various infectious diseases (Wykes and
Lewin 2018). Promising results have already been reported
for PD1 blockade in patients with PML since 2019, as these
treatments (such as pembrolizumab and nivolumab) have
been shown to trigger an effector response mediated by JCV-
specific ­CD4+ and ­CD8+ T cells, leading to immune recon-
stitution and clearance of the virus in the cerebrospinal fluid
(CSF) (Bernard-Valnet et al. 2021; Cortese et al. 2019; Walter
et al. 2019). About half of the PML patients who received
PD1 blockade in these studies experienced improvements or
stabilization (Bernard-Valnet et al. 2021). In addition to PML,
PD1 blockade is being explored as a potential treatment for
other chronic viral infections, including HIV, hepatitis B virus
(HBV), and hepatitis C virus (HCV), although more evidence
is needed to confirm its effectiveness in these contexts (Chen
et al. 2020; Jubel et al. 2020).
In this retrospective study, we analyzed the outcomes of
patients with PML who received PD1 blockade treatments
at an encephalitis center in China. The aim was to contribute
further evidence to this field.
Materials and methods
Participants and study design
This is an observational, retrospective study conducted at the
encephalitis center of Peking Union Medical College Hospi-
tal, known as the National Center for Autoimmune Encepha-
litis Quality Improvement. Our analysis focused on patients
with PML who underwent PD1 blockade treatment between
October 1, 2020, and October 1, 2022. To identify patients
with PML, we conducted a comprehensive search within
our hospital information system using the discharge diag-
nosis terms “progressive multifocal leukoencephalopathy”
or “PML.” Subsequently, we screened all identified patients
with PML for the usage of the following immune checkpoint
inhibitors: “nivolumab,” “ipilimumab,” “pembrolizumab,”
“lambrolizumab,” “atezolizumab,” “tremelimumab,” “ticili-
mumab,” “avelumab,” or “durvalumab.” We extracted all rel-
evant individual-level medical information, including clinical,
radiological, and laboratory data, as well as treatment details
and outcomes, from the electronic medical records.
This study was approved by the institutional review board
of Peking Union Medical College Hospital (I-23ZM0001).
All patients provided written informed consent to receive
off-label treatment with pembrolizumab. The study was car-
ried out in compliance with the Declaration of Helsinki.
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Journal of NeuroVirology
Laboratory evaluation
Metagenomic next-generation sequencing (mNGS) of CSF
samples was performed according to a standard flow, which
has been described elsewhere (Fan et al. 2018, 2020b). The
absolute counts of lymphocytes, B cells, T cells, and NK
cells were identified by flow cytometry.
PD1 blockade regimen
At our encephalitis center, patients received pembrolizumab
intravenously at a dose of 2–3 mg/kg of body weight (100 or 200
mg in total) every 3 to 8 weeks, for a maximum of four doses.
During PD1 blockade therapy, we conducted regular monitoring
of blood routine and biochemical parameters, urinalysis, creatine
kinase, high-sensitivity troponin I, brain natriuretic peptide lev-
els, thyroid function tests, and adrenocorticotropic hormone and
cortisol levels, as well as electrocardiograms.
Results
Clinical findings
Four PML patients who received treatment with pembroli-
zumab were identified. Their clinical characteristics are
summarized in Table 1. Three of the patients experienced
improvement, while one experienced aggravation. Patients
who responded well to pembrolizumab showed symptom
stabilization after 8 weeks of treatment. Immune reconsti-
tution inflammatory syndrome or immune-related adverse
events were not observed in our patients.
Case 1 A 19-year-old male presented with a 5-week his-
tory of progressive cognitive decline and right hemiplegia.
His symptoms worsened after intravenous immunoglobu-
lin (IVIG) and pulse corticosteroid therapy. He then devel-
oped a decreased level of consciousness. He had a history
of recurrent pyogenic infections and hypogammaglobu-
linemia, for which he had received regular IVIG treatment
until the age of ten. On admission, he exhibited decorticate
posturing. Laboratory investigations revealed markedly
low levels of serum IgG and IgA. Whole exome sequenc-
ing (WES) detected mutations in the CD40 ligand (CD40L)
gene (CD40LG) (c.611C > T), which he inherited from his
mother. This finding was confirmed by Sanger sequencing.
Brain magnetic resonance imaging (MRI) showed diffuse T2
hyperintensities without contrast enhancement (Fig. 1A–D).
CSF analysis revealed mild lymphocytosis (CSF cytology)
with normal protein level. JCV was detected in the CSF by
mNGS (43 specific reads), and CSF JCV polymerase chain
reaction (PCR) revealed a viral load of 7.36 × ­102 copies/
Journal of NeuroVirology

Table 1  Clinical features of the four patients treated with pembroli- specific reads), and CSF JCV PCR revealed a viral load of
zumab 1.68 × ­102 copies/mL. He was diagnosed with PML. The
Case 1 Case 2 Case 3 Case 4 patient received pembrolizumab, with a dosage of 200 mg
intravenously every 4 weeks for three doses. The symptoms
Age 19 31 51 54
improved gradually, and he was able to walk without assis-
Sex M M M M
tance about 6 months after the first admission. The brain
Immunodeficiencies X-HIGM CIDa CIDb CIDc
MRI indicated the stabilization of the lesions (Fig. 1M–P).
Time from Sx to Tx (w) 6 40 16 54
He remained stable during the follow-up period.
Total doses of PEM 2 3 4 4
mRS prior to Tx 5 4 5 5
Case 3 A 51-year-old man with consanguineous parents
mRS at last F/U 5 2 4 3
presented with a 3-month history of dizziness, dysarthria,
Time from Tx to CI (w) NA 8 8 8
and unsteady gait. Brain MRI with contrast revealed T2
Doses of PEM before CI NA 2 2 2
hyperintensities in the right cerebellum and brachium pon-
IRIS None None None None
tis without enhancement, suggesting CNS demyelination
irAEs None None None None
(Fig. 1Q–X). Pulse corticosteroid was administered, but
F/U time (w) 81 77 54 26
his symptoms worsened after treatment. Brain biopsy was
CI continuous improvement, F/U follow-up, irAEs immune-related performed, which showed a demyelinating pattern with
adverse events, IRIS immune reconstitution inflammatory syndrome, foam cells, bizarre-looking glial cells, and scattered lym-
mRS modified Rankin Scale, NA not applicable, PEM pembroli- phocytes (Fig. 2). On admission, the patient had bilateral
zumab, CID combined immunodeficiency, Sx symptoms, Tx treatment
a
ataxia, with the right upper limbs more affected, and was
Screening for HIV infection, cancers, autoimmune diseases, and
hereditary disorders (whole exome sequencing) did not reveal any
bedridden due to severe dizziness and vomiting aggravated
positive results by head movements. Laboratory tests revealed decreased T
b
T cell counts and IgG levels remained persistently low. However, and B cell counts. Repeat brain MRI showed enlargement of
screening for HIV infection, cancers, and autoimmune diseases all the previous lesion. The CSF JCV PCR returned a negative
came back negative. Whole exome sequencing showed a copy num- result, whereas JCV was detected in both the CSF (with 25
ber variation in the region chr19:53,792,911–54,327,464, including
NLRP12, DPRX, and other genes
specific reads) and brain tissue (with 19,894 specific reads)
c obtained from the previous biopsy using mNGS. Therefore,
The count of naïve ­CD4+ T cells was 5/μL. Screening for HIV infec-
tion, cancers, autoimmune diseases, and hereditary disorders through immunostaining for JCV capsid proteins was conducted
whole exome sequencing did not yield any positive results on the prior brain biopsy tissue, uncovering SV40-positive
inclusions within infected oligodendrocytes, affirming
JCV infection (Fig. 2B). The patient was diagnosed with
mL. He was diagnosed with PML and X-linked hyper-IgM PML and treated with pembrolizumab at a dose of 200 mg
syndrome (X-HIGM). Treatment with pembrolizumab was intravenously every 3 weeks for four doses. Gradual symp-
initiated at a dose of 200 mg intravenously every 4 weeks tom improvement was observed, with the lesions showing
for two doses. IVIG and mirtazapine were also administered. improvement (Fig. 1A7–A10) after the initial aggravation
However, the patient’s condition did not improve, and brain (Fig. 1A3–A6) within the first 6 weeks of treatment, and the
MRI showed progression of the lesions (Fig. 1E–H). He patient regained the ability to stand and eat without assis-
remained unconscious and required mechanical ventilation tance approximately 3 months after discharge. Follow-up
during follow-up. assessments showed stable neurological symptoms.

Case 2 A 31-year-old man presented with a 9-month history
of unsteady gait and 4 months of ataxia in the upper limbs.
He had a past medical history of hepatitis B and several
infections, including pulmonary infection and infectious
colitis, in the last few years. Despite receiving antitubercu-
losis drugs and glucocorticoids, his symptoms worsened. On
admission, the neurological examination revealed intention
tremor in the finger-to-nose test, limb ataxia, and a promi-
nent wide-based gait. He required assistance to walk. Labo-
ratory tests revealed low levels of serum IgM and IgA and
decreased T and B cell counts. Brain MRI showed FLAIR
hyperintensities in the right frontal lobe and cerebellum
(Fig. 1I–L). JCV was detected in the CSF by mNGS (16
Case 4 A 54-year-old man with a 10-year history of scle-
rosing glomerulonephritis presented with blurred vision
for 12 months, weakness of the lower limbs for 2 months,
and cognitive decline for 1 month. He was maintained on
low-dose corticosteroids. MRI of the brain performed by
a local hospital revealed choroid plexus papilloma and T2
hyperintensity in several brain regions without enhancement
(Fig. 1A11–A14). On admission, the patient was unable to
stand and self-feed. Lumbar puncture was performed; the
CSF JCV PCR yielded a negative result, while JCV was
detected in the CSF using mNGS (75 specific reads). He was
diagnosed with PML and treated with pembrolizumab at a
dose of 200 mg intravenously every three to 4 weeks for four

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 Journal of NeuroVirology

Fig. 1  Findings on magnetic resonance imaging (MRI) of the brain in ▸

all the cases in this study. A–H Brain MRI findings of Case 1. Brain
MRI performed 6 weeks after symptom onset showing diffuse white
matter T2 hyperintensities (A–D). The patient’s symptoms wors-
ened, and the lesions progressed 4 weeks after treatment (E–H). I–P
Brain MRI findings of Case 2. Brain MRI performed 10 months after
symptom onset showing FLAIR hyperintensities in the right frontal
lobe and cerebellum (I–K). The lesion in the right frontal lobe was
enhanced (L). The patient’s symptoms improved, and the lesions sta-
bilized 2 months after treatment (M–P). Q–A10 Brain MRI findings
of Case 3. Q–X Brain MRI performed 4 months after symptom onset
showing T2 hyperintensities in the bilateral cerebellum and right bra-
chium pontis without enhancement. Y–A2 The lesions enlarged about
1 week after treatment (the first dose of pembrolizumab). A3–A6 The
lesions further progressed about 6 weeks after treatment (2 weeks
after the second dose). A7–A10 The lesions stabilized 3 months after
treatment with improvement of symptoms. A11–A18 Brain MRI
findings of Case 4. Brain MRI performed 17 months after symptom
onset revealing T2 hyperintensities in the bilateral frontal and pari-
etal lobes, left occipital lobe, periventricular white matter, and cor-
pus callosum, without enhancement (A11–A14). Brain MRI was not
repeated until 6 months after treatment, which showed enlargement of
the previous lesions (A15–A18)

doses. Meanwhile, serum IgG level was decreased and regu-

lar IVIG was given, and corticosteroids was tapered over a
period of 2 months. The patient exhibited gradual clinical
improvement and achieved independent walking and self-
feeding approximately 5 months after admission, despite a
brain MRI performed 6 months after treatment revealing
enlargement of the previous lesions.

Laboratory and neuroimaging findings

The laboratory findings of the four patients are summarized

in Table 2. Among them, only one patient (Case 2) showed
mild pleocytosis. Before treatment, three patients (Cases
2–4) had significantly reduced cell counts of C ­ D3+ T lym-
+ +
phocyte, ­CD4 T lymphocyte, and ­CD8 T lymphocyte, and
one patient (Case 4) had a significantly reduced cell count
of ­CD19+ B lymphocyte. Additionally, two patients (Cases
1 and 2) had significantly reduced cell counts of NK cells.
After treatment, the cell counts of C ­ D3+ T lymphocyte,
+ +
­CD4 T lymphocyte, and C ­ D8 T lymphocyte significantly
increased in two patients (Cases 2 and 3). All three patients
(Cases 2–4) who underwent repeat lumbar puncture after
treatment tested negative for JCV PCR.
Brain MRI performed before and after treatment is shown
in Fig. 1. Disease progression with lesion enlargement was
observed in Case 1, while clinical improvement was observed
in three patients. In Case 3, where repeated brain MRIs were
conducted, the lesions initially enlarged about 6 weeks after
treatment (Fig. 1A3–A6), but stabilized 3 months after treat-
ment (Fig. 1A7–A10). In Case 4, a follow-up brain MRI was
not performed until 6 months after treatment, which revealed
an increase in the size of the lesions compared to their size

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Journal of NeuroVirology
Fig. 2  Histopathology of the brain biopsy in Case 3. A Hematoxy-
lin–eosin (H&E) stain of brain biopsy, showing numerous foam cells
and scattered lymphocytes (× 100). B Immunostaining for JCV capsid
proteins reveals the presence of infected glial cells (× 200). C CD3
prior to treatment (Fig. 1A15–A18). Although the brain lesions
in Case 1 and Case 3 had increased in size, they did not show
any contrast enhancement, which suggests that IRIS is an
unlikely explanation. In Case 4, a contrast brain MRI was not
feasible due to renal failure.
Discussion
We report the use of PD1 blockade in the treatment of PML at
an encephalitis center in China. Among four patients treated
with pembrolizumab, three showed improvement, and one sur-
vived. In patients who respond to PD1 blockade, symptoms
typically stabilize around 2 months after treatment.
T cell exhaustion, which is associated with the expression
of inhibitory molecules such as PD1 and its receptor PD1
ligand 1 (PDL1), plays a role in PML (Wherry and Kurachi
2015). Previous studies demonstrated that the expression of
PD1 is elevated on C ­ D4+ and C
­ D8+ T cells in patients with
+
PML; besides, P ­ D1 lymphocytes and P ­ DL1+ ­CD68+ cells
have been observed in PML brain lesions (Beck and Cortese
immunostains, showing slight infiltration of T lymphocytes in the
lesion (× 200). D CD68 immunostains, showing extensive infiltration
of mononuclear phagocytes in the lesion (× 200)
2020; Sanjo et al. 2019). Recovery of anti-JCV C ­ D4+ and
+
­CD8 T cell responses corresponds to PML patients’ sur-
vival (Gheuens et al. 2011). PD1 blockade led to increased
JCV-specific ­CD8+ interferon γ response in T cells from a
subset of healthy volunteers and one patient with active PML
(Beck and Cortese 2020).
Several cases of PML treated with PD1 blockade have
been reported, primarily through case reports, case series,
and retrospective studies (Beudel et al. 2021; Cortese et al.
2019; Darcy et al. 2022; Grassl et al. 2020; Lambert et al.
2022; Mahler et al. 2020; Möhn et al. 2021; Pinnetti et al.
2022; Roos-Weil et al. 2021; Volk et al. 2021; Walter et al.
2019). Among these patients, pembrolizumab is the most
commonly used drug, followed by nivolumab. The patients
in these studies had various immunodeficiencies, including
hematological malignancies, primary immunodeficiency,
autoimmune diseases, solid organ transplants, AIDS, and
neoplasms, with hematological malignancies being the most
common underlying disease. Approximately half of these
patients showed improvement or stabilization with treat-
ment. According to a retrospective study, immune-related
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 Journal of NeuroVirology

Table 2  Laboratory findings of Case 1 Case 2 Case 3 Case 4

the four patients treated with
pembrolizumab CSF findings prior to Tx
Pressure ­(mmH2O) 120 135 105 145
WBC (× ­106/L) 2 8 2 2
Glucose (mmol/L) 2.9 3.0 3.7 3.7
Protein (g/L) 0.43 0.37 0.63 0.41
SOB Negative Negative Negative Positive
Pre-/post-treatment
Lymphocyte (× ­106/L) 1672/2536 620/1250 648/900 680/840
­CD3+ T cell (× ­106/L) 1503/2224 435/953 362/643 445/423
­CD4+ T cell (× ­106/L) 637/943 221/529 278/530 186/188
­CD8+ T cell (× ­106/L) 731/1042 182/368 72/102 227/208
­CD19+ B cell (× ­106/L) 130/208 129/113 142/124 3/36
NK cell (× ­106/L) 30/99 58/136 122/93 231/357
IgG (g/L) 12.05†/11.02 9.08/10.92 3.53/5.88† 8.77/11.8
IgA (g/L) 0.32/0.29 0.24/0.24 1.26/1.08 1.31/1.19
IgM (g/L) 7.4/7.87 0.38/0.94 2.06/1.33 1.04/1.79
CSF mNGS (JCV-specific reads) 43/NA 16/31 25/negative 75/negative

CD cluster of differentiation, CSF cerebrospinal fluid, Ig immunoglobulin, IL interleukin, JCV JC virus,

NA not applicable, mNGS metagenomic next-generation sequencing, NK natural killer, PCR polymerase
chain reaction, SOB specific oligoclonal band, Tx treatment, WBC white blood cell
a
Post-treatment with intravenous immunoglobulin

adverse events (irAEs) occurred in about 30% of patients,
and immune reconstitution inflammatory syndrome (IRIS)
was observed in 20% of patients (Boumaza et al. 2023).
Notably, two patients developed PML after treatment with
nivolumab (Hoang et al. 2019; Martinot et al. 2018), and
one patient developed PML after treatment with durvalumab
(Vinatier et al. 2022). In the present study, three out of four
patients showed improvement after treatment, and no cases
of irAEs or IRIS were observed.
PD1 blockade appears to require some time to become
effective. According to the current study, symptoms usually
become stable around 2 months after receiving two doses of
pembrolizumab. The neuroimaging results of Case 3 were
consistent with this phenomenon, in which the brain lesions
initially increased in size in the MRI performed 1 week and
6 weeks after treatment. However, as symptoms improved,
the lesions stopped growing in the brain MRI conducted 3
months after treatment.
Previous studies have shown that achieving an unde-
tectable viral load in the CSF and a decrease in lesions
visualized on T2-weighted MRI after ICI administration
is associated with a good clinical response (Lambert et al.
2021). However, primary immunodeficiency leading to
low CD4 + T cells may not be effective, especially when
given late in the disease course (Küpper et al. 2019). In
the current study, it was observed that three patients who
responded to PD1 blockade were negative for CSF JCV
PCR after treatment. Moreover, patients with decreased
peripheral blood T cell counts appeared to benefit from
PD1 blockade treatment, which primarily enhances T cell
effector function.
There are some limitations for this retrospective study.
First, brain MRI was not regularly performed during the
treatment in some patients. Second, PD1 expression on
­C D4 + and ­C D8 + T lymphocytes was not tested. Third,
regular follow-up visits were difficult to maintain during
the coronavirus disease 2019 pandemic.
Conclusion
In conclusion, immune checkpoint inhibitors targeting
PD1 show promise as a novel therapeutic option for PML.
However, further prospective studies are needed to con-
firm their efficacy.
Funding This study was funded by the National High Level Hospi-
tal Clinical Research Funding (Grant No. 2022-PUMCH-B-120) and
CAMS Innovation Fund for Medical Sciences (Grant No. CIFMS:
2021-I2M-C&T-A-002).
Declarations
Conflict of interest The authors declare no competing interests.

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Journal of NeuroVirology

References Lambert N, Dauby S, Dive D, Sadzot B, Maquet P (2022) Atezoli-

zumab treatment for progressive multifocal leukoencephalopathy.
Emerg Infect Dis 28:253–256
Beck ES, Cortese I (2020) Checkpoint inhibitors for the treatment of
Lambert N, El Moussaoui M, Maquet P (2021) Immune checkpoint
JC virus-related progressive multifocal leukoencephalopathy. Curr
inhibitors for progressive multifocal leukoencephalopathy: iden-
Opin Virol 40:19–27
tifying relevant outcome factors. Eur J Neurol 28:3814–3819
Bennett KM, Fernandes PM (2020) Novel treatments for progressive
Mahler C, Andrews M, Henson SM, Gnanapavan S (2020) Sequential inter-
multifocal leukoencephalopathy. Br J Hosp Med 81:1–9
leukin 2 and pembrolizumab use in progressive multifocal leukoen-
Bernard-Valnet R, Koralnik IJ, Du Pasquier R (2021) Advances in treatment
cephalopathy. Neurol Neuroimmunol Neuroinflamm 7:e756
of progressive multifocal leukoencephalopathy. Ann Neurol 90:865–873
Major EO, Yousry TA, Clifford DB (2018) Pathogenesis of progressive multi-
Beudel M, Rövekamp F, van de Beek D, Brouwer M (2021) Single-
focal leukoencephalopathy and risks associated with treatments for mul-
dose pembrolizumab treatment for progressive multifocal leu-
tiple sclerosis: a decade of lessons learned. Lancet Neurol 17:467–480
koencephalopathy. Neurol Neuroimmunol Neuroinflamm 8:e1021
Martinot M, Ahle G, Petrosyan I, Martinez C, Gorun DM, Mohseni-
Boumaza X, Bonneau B, Roos-Weil D, Pinnetti C, Rauer S, Nitsch
Zadeh M, Fafi-Kremer S, Tebacher-Alt M (2018) Progressive
L, Del Bello A, Jelcic I, Sühs KW, Gasnault J, Goreci Y, Grauer
multifocal leukoencephalopathy after treatment with nivolumab.
O, Gnanapavan S, Wicklein R, Lambert N, Perpoint T, Beudel
Emerg Infect Dis 24:1594–1596
M, Clifford D, Sommet A, Cortese I, Martin-Blondel G (2023)
Möhn N, Wattjes MP, Adams O, Nay S, Tkachenko D, Salge F, Heine
Progressive multifocal leukoencephalopathy treated by immune
J, Pars K, Höglinger G, Respondek G, Stangel M, Skripuletz T,
checkpoint inhibitors. Ann Neurol 93:257–270
Jacobs R, Sühs KW (2021) PD-1-inhibitor pembrolizumab for
Chen H, Moussa M, Catalfamo M (2020) The role of immunomodula-
treatment of progressive multifocal leukoencephalopathy. Ther
tory receptors in the pathogenesis of HIV infection: a therapeutic
Adv Neurol Disord 14:1756286421993684
opportunity for HIV cure? Front Immunol 11:1223–1223
Pinnetti C, Cimini E, Vergori A, Mazzotta V, Grassi G, Mondi A,
Cortese I, Muranski P, Enose-Akahata Y, Ha SK, Smith B, Monaco M,
Forbici F, Amendola A, Grisetti S, Baldini F, Candela C, Casetti
Ryschkewitsch C, Major EO, Ohayon J, Schindler MK, Beck E,
R, Campioni P, Capobianchi MR, Agrati C, Antinori A (2022)
Reoma LB, Jacobson S, Reich DS, Nath A (2019) Pembrolizumab
Use of pembrolizumab for treatment of progressive multifocal
treatment for progressive multifocal leukoencephalopathy. N Engl
leukoencephalopathy in people living with HIV. Viruses 14:970
J Med 380:1597–1605
Roos-Weil D, Weiss N, Guihot A, Uzunov M, Bellanger A, Eymard B,
Cortese I, Reich DS, Nath A (2021) Progressive multifocal leukoen-
Saadoun D, Houillier C, Idbaih A, Demeret S, Deback C, Leblond
cephalopathy and the spectrum of JC virus-related disease. Nat
V, Galanaud D, Shor N, Pourcher V (2021) Immune checkpoint
Rev Neurol 17:37–51
inhibitors for progressive multifocal leukoencephalopathy: a new
Darcy S, Alexander M, McCarthy A, O’Dowd S (2022) Pembroli-
gold standard? J Neurol 268:2458–2465
zumab treatment of inflammatory progressive multifocal leukoen-
Sanjo N, Nose Y, Shishido-Hara Y, Mizutani S, Sekijima Y, Aizawa H,
cephalopathy: a report of two cases. J Neurovirol 28:145–150
Tanizawa T, Yokota T (2019) A controlled inflammation and a regula-
Fan S, Qiao X, Liu L, Wu H, Zhou J, Sun R, Chen Q, Huang Y, Mao C,
tory immune system are associated with more favorable prognosis of
Yuan J, Lu Q, Ge Y, Li Y, Ren H, Wang J, Cui L, Zhao W, Guan H
progressive multifocal leukoencephalopathy. J Neurol 266:369–377
(2018) Next-generation sequencing of cerebrospinal fluid for the
Vinatier E, Poli C, Giltat A, Nunes-Gomes C, Orvain C, Hunault-
diagnosis of neurocysticercosis. Front Neurol 9:471
Berger M, Jeannin P, Thépot S (2022) Progressive multifocal leu-
Fan S, Ren H, Zhao L, Yin J, Feng G, Wang J, Guan H (2020a) Neurological
koencephalopathy after durvalumab treatment for acute myeloid
immune-related adverse events associated with immune checkpoint
leukemia: a consequence of an immune reconstitution inflamma-
inhibitors: a review of the literature. Asia Pac J Clin Oncol 16:291–298
tory syndrome? Ejhaem 3:958–961
Fan S, Yuan H, Liu L, Li H, Wang S, Zhao W, Wu Y, Wang P, Hu Y,
Volk T, Warnatz K, Marks R, Urbach H, Schluh G, Strohmeier V,
Han J, Lyu Y, Zhang W, Chen P, Wu H, Gong Y, Ma Z, Li Y, Yu
Rojas-Restrepo J, Grimbacher B, Rauer S (2021) Pembrolizumab
J, Qiao X, Li G, Zhao Y, Wang D, Ren H, Peng B, Cui L, Wang
for treatment of progressive multifocal leukoencephalopathy in
J, Guan H (2020b) Pseudorabies virus encephalitis in humans: a
primary immunodeficiency and/or hematologic malignancy: a
case series study. J Neurovirol 26:556–564
case series of five patients. J Neurol 269:973–981
Gheuens S, Bord E, Kesari S, Simpson DM, Gandhi RT, Clifford DB,
Walter O, Treiner E, Bonneville F, Mengelle C, Vergez F, Lerebours
Berger JR, Ngo L, Koralnik IJ (2011) Role of ­CD4+ and ­CD8+ T cell
F, Delobel P, Liblau R, Martin-Blondel G (2019) Treatment of
responses against JC virus in the outcome of patients with progres-
progressive multifocal leukoencephalopathy with nivolumab. N
sive multifocal leukoencephalopathy (PML) and PML with immune
Engl J Med 380:1674–1676
reconstitution inflammatory syndrome. J Virol 85:7256–7263
Wei SC, Duffy CR, Allison JP (2018) Fundamental mechanisms of immune
Grassl N, Bunse L, Beutel T, Klockziem M, Gass A, Platten M, Eisele P
checkpoint blockade therapy. Cancer Discov 8:1069–1086
(2020) Nivolumab for treatment of progressive multifocal leukoen-
Wherry EJ, Kurachi M (2015) Molecular and cellular insights into T
cephalopathy in Sézary syndrome. Eur J Neurol 27:2373–2374
cell exhaustion. Nat Rev Immunol 15:486–499
Hoang E, Bartlett NL, Goyal MS, Schmidt RE, Clifford DB (2019) Pro-
Wykes MN, Lewin SR (2018) Immune checkpoint blockade in infec-
gressive multifocal leukoencephalopathy treated with nivolumab.
tious diseases. Nat Rev Immunol 18:91–104
J Neurovirol 25:284–287
Jubel JM, Barbati ZR, Burger C, Wirtz DC, Schildberg FA (2020) The
Publisher's Note Springer Nature remains neutral with regard to
role of PD-1 in acute and chronic infection. Front Immunol 11:487
jurisdictional claims in published maps and institutional affiliations.
Khanna N, Elzi L, Mueller NJ, Garzoni C, Cavassini M, Fux CA, Vernazza
P, Bernasconi E, Battegay M, Hirsch HH (2009) Incidence and out-
Springer Nature or its licensor (e.g. a society or other partner) holds
come of progressive multifocal leukoencephalopathy over 20 years of
exclusive rights to this article under a publishing agreement with the
the Swiss HIV Cohort Study. Clin Infect Dis 48:1459–1466
author(s) or other rightsholder(s); author self-archiving of the accepted
Küpper C, Heinrich J, Kamm K, Bücklein V, Rothenfusser S, Straube A
manuscript version of this article is solely governed by the terms of
(2019) Pembrolizumab for progressive multifocal leukoencepha-
such publishing agreement and applicable law.
lopathy due to primary immunodeficiency. Neurol Neuroimmunol
Neuroinflamm 6:e628

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