Blackmon JT, Viator TM, Conry RM.

J Neurol Neuromedicine (2016) 1(4): 39-45 Neuromedicine

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Central nervous system toxicities of anti-cancer immune checkpoint

blockade
Jonathan T. Blackmon1, Toni M. Viator2, Robert M. Conry3*
1
Covenant College, USA
University of Alabama at Birmingham, USA
2

3
Division of Hematology Oncology, University of Alabama at Birmingham, USA

Article Info
ABSTRACT

Article Notes Immune checkpoint inhibitors (CPIs) which unleash suppressed antitumor
Received: June 27, 2016 immune responses are revolutionizing the systemic treatment of cancer.
Accepted: July 30, 2016 Durable responses and prolongation of survival come at a price of frequent
immune-related adverse events resulting from inflammation of normal tissues.
*Correspondence: Herein, we review serious central nervous system (CNS) toxicities of immune
Dr. Robert M. Conry, MD
CPIs including ipilimumab, nivolumab, pembrolizumab and atezolizumab. Case
Melanoma Program Director
Associate Professor, Division of Hematology Oncology, reports of 20 patients with CPI-associated encephalitis, meningitis, or myelitis
University of Alabama at Birmingham were reviewed as well as data from large scale registration trials. The overall
2145 Bonner Way,Birmingham, AL 35243, USA Telephone: incidence of serious immune-related CNS toxicities is approximately 0.4-1%
(205) 978-0257 with the potential for hundreds of cases annually in the United States. Patients
Fax: (205) 978-3928 suspected of having serious CPI-associated CNS toxicity should have a neurology
Email: [email protected] consult, lumbar puncture, and MRI of the affected regions. If confirmed, the
© 2016 Conry RM. This article is distributed under the terms of
offending drug should be permanently discontinued and high dose intravenous
the Creative Commons Attribution 4.0 International License steroids initiated, preferably with 500-1,000 mg of methylprednisolone daily.
With timely diagnosis and appropriate management, the majority of patients
Keywords experience complete neurologic recovery. As the array of indications for CPIs
Encephalitis rapidly increases, it is imperative for clinicians to have a high index of suspicion
Meningitis for immune-related CNS toxicities.
Myelitis
Ipilimumab
Nivolumab
Pembrolizumab Abbreviations: CPI: checkpoint inhibitor, CNS: central nervous
Immune Checkpoint Inhibitor
system, CTLA: cytotoxic T-lymphocyte antigen, PD: programmed
cell death, PD-L: PD-1 ligand, APCs: antigen presenting cells,
MRI: magnetic resonance imaging, PRES: posterior reversible
encephalopathy syndrome, CSF: cerebrospinal fluid
Intorduction
Immune checkpoints refer to a variety of inhibitory pathways
integral to the immune system that maintain self-tolerance and
modulate the duration and magnitude of physiological immune
responses to minimize collateral tissue damage. Key checkpoints
exploited for anti-cancer therapy include cytotoxic T-lymphocyte
antigen (CTLA)-4 and programmed cell death (PD)-1 proteins on
the surface of T-cells which respectively bind to B7-1 and B7-2 on
antigen presenting cells (APCs) or PD-1 ligands (PD-L1 and PD-
L2) on tumor cells or APCs1-3 Physiologic engagement of CTLA-4
tolerizes effector T-cells and enhances the immunosuppressive
effects of regulatory T-cells in the systemic circulation and lymph
nodes4. In contrast, binding of the PD-1 receptor to its ligands
occurs primarily in peripheral tissues such as tumor-infiltrating
lymphocytes and promotes T-cell exhaustion that limits cytokine
release, proliferation, and cytolytic activity5. Ipilimumab, an anti-

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CTLA-4 monoclonal antibody, was FDA-approved for related adverse events observed with ipilimumab, which
first line treatment of advanced melanoma in 20116,7. targets CTLA-4, is thought to be a consequence of systemic
Pembrolizumab and nivolumab are anti-PD-1 monoclonal versus peripheral effects of CTLA-4 and PD-1 inhibition,
antibodies approved by the FDA in 2014 for advanced respectively4,5. Serious adverse events are managed by
melanoma and now collectively also indicated for non- holding the checkpoint inhibitor and initiating high dose
small cell lung cancer, renal cell carcinoma and Hodgkin’s steroids, typically 1-2mg/kg of oral prednisone daily to
lymphoma8-12. Most recently, atezolizumab, an anti- taper gradually over one month15.
PD-L1 monoclonal antibody binding to the other side
Serious neurological adverse events affect
of the PD-1/PD-L1 interaction, was FDA-approved for
approximately 1% of patients receiving immune
advanced urothelial carcinoma13. These immune CPIs
checkpoint inhibitors16,17. Transient sensory and motor
are rapidly revolutionizing the systemic therapy of
peripheral neuropathies are the most common. Rare
cancer. The American Society of Clinical Oncology cited
cases of autonomic neuropathy, Guillian-Barre syndrome,
immunotherapy as the 2016 clinical cancer advance of the
and myasthenia gravis-type syndrome affecting the
year, and immunotherapy has recently earned its place as
peripheral nervous system have also been reported16,18,19.
one of the five pillars of cancer treatment alongside surgery,
Since melanocytes and Schwann cells are derived from
radiotherapy, chemotherapy, and targeted therapy14.
neural crest with antigenic similarity, the pathogenesis of
Durable responses and prolongation of survival with immune-related neuropathy often involves autoantibodies
immune checkpoint inhibitors come at a price of frequent against shared ganglioside epitopes19. Herein, we review
immune-related toxicities resulting from inflammation of serious CNS toxicities of immune checkpoint inhibitors.
normal tissues. The most frequent grade 3 or 4 serious Although uncommon, these events pose significant risk
adverse events include dermatitis, colitis, hepatitis, for long-term morbidity or mortality if not recognized
thyroiditis, hypophysitis, pneumonitis, and nephritis15. early and appropriately treated. A systematic review of
Collectively, serious adverse events affect approximately the English literature using PubMed and Google Scholar
15% of patients receiving anti-PD-1 therapy, 25-40% of completed June 22, 2016 revealed 20 relevant case
those receiving ipilimumab, and 55% of patients receiving reports with patient characteristics summarized in Table
combination treatment with ipilimumab and an anti- 1. Immunosuppressive treatment for CNS adverse events
PD-1 antibody1-3,6,7. The higher incidence of immune- and clinical outcomes are provided in Table 2. The great

Duration of CPI CSF

Patient Age Cancer CPI CNS Toxicity MRI abnormal Reference
before onset lymphocytosis
1 41 Melanomaa Ipib Ec (splenium)d 3 doses (2 mo)e yes -bf yes 16
2 50 Melanoma Ipi E (granulomatous) NS doses (2 mo)
g
yes -b yes 15
3 76 Melanoma Ipi E (splenium) 4 doses (4 mo) yes -b NS 20
4 71 Melanoma-unknown primary Ipi E 2 doses (3 mo) no -b no 21
5 58 Melanoma-vaginal Ipi E (PRES)h 1 dose (<1 mo) yes -b NS 22
6 64 Prostate Ipi E 7 doses (12 mo) no -b no 23
7 NS Pancreatic Ipi E 2 doses (1 mo) no -b no 24
8 55 Melanoma Ipi + Nivoi E 1 dose (<1 mo) no -b yes 25
9 65 Small Cell Lung Ipi + Nivo E (limbic) 1 dose (<1 mo) yes -b yes 25
10 26 Hodgkin's Lymphoma Ipi → Pembroj E (PRES) 5 doses (8 mo) yes -b NS 26
11 70 Non-Small Cell Lung Nivo E (limbic) 14 doses (NS mo) yes -b NS 27
12 64 Melanoma Pembro E (limbic) 18 doses (12 mo) yes -b yes 28
13 51 Melanoma Pembro E (splenium) 36 doses (21 mo) yes -b no 29
14 56 Melanoma-ocular Ipi Meningitis, E 4 doses (4 mo) yes -b yes 30
15 52 Melanoma Ipi Meningitis 1 dose (1 mo) NS yes 15
16 56 Melanoma Ipi Meningitis 4 doses (NS mo) no -b/yes -sk yes 31
17 51 Melanoma Ipi Meningitis 1 dose (<1 mo) no -b yes 32
18 NS Renal Cell Ipi Meningitis 4 doses (NS mo) no -b yes 33
19 58 Melanoma Ipi Myelitis 2 doses (5 mo) no -b/yes -s yes 34
20 45 Melanoma Ipi Myelitis, E (PRES) 4 doses (3 mo) yes -b/yes -s yes 35
Median 4 doses (3 mo)
a
Cutaneous melanoma unless otherwise specified; b Ipilimumab; c Encephalitis; d Focal involvement of the splenium of the corpus callosum
on brain MRI; e Months; f Brain MRI ; g Not specified; h Posterior Reversible Encephalopathy Syndrome; i Nivolumab; j Pembrolizumab;
k
Spinal MRI
Table 1. Patient Characteristics from Case Reports

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Blackmon JT, Viator T, Conry RM. J Neurol Neuromedicine (2016) 1(4): 39-45 Journal of Neurology & Neuromedicine

Patient Steroidsa Other Immunosupression Time to Recovery Neurologic Recovery Tumor Response
1 180 mg None 3 mob Complete CR
2 HDc None <1 mo Complete ND
3 HD Cytoxan 2 mo None ND
4 1,000 mg None <1 mo Complete SD
5 NSd None <1 mo Complete PD
6 1,000 mg None 10 mo Partial CR
7 NS None NS Complete ND
8 1,000 mg IVIge + Rituximab 4 mo Complete PR
9 48 mg None 1 mo Complete PR
10 None None <1 mo Complete PR
11 112 mgf None NA Death ND
12 HD None 5+ mo None SD
13 1,000 mg None 2 mo Partial ND
14 112 mgf None 3 mo Complete ND
15 NS None NS Complete PD
16 1,000 mg IVIg 24 mo Complete CR
17 43 mg None <1 mo Complete SD
18 HD None <1 mo Complete ND
19 HD IVIg 7+ mo None PD
20 56 mgf Infliximab 2+ mo None ND
Median 2 mo
a
Daily methylprednisone dose or equivalent; b Months; c High dose, not otherwise specified; d
Steroids given but dose not specified; e

Intravenous Immunoglobulin; f Assuming 70 kg body weight

ND: No Data CR: Complete Response PR: Partial Response SD: Stable Disease PD: Progressive Disease
Table 2. Treatment and Clinical Outcomes from Case Reports

majority of case reports included an exhaustive search to administered. There was considerable variation in onset of
exclude infection, tumor progression, or other etiologies encephalitis ranging from less than 1 month to 21 months
for CNS dysfunction, which was attributed in all cases to after CPI initiation with 1 to 36 doses administered. As
immune-related adverse events of checkpoint inhibition. with encephalitis from other causes, the most frequent
Published reports of large scale, registration-enabling trials signs and symptoms included headache, fever, confusion,
were also reviewed pertaining to the four FDA-approved disorientation, memory impairment, somnolence, and
checkpoint inhibitors. Warnings and precautions from the gait ataxia. Tremors, seizures, and hallucinations were
full prescribing information for each drug were examined also frequently reported. Symptom onset was typically
to better estimate the incidence of serious CNS toxicities. acute to subacute over days to a few weeks. One patient
Tumor pseudoprogression is another mechanism of CNS apparently had chronic onset with gradual decline of
deterioration associated with immune checkpoint blockade memory and language proficiency over one year preceding
that is not the subject of this review36,37. Pseudoprogression the diagnosis of encephalitis28. Focal abnormalities were
refers to increased mass effect at tumor foci resulting from reported on magnetic resonance imaging (MRI) of the
a desired influx of T-lymphocytes and other inflammatory brain in 11 of 15 patients (73%) with encephalitis (Table
cells following immune checkpoint blockade. 1). Recurring patterns on brain MRI included involvement
of the limbic system, the splenium of the corpus callosum,
Summary of case reports or posterior reversible encephalopathy (PRES) in three
patients each. Biopsy of a splenial lesion in patient 3
Encephalitis revealed acute and subacute inflammatory demyelination
Thirteen case reports of immune-related pure (20). Cerebrospinal fluid (CSF) revealed lymphocytic
encephalitis and two additional cases associated with inflammation in five patients (56%) with pure encephalitis
meningitis or myelitis were identified. Ipilimumab and was normal in the remaining four patients examined.
monotherapy was responsible for 9 of 15 cases (60%), Electroencephalograms showed generalized slowing in
simultaneous or sequential use of ipilimumab with an four of five encephalitis patients examined (80%), two of
anti-PD-1 antibody accounted for another 20%, and the whom had non-diagnostic brain MRIs23,25,28,30,35. Subclinical
remaining 20% involved anti-PD-1 monotherapy. Clinical epileptiform activity was also identified in one patient.
onset of pure encephalitis occurred a median of 2.5 months Initial treatment for pure encephalitis consisted of
following initiation of CPI with a median of 3.5 doses steroids in 12 of 13 patients (92%), and one patient

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Blackmon JT, Viator T, Conry RM. J Neurol Neuromedicine (2016) 1(4): 39-45 Journal of Neurology & Neuromedicine

recovered following discontinuation of CPI without in patient 20. CSF showed lymphocytic inflammation
immunosuppressive therapy26. Steroid therapy was in both patients. Biopsy of an enhancing conus lesion
typically intravenous and referred to as “high dose” in 10 of in patient 20 showed necrotizing myelopathy with
12 pure encephalitis patients. The maximum steroid dose lymphocytic infiltration. Initial therapy consisted of high
was specified in seven cases and consisted of 1,000 mg per dose steroids for both patients followed by intravenous
day of methylprednisolone in four and 0.5-2 mg/kg per immunoglobulin or infliximab. Despite subsequent spinal
day of methylprednisolone or equivalent in the remaining MRI showing marked regression of intramedullary edema,
three. Only one case of pure encephalitis was treated with patient 19 achieved no meaningful neurological recovery
immunosuppression other than steroids. Anti-N-Methyl- over seven months. Encephalopathy resolved two weeks
D-aspartate receptor antibodies were documented in the after steroid initiation in patient 20, but no clinically
CSF of this patient who showed no clinical improvement meaningful improvement occurred in myelopathy over two
with 1,000 mg of daily methylprednisolone or intravenous months of treatment.
immunoglobulin but recovered completely following
Discussion
rituximab25 . Among patients with pure encephalitis, 8 of 13
recovered completely (62%) within a median of less than Full prescribing information from the manufacturers
one month. Two patients partially recovered with significant of each of the four FDA-approved immune checkpoint
residual neurologic deficits 2-10 months after onset. Two inhibitors describe a <1% incidence of immune-related
patients survived without meaningful neurologic recovery encephalitis with a more specific incidence of 0.2-
over 2-5 months, and an additional patient’s death was 0.5% calculable from the labels of pembrolizumab and
attributed to immune-related encephalitis27,28. ipilimumab/nivolumab combination therapy. Immune-
related meningitis is cited by the labels of ipilimumab
Meningitis and atezolizumab as affecting fewer than 1% of patients
Five cases of immune-related meningitis were with a more specific incidence of 0.4% calculable among
reported, all following ipilimumab and one associated with patients receiving adjuvant high-dose ipilimumab. A
encephalitis. Clinical onset of meningitis occurred within report of patients from the registration trial for adjuvant
one month following 1-4 doses of ipilimumab (median 4 ipilimumab actually describes lymphocytic meningitis in 7
doses). Reported signs and symptoms were diverse but of 475 patients (1.5%) frequently associated with flu-like
included combinations of fever, severe headache, neck pain symptoms and suggests that pauci-symptomatic meningitis
or rigidity, photophobia, sensory or motor cranial nerve may be under diagnosed in patients with headache that
findings, and gait ataxia. Brain MRI was abnormal in 1 of frequently accompanies CPI therapy31. Thus, data from over
4 patients examined, showing meningeal enhancement30. 3,000 cancer patients involved in registration trials of CPIs
Spinal MRI revealed arachnoiditis in the only patient indicate a combined incidence of serious immune-related
imaged31. CSF universally demonstrated lymphocytosis CNS toxicities in the range of 0.4-1%. For comparison,
with elevated protein. Patient 14 underwent dural biopsy the incidence of paraneoplastic syndromes affecting the
demonstrating acute and chronic inflammation30. Initial CNS among cancer patients not receiving immunotherapy
treatment for immune-related meningitis consisted is < 0.1%38. Furthermore, de novo CNS paraneoplastic
of steroids in all five cases, typically by intravenous syndromes occur predominantly in patients with small cell
administration. Steroids were described as “high dose” lung cancer, breast cancer, or ovarian teratoma rather than
in 4 of 5 cases ranging from 0.5 mg/kg to 1,000 mg daily melanoma as reported here. Statistics from the American
of methylprednisolone or equivalent. One patient also Cancer Society indicate approximately 200,000 people die
received intravenous immunoglobulin31. All five meningitis each year from cancers with an FDA-approved indication
patients recovered completely over periods of 1-24 months for CPIs, suggesting the potential for 800 to 2,000 cases
(median 2 months). annually of immune-related CNS toxicities in this country
as CPIs become more widely used.
Myelitis
Ipilimumab as a single agent or in combination with
Two cases of immune-related myelitis were reported, anti-PD-1 antibodies was associated with 85% of immune-
both following ipilimumab and one associated with related CNS toxicity case reports. This reflects the greater
PRES34,35. Clinical onset of myelitis occurred after two to risk of serious immune-related adverse events of all
four doses of ipilimumab and three to five months following organ systems with ipilimumab: 25% with standard dose
CPI initiation. Presenting symptoms included paraplegia, monotherapy, 40% with high dose monotherapy, and 55%
urinary retention, constipation, and sensory loss in the when combined with anti-PD-1 treatment1,6,7. Melanoma
lower extremities. Spinal MRI demonstrated diffuse involvement in 70% of CNS toxicity case reports likely
intramedullary edema from the cervical cord through the reflects it being the only FDA-approved indication for
cauda equina in patient 19 and focal intramedullary lesions ipilimumab. The incidence of CNS adverse events may be

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increased by concomitant use of CPIs with chemotherapy or is observed, methylprednisolone can be tapered over
kinase inhibitors as described for immune-related toxicities several days to 1-1.5 mg/kg daily followed by discharge
affecting other tissues39,40. Similarly, enhancement of on oral prednisone at 1 mg/kg daily with the daily dose
systemic immunity following local radiotherapy for cancer, reduced by 10 mg every four days to wean steroids over
termed the abscopal effect, may increase the incidence 4-6 weeks. Peak concentrations and the area under the
of immune-related adverse events when combined with curve for free-prednisolone are approximately 4-fold lower
checkpoint blockade41. in CSF than plasma48,49. Thus, the widely used dose of 125
mg daily for colitis, dermatitis, hepatitis, or nephritis may
There is virtually no direct evidence concerning
be insufficient to treat CNS inflammation. All five patients
the pathogenesis of CNS toxicities following immune
with meningitis and 8 of 13 patients with encephalitis
checkpoint blockade. However, clinical observations
recovered completely. The patient with chronic onset of
and murine models of CNS paraneoplastic syndromes encephalitis achieved no neurological recovery but did
provide insight into the mechanisms underlying neuronal stabilize with treatment. Neither patient with myelitis
inflammation. Paraneoplastic disorders of the CNS can be experienced meaningful recovery despite evidence of
divided into four groups based upon pathogenesis. (1) The inflammation responding to immunosuppression. Tumor
classical paraneoplastic disorders, such as anti-Hu, involve response to immune checkpoint blockade was evaluable in
T-cell targeting of CNS neurons with antibodies being 12 of 20 case reports following the onset of CNS toxicity.
a marker of specific immune response but not directly Objective responses occurred in 6 of 12 patients (50%)
pathogenic42. (2) Other syndromes involve antibodies with 3 complete responses (Table 2). Thus, high dose
specific for intracellular synaptic proteins including GAD65, steroids and other immunosuppressive agents required
amphiphysin, and Nova2 where a transgenic mouse model to manage CNS toxicities apparently did not adversely
indicates a combination of cellular and humoral immunity effect the efficacy of checkpoint blockade, consistent with
is required to break CNS tolerance43. (3) Another group observations following the treatment of other serious
involves antibodies to CNS neuronal membrane proteins immune-related adverse events50.These cases indicate the
such as the N-methyl D-aspartate receptor (NMDAR) need for earlier diagnosis and intervention before necrosis
where antibodies are themselves pathogenic44. (4) and irreversible deficits ensue. As CPIs are approved for
Inflammatory demyelinating disorders are associated with a rapidly expanding array of indications, it is increasingly
T-cell activation in the peripheral blood and elevated serum important for neurologists, oncologists, and primary care
levels of inflammatory cytokines and are represented by physicians to understand the diagnosis and treatment of
the experimental autoimmune encephalitis mouse model immune-related CNS toxicities.
of multiple sclerosis45. For example, elevated levels of
interleukin-6 and tumor necrosis factor alpha are associated
Acknowledgement
with cancer immunotherapy and neuroinflammation46,47. The authors thank Hong Tang for expert preparation of
Thus, immune-related CNS toxicities following immune the article.
checkpoint blockade likely involve varied mechanisms
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