World Journal of Oncology, ISSN 1920-4531 print, 1920-454X online, Open Access
Article copyright, the authors; Journal compilation copyright, World J Oncol and Elmer Press Inc
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Volume 14, Number 2, April 2023, pages 109-118

Neurological Adverse Effects of Immune Checkpoint Inhibitors and Chimeric Antigen Receptor T-Cell Therapy


Table 1. Types of Cancer Immunotherapy, Commonly Used Drugs, Target Sites and Mechanism of Action
Types of immunotherapiesDrugsTarget site and mechanism of action
CRT: chimeric antigen receptor; PD-1: programmed death 1; PD-L1: programmed death-ligand 1; CTLA-4: cytotoxic T-lymphocyte antigen-4; MHC: major histocompatibility complex; BCMA: B-cell maturation antigen.
Checkpoint inhibitor [2]Pembrolizumab, nivolumab, dostarlimab-gxlyPD-1 receptorsRemoves inhibitory signals of T-cell activation
Atezolizumab, avelumab, durvalumab, cemiplimabPD-L1 sitesEnables tumor-reactive T cells to mount an effective antitumor response
CAR T-cell therapy [3, 4]Tisagenlecleucel, axicabtagene ciloleucel, lisocabtagene marualeucel, brexucabtagene autoleucelCD-19-directedChimeric/genetically modified T cell expressing receptor for tumor specific antigen
MHC independent T cell binding with specific antigens
Idecabtagene vicleucel, ciltacabtagene autoleucelBCMA-directedCD4+ and CD8+ T cell-mediated tumor lysis via perforin and granzyme exocytosis, death receptor signaling


Table 2. Neurological Side Effects of Cancer Immunotherapy
ImmunotherapyNeurological side effectProbable pathogenesis
CTLA-4: cytotoxic T-lymphocyte antigen-4; AB: antibody; CRT: chimeric antigen receptor; ICANS: immune effector cell-associated neurotoxicity syndrome; IL: interleukin; IFN: interferon; TNF: tumor necrosis factor; CSF: cerebral spinal fluid.
Checkpoint inhibitor [7, 8, 10]Central: encephalitis (0.1-0.2%), aseptic meningitis (0.1-0.2%), hypophysitis (10% in CTLA-4 AB)Antibodies against the self-antigens
Peripheral: polyneuropathy (3%), acute demyelinating polyneuropathy (0.1-0.2%), myasthenia gravis (0.1-0.2%), and necrotizing myositisInfiltration of clonal T cells similar to that present in tumor
Increase in the cytokine levels acting against the normal healthy tissue
Worsening preexisting autoimmunity
CAR T-cell [16-18]ICANS: tremors, headache, lethargy, memory impairment, language difficulties, encephalopathy, agitation, seizures, myoclonus, ataxia, meningismusDisruption of the blood-brain barrier
Progressive multifocal leukoencephalopathyPassage of inflammatory cytokines (IL-6, IFN-γ, TNF-α) and lymphocytes into CSF
Posterior reversible encephalopathy syndrome (PRES)Endothelial and pericyte activation, consumptive coagulopathy, widespread inflammation
Intracranial hemorrhageParenchymal basement membrane and vascular disruption, with cerebral edema, hemorrhage, infarction, and necrosis, and neuronal death
Movement and neurocognitive treatment-emergent adverse events


Table 3. General Investigations and Management of Immune-Related Adverse Events (irAEs)
ICI: immune checkpoint inhibitor; CAR: chimeric antigen receptor; ICU: intensive care unit; IVIG: intravenous immunoglobulin; CRS: cytokine release syndrome; ICANS: immune effector cell-associated neurotoxicity syndrome; CSF: cerebral spinal fluid; EEG: electroencephalography; MRI: magnetic resonance imaging; CT: computed tomography; CK: creatine kinase.
Checkpoint blockade
  Central nervous system [25]MRI brainWithholding ICI therapy
CSF analysisSteroids
Check hormone levels in cases of endocrine dysfunctionIVIG
Paraneoplastic antibodiesHormone replacement therapy as indicated
Other laboratory tests to rule out alternative diagnosisImmunosuppressants
  Peripheral nervous system [10]MRI brain/spine
Electroneuromyography, muscle biopsy if needed
Autoantibody workup
Laboratory tests including CK levels
CAR T-cell therapy [26, 27]MRI brain or CT headUse ICANS grading system to grade disease severity and manage accordingly: grade 1, supportive; grade ≥ 2, add corticosteroids; grade ≥ 3, add close monitoring in the ICU
CSF analysis
Supportive management for seizures and raised intracranial pressure
Can use tocilizumab when concurrent with CRS
Can consider siltuximab, anakinra, and IVIG for refractory cases