World J Oncol

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

Journal website https://www.wjon.org

Review

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 immunotherapies	Drugs	Target 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-gxly	PD-1 receptors	Removes inhibitory signals of T-cell activation
	Atezolizumab, avelumab, durvalumab, cemiplimab	PD-L1 sites	Enables tumor-reactive T cells to mount an effective antitumor response
	Ipilimumab	CTLA-4
CAR T-cell therapy [3, 4]	Tisagenlecleucel, axicabtagene ciloleucel, lisocabtagene marualeucel, brexucabtagene autoleucel	CD-19-directed	Chimeric/genetically modified T cell expressing receptor for tumor specific antigen
			MHC independent T cell binding with specific antigens
	Idecabtagene vicleucel, ciltacabtagene autoleucel	BCMA-directed	CD4⁺ and CD8⁺ T cell-mediated tumor lysis via perforin and granzyme exocytosis, death receptor signaling

Table 1. Types of Cancer Immunotherapy, Commonly Used Drugs, Target Sites and Mechanism of Action

Types of immunotherapies

Drugs

Target 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-gxly

PD-1 receptors

Removes inhibitory signals of T-cell activation

Atezolizumab, avelumab, durvalumab, cemiplimab

PD-L1 sites

Enables tumor-reactive T cells to mount an effective antitumor response

Ipilimumab

CTLA-4

CAR T-cell therapy [3, 4]

Tisagenlecleucel, axicabtagene ciloleucel, lisocabtagene marualeucel, brexucabtagene autoleucel

CD-19-directed

Chimeric/genetically modified T cell expressing receptor for tumor specific antigen

MHC independent T cell binding with specific antigens

Idecabtagene vicleucel, ciltacabtagene autoleucel

BCMA-directed

CD4⁺ and CD8⁺ T cell-mediated tumor lysis via perforin and granzyme exocytosis, death receptor signaling

**Table 2.** Neurological Side Effects of Cancer Immunotherapy
Immunotherapy	Neurological side effect	Probable 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 myositis	Infiltration 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, meningismus	Disruption of the blood-brain barrier
	Progressive multifocal leukoencephalopathy	Passage 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 hemorrhage	Parenchymal basement membrane and vascular disruption, with cerebral edema, hemorrhage, infarction, and necrosis, and neuronal death
	Movement and neurocognitive treatment-emergent adverse events

Table 2. Neurological Side Effects of Cancer Immunotherapy

Immunotherapy

Neurological side effect

Probable 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 myositis

Infiltration 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, meningismus

Disruption of the blood-brain barrier

Progressive multifocal leukoencephalopathy

Passage 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 hemorrhage

Parenchymal 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)
Immunotherapy	Investigation	Management
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 brain	Withholding ICI therapy
	CSF analysis	Steroids
	Check hormone levels in cases of endocrine dysfunction	IVIG
	EEG	Plasmapheresis
	Paraneoplastic antibodies	Hormone replacement therapy as indicated
	Other laboratory tests to rule out alternative diagnosis	Immunosuppressants
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 head	Use 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
	EEG
		Supportive management for seizures and raised intracranial pressure
		Can use tocilizumab when concurrent with CRS
		Can consider siltuximab, anakinra, and IVIG for refractory cases

Table 3. General Investigations and Management of Immune-Related Adverse Events (irAEs)

Immunotherapy

Investigation

Management

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 brain

Withholding ICI therapy

CSF analysis

Steroids

Check hormone levels in cases of endocrine dysfunction

IVIG

EEG

Plasmapheresis

Paraneoplastic antibodies

Hormone replacement therapy as indicated

Other laboratory tests to rule out alternative diagnosis

Immunosuppressants

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 head

Use 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

EEG

Supportive management for seizures and raised intracranial pressure

Can use tocilizumab when concurrent with CRS

Can consider siltuximab, anakinra, and IVIG for refractory cases