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://wjon.elmerpub.com

Review

Volume 17, Number 1, February 2026, pages 1-13

Neurotoxicity of Immunotherapy: Immune Checkpoint Inhibitor-Related Encephalitis vs. Immune Effector Cell-Associated Neurotoxicity Syndrome

↓ **Table 1.** Comparison Between irEncephalitis and ICANS
	irEncephalitis	ICANS
Comparison of pathogenesis, first-line therapy, adjunctive treatments, immune checkpoint inhibitor usage, and monitoring strategies between irEncephalitis and ICANS. CAR-T: chimeric antigen receptor T-cell; CRS: cytokine release syndrome; CSF: cerebrospinal fluid; GFAP: glial fibrillary acidic protein; ICANS: immune effector cell-associated neurotoxicity syndrome; ICE: immune effector cell-associated encephalopathy; ICI: immune checkpoint inhibitor; irEncephalitis: immune-related encephalitis; IVIG: intravenous immunoglobulin; MRI: magnetic resonance imaging; NFL: neurofilament light chain; PLEX: plasma exchange.
Pathogenesis	Autoimmune (T-cell or autoantibody-mediated)	Cytokine-mediated inflammation post-CAR-T therapy
First-line therapy	Corticosteroids	Corticosteroids (ICANS ≥ grade 2); tocilizumab (with CRS)
Adjuncts	IVIG, PLEX, rituximab (autoantibody-driven cases)	Tocilizumab, anakinra (off-label), anti-epileptics
Immune checkpoint use	Discontinue or permanently hold ICIs	Continue CAR-T while managing toxicity if possible
Monitoring	MRI, CSF, autoantibodies	ICE score, cytokine levels, GFAP/NFL in CSF

↓ Table 1. Comparison Between irEncephalitis and ICANS

irEncephalitis

ICANS

Comparison of pathogenesis, first-line therapy, adjunctive treatments, immune checkpoint inhibitor usage, and monitoring strategies between irEncephalitis and ICANS. CAR-T: chimeric antigen receptor T-cell; CRS: cytokine release syndrome; CSF: cerebrospinal fluid; GFAP: glial fibrillary acidic protein; ICANS: immune effector cell-associated neurotoxicity syndrome; ICE: immune effector cell-associated encephalopathy; ICI: immune checkpoint inhibitor; irEncephalitis: immune-related encephalitis; IVIG: intravenous immunoglobulin; MRI: magnetic resonance imaging; NFL: neurofilament light chain; PLEX: plasma exchange.

Pathogenesis

Autoimmune (T-cell or autoantibody-mediated)

Cytokine-mediated inflammation post-CAR-T therapy

First-line therapy

Corticosteroids

Corticosteroids (ICANS ≥ grade 2); tocilizumab (with CRS)

Adjuncts

IVIG, PLEX, rituximab (autoantibody-driven cases)

Tocilizumab, anakinra (off-label), anti-epileptics

Immune checkpoint use

Discontinue or permanently hold ICIs

Continue CAR-T while managing toxicity if possible

Monitoring

MRI, CSF, autoantibodies

ICE score, cytokine levels, GFAP/NFL in CSF

↓ **Table 2.** ICE Score
Neurologic status	Grade 1	Grade 2	Grade 3	Grade 4
ASTCT ICE scoring system for ICANS, detailing neurologic status and associated clinical findings across severity grades. ASTCT: American Society for Transplantation and Cellular Therapy; ICANS: immune effector cell-associated neurotoxicity syndrome; ICE: immune effector cell-associated encephalopathy; ICP: intracranial pressure.
ICE score	7 - 9	3 - 6	1 - 2	0
Consciousness	Spontaneously awake	Awakens to voice	Awakens to tactile stimulus	Unresponsive to all stimuli, coma or obtundation
Seizure	N/A	N/A	Seizure ≤ 5 min	Seizure > 5 min or intractable
Motor findings	N/A	N/A	N/A	Severe hemiparesis or global paresis
ICP/cerebral edema	N/A	N/A	Focal edema	Diffuse cerebral edema, cranial nerve palsy, brainstem edema, Cushing’s triad

↓ Table 2. ICE Score

Neurologic status

Grade 1

Grade 2

Grade 3

Grade 4

ASTCT ICE scoring system for ICANS, detailing neurologic status and associated clinical findings across severity grades. ASTCT: American Society for Transplantation and Cellular Therapy; ICANS: immune effector cell-associated neurotoxicity syndrome; ICE: immune effector cell-associated encephalopathy; ICP: intracranial pressure.

ICE score

7 - 9

3 - 6

1 - 2

Consciousness

Spontaneously awake

Awakens to voice

Awakens to tactile stimulus

Unresponsive to all stimuli, coma or obtundation

Seizure

N/A

Seizure ≤ 5 min

Seizure > 5 min or intractable

Motor findings

N/A

Severe hemiparesis or global paresis

ICP/cerebral edema

N/A

Focal edema

Diffuse cerebral edema, cranial nerve palsy, brainstem edema, Cushing’s triad

↓ **Table 3.** Grading and Treatment of ICANS
ASTCT grade	Without CRS	With CRS
Management algorithms for ICANS according to ASTCT grade, stratified by the presence or absence of concomitant CRS, highlighting escalation steps from supportive care to intensive immunosuppressive therapies. ASTCT: American Society for Transplantation and Cellular Therapy; CRS: cytokine release syndrome; ICANS: immune effector cell-associated neurotoxicity syndrome; ICU: intensive care unit; IV: intravenous.
Grade 1	Supportive care only	Tocilizumab 8 mg/kg (max 800 mg) IV over 1 h, repeat per ASTCT/institutional protocol when CRS persists (observe maximum total dosing limits)
Grade 2	Dexamethasone 10 mg IV, repeat every 6 - 12 h if needed	As in grade 1 + ICU if CRS ≥ grade 2
Grade 3	ICU care, dexamethasone 10 mg q6h or methylprednisolone 1 mg/kg q12h, consider imaging every 2 - 3 days	Same as grade 1
Grade 4	ICU and respiratory support, methylprednisolone 1,000 mg/day for 3 days then taper, consider anakinra 100 mg q12h if steroid-resistant	Same as grade 1

↓ Table 3. Grading and Treatment of ICANS

ASTCT grade

Without CRS

With CRS

Management algorithms for ICANS according to ASTCT grade, stratified by the presence or absence of concomitant CRS, highlighting escalation steps from supportive care to intensive immunosuppressive therapies. ASTCT: American Society for Transplantation and Cellular Therapy; CRS: cytokine release syndrome; ICANS: immune effector cell-associated neurotoxicity syndrome; ICU: intensive care unit; IV: intravenous.

Grade 1

Supportive care only

Tocilizumab 8 mg/kg (max 800 mg) IV over 1 h, repeat per ASTCT/institutional protocol when CRS persists (observe maximum total dosing limits)

Grade 2

Dexamethasone 10 mg IV, repeat every 6 - 12 h if needed

As in grade 1 + ICU if CRS ≥ grade 2

Grade 3

ICU care, dexamethasone 10 mg q6h or methylprednisolone 1 mg/kg q12h, consider imaging every 2 - 3 days

Same as grade 1

Grade 4

ICU and respiratory support, methylprednisolone 1,000 mg/day for 3 days then taper, consider anakinra 100 mg q12h if steroid-resistant

Same as grade 1

↓ **Table 4.** Clinical Grading and Corresponding Treatment Recommendations for irEncephalitis
Grade	Clinical features	Treatment strategy
Clinical grading and corresponding treatment recommendations for irEncephalitis, based on symptom severity, imaging findings, CSF abnormalities, and presence of autoantibodies. CSF: cerebrospinal fluid; ICI: immune checkpoint inhibitor; ICU: intensive care unit; irEncephalitis: immune-related encephalitis; IVIG: intravenous immunoglobulin; MRI: magnetic resonance imaging.
Grade 1	Mild symptoms (e.g., headache, low-grade fever, mild cognitive changes), stable neurological exam	Hold ICIs, initiate oral corticosteroids (e.g., prednisone 0.5 - 1 mg/kg/day), close monitoring
Grade 2	Moderate symptoms (e.g., confusion, disorientation), abnormal findings on MRI or CSF, no severe functional impairment	Discontinue ICIs, high-dose IV corticosteroids (e.g., methylprednisolone 1 - 2 mg/kg/day), neurology consult
Grade 3	Severe symptoms (e.g., seizures, focal neurologic deficits), evidence of CNS inflammation, positive autoantibodies	Escalate to IVIG or plasmapheresis if refractory; consider rituximab or mycophenolate depending on antibody profile
Grade 4	Life-threatening symptoms (e.g., status epilepticus, coma), diffuse brain involvement, ICU-level care	ICU care, aggressive immunosuppression (methylprednisolone pulse 1,000 mg/day for 3 - 5 days), consider cyclophosphamide

↓ Table 4. Clinical Grading and Corresponding Treatment Recommendations for irEncephalitis

Grade

Clinical features

Treatment strategy

Clinical grading and corresponding treatment recommendations for irEncephalitis, based on symptom severity, imaging findings, CSF abnormalities, and presence of autoantibodies. CSF: cerebrospinal fluid; ICI: immune checkpoint inhibitor; ICU: intensive care unit; irEncephalitis: immune-related encephalitis; IVIG: intravenous immunoglobulin; MRI: magnetic resonance imaging.

Grade 1

Mild symptoms (e.g., headache, low-grade fever, mild cognitive changes), stable neurological exam

Hold ICIs, initiate oral corticosteroids (e.g., prednisone 0.5 - 1 mg/kg/day), close monitoring

Grade 2

Moderate symptoms (e.g., confusion, disorientation), abnormal findings on MRI or CSF, no severe functional impairment

Discontinue ICIs, high-dose IV corticosteroids (e.g., methylprednisolone 1 - 2 mg/kg/day), neurology consult

Grade 3

Severe symptoms (e.g., seizures, focal neurologic deficits), evidence of CNS inflammation, positive autoantibodies

Escalate to IVIG or plasmapheresis if refractory; consider rituximab or mycophenolate depending on antibody profile

Grade 4

Life-threatening symptoms (e.g., status epilepticus, coma), diffuse brain involvement, ICU-level care

ICU care, aggressive immunosuppression (methylprednisolone pulse 1,000 mg/day for 3 - 5 days), consider cyclophosphamide

↓ **Table 5.** Incidence of ICANS in Key T-Cell Engaging Therapies (Phase II or Later)
Therapy (type)	Targets (tumor × T-cell)	Indication (tumor type)	Status	ICANS incidence (any; grade ≥ 3)
ICANS incidence for prominent T-cell engager therapies (including bispecific T-cell engagers, bispecific antibodies, and TCR-mimic constructs) that are approved or in phase II/III development. Both overall ICANS frequency (any grade) and the incidence of high-grade (≥ 3) ICANS are provided where available, along with each agent’s targets, cancer indication, regulatory status. B-ALL: B-cell acute lymphoblastic leukemia; CRS: cytokine release syndrome; DLBCL: diffuse large B-cell lymphoma; FL: follicular lymphoma; ICANS: immune effector cell-associated neurotoxicity syndrome; LBCL: large B-cell lymphoma; MM: multiple myeloma; NHL: non-Hodgkin lymphoma; RR: relapsed/refractory.
Blinatumomab (BiTE)	CD19 × CD3	B-ALL (RR)	FDA-approved	57% any neurotoxicity; ∼ 11-13% grade ≥ 3 ICANS [102, 103]
Teclistamab (BsAb)	BCMA × CD3	RRMM	FDA-approved	6% any ICANS; ∼ 2% grade ≥ 3 ICANS [104]
Talquetamab (BsAb)	GPRC5D × CD3	RRMM	FDA-approved	9% any ICANS; ∼ 6% grade ≥ 3 neurologic toxicity
Elranatamab (BsAb)	BCMA × CD3	RRMM	FDA-approved	∼ 3-4% any ICANS; 0% grade ≥ 3 ICANS reported [105]
Epcoritamab (BsAb)	CD20 × CD3	3L+ R/R LBCL	FDA-approved	6% any ICANS (all grade 1-2); ∼ 0% grade ≥ 3 (one fatal ICANS ∼ 0.6%) [106]
Glofitamab (BsAb)	CD20 × CD3	R/R DLBCL	FDA-approved	4.8% any ICANS; ∼ 0% grade ≥ 3 ICANS (2.1% grade ≥ 3 neuro events) [107]
Mosunetuzumab (BsAb)	CD20 × CD3	R/R FL, 3L+	FDA-approved	∼ 1% any ICANS (grade 1-2 only); 0% grade ≥ 3 ICANS [108]
Odronextamab (BsAb)	CD20 × CD3	B-cell NHL (R/R DLBCL, FL - phase II ELM-2 trial)	Phase II	0% ICANS reported (none observed in trials) [109]
Tebentafusp (TCR-CD3)	gp100-HLA*A2:01 × CD3	Uveal melanoma (metastatic)	FDA-approved	< 1% ICANS (CRS common; no significant ICANS reported) [110]

↓ Table 5. Incidence of ICANS in Key T-Cell Engaging Therapies (Phase II or Later)

Therapy (type)

Targets (tumor × T-cell)

Indication (tumor type)

Status

ICANS incidence (any; grade ≥ 3)

ICANS incidence for prominent T-cell engager therapies (including bispecific T-cell engagers, bispecific antibodies, and TCR-mimic constructs) that are approved or in phase II/III development. Both overall ICANS frequency (any grade) and the incidence of high-grade (≥ 3) ICANS are provided where available, along with each agent’s targets, cancer indication, regulatory status. B-ALL: B-cell acute lymphoblastic leukemia; CRS: cytokine release syndrome; DLBCL: diffuse large B-cell lymphoma; FL: follicular lymphoma; ICANS: immune effector cell-associated neurotoxicity syndrome; LBCL: large B-cell lymphoma; MM: multiple myeloma; NHL: non-Hodgkin lymphoma; RR: relapsed/refractory.

Blinatumomab (BiTE)

CD19 × CD3

B-ALL (RR)

FDA-approved

57% any neurotoxicity; ∼ 11-13% grade ≥ 3 ICANS [102, 103]

Teclistamab (BsAb)

BCMA × CD3

RRMM

FDA-approved

6% any ICANS; ∼ 2% grade ≥ 3 ICANS [104]

Talquetamab (BsAb)

GPRC5D × CD3

RRMM

FDA-approved

9% any ICANS; ∼ 6% grade ≥ 3 neurologic toxicity

Elranatamab (BsAb)

BCMA × CD3

RRMM

FDA-approved

∼ 3-4% any ICANS; 0% grade ≥ 3 ICANS reported [105]

Epcoritamab (BsAb)

CD20 × CD3

3L+ R/R LBCL

FDA-approved

6% any ICANS (all grade 1-2); ∼ 0% grade ≥ 3 (one fatal ICANS ∼ 0.6%) [106]

Glofitamab (BsAb)

CD20 × CD3

R/R DLBCL

FDA-approved

4.8% any ICANS; ∼ 0% grade ≥ 3 ICANS (2.1% grade ≥ 3 neuro events) [107]

Mosunetuzumab (BsAb)

CD20 × CD3

R/R FL, 3L+

FDA-approved

∼ 1% any ICANS (grade 1-2 only); 0% grade ≥ 3 ICANS [108]

Odronextamab (BsAb)

CD20 × CD3

B-cell NHL (R/R DLBCL, FL - phase II ELM-2 trial)

Phase II

0% ICANS reported (none observed in trials) [109]

Tebentafusp (TCR-CD3)

gp100-HLA*A2:01 × CD3

Uveal melanoma (metastatic)

FDA-approved

< 1% ICANS (CRS common; no significant ICANS reported) [110]