A Concise Review of Neurologic Complications Associated with Chimeric Antigen Receptor T-cell Immunotherapy

Key points

Toxicities after chimeric antigen receptor–engineered T-cell therapy

CD19-targeting CAR-T cells have been wildly successful in treating some hematologic malignancies; however, CAR-T therapy is associated with severe adverse effects, such as cytokine release syndrome (CRS), as well as a bizarre, idiosyncratic, largely reversible encephalopathy, termed immune effector cell–associated neurotoxicity syndrome (ICANS), summarized in Table 1. This syndrome may accompany CRS or occur independently.3, 4, 5 CRS and ICANS are the most common CAR-T–associated toxicities.

Clinical manifestations of immune effector cell–associated neurotoxicity syndrome

ICANS presentation is variable and manifests with encephalopathy and focal neurologic deficits, in particular aphasia and seizures. In a majority of cases reported in the literature as well as in the author’s experience, there is complete resolution of low-grade ICANS. Fatal manifestations of ICANS include intracerebral hemorrhage and malignant cerebral edema. The estimated incidence of fatal ICANS is less than 5% from all acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma

Clinical risk factors and laboratory markers of immune effector cell–associated neurotoxicity syndrome

Clinical risk factors associated with an increased risk of ICANS include the disease type and burden as well as CAR-T treatment specifics. ICANS is more common in ALL than lymphoma and appears to be negligible in multiple myeloma and solid tumors to date. Higher disease burden, in particular, the percent of marrow disease in ALL, has been associated with increased risk of ICANS. Higher CAR-T cell dose and higher peak CAR-T expansion in the blood have been associated with ICANS.

The particular

Pathologic findings of immune effector cell–associated neurotoxicity syndrome after chimeric antigen receptor–engineered T-cell therapy

In 2018, Santomasso and colleagues⁹ described characteristic radiographic findings associated with ICANS in patients treated with CAR-T therapy. MRI findings associated with ICANS include T2/fluid-attenuated inversion recovery (FLAIR) signal hyperintensity present in the thalami, periventricular white matter, external capsule, extreme capsule, claustrum, and dorsal pons. Some of these elements are similar to the radiographic findings seen in extrapontine myelinolysis and to findings seen on

Management of immune effector cell–associated neurotoxicity syndrome

Current management protocols differ between institutions. In many institutions, however, the assistance of neurology specialists is required from day 1 of hospitalization. ICANS is largely treated with corticosteroids, such as dexamethasone and methylprednisolone, as well as antiepileptics and CSF diversion, although there is concern that corticosteroids may have a negative impact on the therapeutic functions of CAR-T cells.21, 22, 23 ICANS frequently is treated with an anticonvulsant

Case presentation

A 26-year-old man with refractory large B-cell lymphoma with predominantly mediastinal disease underwent a Yescarta infusion and tolerated this without issue. On day 1 postinfusion, the patient became febrile to 39.1°C and tachycardic with a heart rate of 132 beats per minute. His blood pressure and oxygenation saturation remained normal. On days 1 to 3, the patient remained febrile without hypotension, hypoxia, or organ dysfunction and was nonencephalopathic. By the afternoon of day 3, the

Potential Mechanisms of Immune Effector Cell–Associated Neurotoxicity Syndrome

One proposed common pathway of CRS and subsequent ICANS is as follows: activated CAR-T cells release effector cytokines that, in turn, activate endothelial cells and antigen-presenting cells and macrophages. These cells produce IL-6, driving the onset of CRS. Robust systemic cytokine production results in cytokine-mediated endothelial activation, which results in altered cerebrovascular regulation and blood-brain barrier dysfunction as well as vascular dysfunction, astrocytic injury, and, in

Summary

In conclusion, ICANS is mild and reversible in most cases. The pathogenesis of this disorder is similar but distinct from CRS and involves blood-brain barrier permeability, endothelial cell dysfunction, and excitotoxicity. Preexisting neurologic comorbidities are associated with clinically significant ICANS, among many other risk factors associated with this occurrence. Additionally, the CAR-T cell product itself seems to have a significant influence on ICANS incidence and severity. Ongoing

Clinicals Care Points

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  ICANS presentation is variable and manifests with encephalopathy and focal neurologic deficits, in particular aphasia and seizures.

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  In the majority of reported cases, there is complete resolution of low-grade ICANS.

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  History of neurologic disease, high tumor burden, early CRS, abnormal MRI brain are all proposed risk factors for ICANS.

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  Management of ICANS includes the use of corticosteroids such as dexamethasone and methylprednisolonde, anti-epileptics and CSF diversion.

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  Treatments under

Disclosure

S.S. Kenderian is an inventor on patents in the field of CAR immunotherapy that are licensed to Novartis (through an agreement between Mayo Clinic, University of Pennsylvania, and Novartis), Humanigen (through Mayo Clinic), and Mettaforge (through Mayo Clinic). S.S. Kenderian receives research funding from Kite, Gilead, Juno, Celgene, Novartis, Humanigen, MorphoSys, Tolero, Sunesis, and Lentigen. S.S. Kenderian has participated in advisory boards with Humanigen, Kite, and Juno.