Mechanisms of immune effector cell‐associated neurotoxicity syndrome after CAR‐T treatment

Abstract

Chimeric antigen receptor T-cell (CAR-T) treatment has revolutionized the landscape of cancer therapy with significant efficacy on hematologic malignancy, especially in relapsed and refractory B cell malignancies. However, unexpected serious toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) still hamper its broad application. Clinical trials using CAR-T cells targeting specific antigens on tumor cell surface have provided valuable information about the characteristics of ICANS. With unclear mechanism of ICANS after CAR-T treatment, unremitting efforts have been devoted to further exploration. Clinical findings from patients with ICANS strongly indicated existence of overactivated peripheral immune response followed by endothelial activationinduced blood-brain barrier (BBB) dysfunction, which triggers subsequent central nervous system (CNS) inflammation and neurotoxicity. Several animal models have been built but failed to fully replicate the whole spectrum of ICANS in human. Hopefully, novel and powerful technologies like single-cell analysis may help decipher the precise cellular response within CNS from a different perspective when ICANS happens. Moreover, multidisciplinary cooperation among the subjects of immunology, hematology, and neurology will facilitate better understanding about the complex immune interaction between the peripheral, protective barriers, and CNS in ICANS. This review elaborates recent findings about ICANS after CAR-T treatment from bed to bench, and discusses the potential cellular and molecular mechanisms that may promote effective management in the future.

CAR T-cell-associated neurotoxicity in central nervous system hematologic disease: Is it still a concern?

“…The mechanism of CAR T-cell neurotoxicity remains to be well-elucidated, and several mechanisms of ICANS after CAR T-cell treatment have been described ( 29 ). The most widely accepted mechanism of CAR T-cell neurotoxicity is driven by systemic inflammation and cytokine production.…”

“…This triggers a further local inflammatory response and CNS inflammation with subsequent astrocyte injury and microglial activation. It then results in abnormal neuronal function related to the dysregulation of neuroglial cells and neurotransmitters ( 29 ). In addition, cerebral multifocal hemorrhage in patients with ICANS indicates thrombotic microangiopathy compromising BBB function ( 29 ).…”

“…It then results in abnormal neuronal function related to the dysregulation of neuroglial cells and neurotransmitters ( 29 ). In addition, cerebral multifocal hemorrhage in patients with ICANS indicates thrombotic microangiopathy compromising BBB function ( 29 ). Targeting of cerebral CD19-expressing pericytes can disrupt the BBB and contribute to the development of ICANS.…”

Tumor microenvironment and CAR‐T cell immunotherapy in B‐cell lymphoma

“…The entry of peripheral immune cells and cytokines into the CNS can lead to CNS inflammation. Activated astrocytes release IL‐6 and GM‐CSF, which induces microglial activation to produce additional IL‐1β, IL‐6, and TNF‐α, further impairing neuronal function 108 . Clinical observations have shown that higher tumor burden, prior lymphocyte depletion, larger CAR‐T cell infusion doses, and more rapid CAR‐T cell expansion in vivo are also associated with the occurrence and severity of ICANS 108,109 .…”

“…Activated astrocytes release IL‐6 and GM‐CSF, which induces microglial activation to produce additional IL‐1β, IL‐6, and TNF‐α, further impairing neuronal function 108 . Clinical observations have shown that higher tumor burden, prior lymphocyte depletion, larger CAR‐T cell infusion doses, and more rapid CAR‐T cell expansion in vivo are also associated with the occurrence and severity of ICANS 108,109 . The destruction of blood–brain barrier (BBB) also leads to the migration of T cells (including CAR‐T cells) to the brain parenchyma, and the levels of cytokines and proteins would be increased in the cerebrospinal fluid, then leading to CNS inflammation and toxicity.…”