Chimeric Antigen Receptor T Cell-Related Neurotoxicity: Mechanisms, Clinical Presentation, and Approach to Treatment

Rice, Jessica; Nagle, Sarah; Randall, Julie; Hinson, Holly E.

doi:10.1007/s11940-019-0580-3

Cited by 80 publications

(67 citation statements)

References 43 publications

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“…To begin, we will review the typical clinical presentation and impact of ICANS to emphasize the features that may shed light on a pathophysiologic understanding from a cytokine perspective. Comprehensive reviews of clinical presentation, findings on clinical studies such as brain imaging, CSF examination, and electroencephalography (EEG), as well as toxicity grading and interventions, are available elsewhere (1,(14)(15)(16)(17)(18).…”

Section: Clinical Phenotype Of Neurologic Dysfunction In Car T Cell Tmentioning

confidence: 99%

Cytokines in CAR T Cell–Associated Neurotoxicity

et al. 2020

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Chimeric antigen receptor (CAR) T cells provide new therapeutic options for patients with relapsed/refractory hematologic malignancies. However, neurotoxicity is a frequent, and potentially fatal, complication. The spectrum of manifestations ranges from delirium and language dysfunction to seizures, coma, and fatal cerebral edema. This novel syndrome has been designated immune effector cell–associated neurotoxicity syndrome (ICANS). In this review, we draw an arc from our current understanding of how systemic and potentially local cytokine release act on the CNS, toward possible preventive and therapeutic approaches. We systematically review reported correlations of secreted inflammatory mediators in the serum/plasma and cerebrospinal fluid with the risk of ICANS in patients receiving CAR T cell therapy. Possible pathophysiologic impacts on the CNS are covered in detail for the most promising candidate cytokines, including IL-1, IL-6, IL-15, and GM-CSF. To provide insight into possible final common pathways of CNS inflammation, we place ICANS into the context of other systemic inflammatory conditions that are associated with neurologic dysfunction, including sepsis-associated encephalopathy, cerebral malaria, thrombotic microangiopathy, CNS infections, and hepatic encephalopathy. We then review in detail what is known about systemic cytokine interaction with components of the neurovascular unit, including endothelial cells, pericytes, and astrocytes, and how microglia and neurons respond to systemic inflammatory challenges. Current therapeutic approaches, including corticosteroids and blockade of IL-1 and IL-6 signaling, are reviewed in the context of what is known about the role of cytokines in ICANS. Throughout, we point out gaps in knowledge and possible new approaches for the investigation of the mechanism, prevention, and treatment of ICANS.

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Section: Clinical Phenotype Of Neurologic Dysfunction In Car T Cell Tmentioning

confidence: 99%

Cytokines in CAR T Cell–Associated Neurotoxicity

et al. 2020

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“…One patient did develop grade 3 CRS despite relatively low medullary disease burden; although disease burden is the best characterized risk factor for CRS, the effect of other variables such as T‐cell phenotype and function of the product and the gene polymorphisms in the CAR‐T recipient remain unclear. It is important to recognize that the mechanism behind neurotoxicity remains incompletely understood . Two recent analyses in adult patients with ICANS found evidence of endothelial activation with subsequent compromise of the blood‐brain barrier .…”

Section: Discussionmentioning

confidence: 99%

“…It is important to recognize that the mechanism behind neurotoxicity remains incompletely understood. 16 Two recent analyses in adult patients with ICANS found evidence of endothelial activation with subsequent compromise of the blood-brain barrier. 11,12 Increased permeability correlated with the degree of neurotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Chimeric antigen receptor T‐cell therapy in patients with neurologic comorbidities

Rubinstein

Nelson

Krupski

et al. 2020

Pediatric Blood & Cancer

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Chimeric antigen receptor T cells (CAR‐T) are an effective and potentially durable treatment for refractory and multiply relapsed B‐cell acute lymphoblastic leukemia. Neurotoxicity is frequent after CAR‐T cell therapy. Mechanisms driving neurotoxicity are incompletely understood, and symptoms can range from transient and mild to severe and life‐threatening. Providers have exercised caution in providing CAR‐T to patients with neurological comorbidities or extramedullary disease. Here, we report three patients with prior significant neurologic morbidity who safely tolerated CAR‐T cell infusion after bridging therapy with conventional chemotherapy.

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“…In contrast, the incidence of severe CRS with axicabtagene ciloleucel in ALL and NHL patients was 13 and 29%, respectively. ICANS clinically manifests with the deterioration of neurological function starting from word-finding difficulty with stuttering, writing impairment, and decreased concentration and progressing to more severe cases with a depressed level of consciousness, convulsive or non-convulsive seizures, and at times raised intracranial pressure/cerebral edema (38). The pathophysiology of ICANS is still not completely understood, and the mechanism is believed to be related to endothelial activation and blood-brain barrier disruption.…”

Section: Toxicities Associated With Car-t Therapymentioning

confidence: 99%

Chimeric Antigen Receptor T-Cells in B-Acute Lymphoblastic Leukemia: State of the Art and Future Directions

et al. 2020

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Use of adoptive T-cell therapy modified with chimeric antigen receptor (CAR-T) has revolutionized treatment of patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). CART cells directed against CD19 antigen have produced response rates as high as 90% in clinical trials for r/r BALL. Despite high rates of complete remissions, the durability of responses has been sub-optimal with frequent relapses, especially in adult BALL population. Systemic toxicities from CART therapy and standardization of toxicities grading and management is another major hurdle in the development of CART field. In this review, we discuss the latest evidence of CART therapy in BALL , potential mechanisms of relapse and barriers to CART cell therapy in BALL. We also debate the role of allogeneic hematopoietic stem cell transplant (allo-HCT) post CART therapy.

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Chimeric Antigen Receptor T Cell-Related Neurotoxicity: Mechanisms, Clinical Presentation, and Approach to Treatment

Cited by 80 publications

References 43 publications

Cytokines in CAR T Cell–Associated Neurotoxicity

Cytokines in CAR T Cell–Associated Neurotoxicity

Chimeric antigen receptor T‐cell therapy in patients with neurologic comorbidities

Chimeric Antigen Receptor T-Cells in B-Acute Lymphoblastic Leukemia: State of the Art and Future Directions

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