Lymphodepletion chemotherapy followed by infusion of CD19-targeted chimeric antigen receptor (CAR)-modified T (CAR-T) cells can be complicated by neurologic adverse events (AEs) in patients with refractory B cell malignancies. In 133 adults treated with CD19 CAR-T cells we found that acute lymphoblastic leukemia, high CD19+ cells in bone marrow, high CAR-T cell dose, cytokine release syndrome, and preexisting neurologic comorbidities were associated with increased risk of neurologic AEs. Patients with severe neurotoxicity demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier (BBB) permeability. The permeable BBB failed to protect the CSF from high concentrations of systemic cytokines including IFN-γ, which induced brain vascular pericyte stress and their secretion of endothelium-activating cytokines. Endothelial activation and multifocal vascular disruption were found in the brain of a patient with fatal neurotoxicity. Biomarkers of endothelial activation were higher before treatment in patients who subsequently developed grade ≥4 neurotoxicity.

Lymphodepletion chemotherapy followed by infusion of CD19-specific chimeric antigen receptor-modified (CAR) T cells has produced impressive antitumor responses in patients with refractory CD19 B-cell malignancies but is often associated with cytokine release syndrome (CRS). Our understanding of CRS continues to evolve, and identification of the kinetics of CRS and predictive clinical and laboratory biomarkers of severity are needed to evaluate strategies to mitigate toxicity. We report the clinical presentation of and identify biomarkers of severe CRS in 133 adult patients who received CD19 CAR T cells. CRS developed in 70% of patients, including 62.5% with grade 1 to 3 CRS (grade 1, 26%; grade 2, 32%; grade 3, 4.5%), 3.8% with grade 4, and 3.8% with grade 5. A majority of cases of grade ≥4 CRS occurred during CAR T-cell dose finding. Multivariable analysis of baseline characteristics identified high marrow tumor burden, lymphodepletion using cyclophosphamide and fludarabine, higher CAR T-cell dose, thrombocytopenia before lymphodepletion, and manufacturing of CAR T cells without selection of CD8 central memory T cells as independent predictors of CRS. Severe CRS was characterized by hemodynamic instability, capillary leak, and consumptive coagulopathy. Angiopoietin-2 and von Willebrand factor, which are biomarkers of endothelial activation, were increased during severe CRS and also before lymphodepletion in patients who subsequently developed CRS. We describe a classification-tree algorithm to guide studies of early intervention after CAR T-cell infusion for patients at high risk of severe CRS. These data provide a framework for early intervention studies to facilitate safer application of effective CD19 CAR T-cell therapy.

Summary Some of the most common causes of blindness involve the degeneration of photoreceptors in the neural retina; photoreceptor replacement therapy might restore some vision in these individuals. Embryonic stem (ES) cells could in principle provide a source of photoreceptors to repair the retina. We have previously shown that retinal progenitors can be efficiently derived from human ES cells. We now show that retinal cells derived from human ES cells will migrate into mouse retinas following intra-ocular injection, settle into the appropriate layers and express markers for differentiated cells, including both rod and cone photoreceptor cells. After transplantation of the cells into the subretinal space of adult Crx -/- mice (a model of Leber's Congenital Amaurosis), the hES cell derived retinal cells differentiate into functional photoreceptors and restore light responses to the animals. These results demonstrate that hES cells can, in principle, be used for photoreceptor replacement therapies.

Neurotoxicity is an important and common complication of chimeric antigen receptor-T cell therapies. Acute neurologic signs and/or symptoms occur in a significant proportion of patients treated with CD19-directed chimeric antigen receptor-T cells for B-cell malignancies. Clinical manifestations include headache, confusion, delirium, language disturbance, seizures and rarely, acute cerebral edema. Neurotoxicity is associated with cytokine release syndrome, which occurs in the setting of in-vivo chimeric antigen receptor-T cell activation and proliferation. The mechanisms that lead to neurotoxicity remain unknown, but data from patients and animal models suggest there is compromise of the blood-brain barrier, associated with high levels of cytokines in the blood and cerebrospinal fluid, as well as endothelial activation. Corticosteroids, interleukin-6targeted therapies, and supportive care are frequently used to manage patients with neurotoxicity, but high-quality evidence of their efficacy is lacking.

Objective: To test whether systemic cytokine release is associated with central nervous system inflammatory responses and glial injury in immune effector cell-associated neurotoxicity syndrome (ICANS) after chimeric antigen receptor (CAR)-T cell therapy in children and young adults. Methods: We performed a prospective cohort study of clinical manifestations as well as imaging, pathology, CSF, and blood biomarkers on 43 subjects ages 1 to 25 who received CD19-directed CAR/T cells for acute lymphoblastic leukemia (ALL). Results: Neurotoxicity occurred in 19 of 43 (44%) subjects. Nine subjects (21%) had CTCAE grade 3 or 4 neurological symptoms, with no neurotoxicity-related deaths. Reversible delirium, headache, decreased level of consciousness, tremor, and seizures were most commonly observed. Cornell Assessment of Pediatric Delirium (CAPD) scores ≥9 had 94% sensitivity and 33% specificity for grade ≥3 neurotoxicity, and 91% sensitivity and 72% specificity for grade ≥2 neurotoxicity. Neurotoxicity correlated with severity of cytokine release syndrome, abnormal past brain magnetic resonance imaging (MRI), and higher peak CAR-T cell numbers in blood, but not cerebrospinal fluid (CSF). CSF levels of S100 calciumbinding protein B and glial fibrillary acidic protein increased during neurotoxicity, indicating astrocyte injury. There were concomitant increases in CSF white blood cells, protein, interferon-γ (IFNγ), interleukin (IL)-6, IL-10, and granzyme B (GzB), with concurrent elevation of serum IFNγ IL-10, GzB, granulocyte macrophage colony-stimulating factor, macrophage inflammatory protein 1 alpha, and tumor necrosis factor alpha, but not IL-6. We did not find direct evidence of endothelial activation. Interpretation: Our data are most consistent with ICANS as a syndrome of systemic inflammation, which affects the brain through compromise of the neurovascular unit and astrocyte injury.

Gardner et al report that early intervention with tocilizumab and steroids at the first signs of mild cytokine release syndrome (CRS) following CD19 chimeric antigen receptor (CAR) T-cell infusion for B-cell acute lymphocytic leukemia reduces the development of life-threatening severe CRS without having a negative impact on antileukemic effect.

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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.