Glial injury in neurotoxicity after pediatric CD19‐directed chimeric antigen receptor T cell therapy

Abstract

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.

Reply to the Letter “COVID‐19‐Associated Encephalopathy and Cytokine‐Mediated Neuroinflammation”

“…The high levels of interleukins in CSF compared with serum, as well as the increase of CNS-specific GFAP, speak against passive leakage across the blood-brain barrier, and instead suggest an intrathecally active inflammatory process. Several works reported similar cases during the last months, [4][5][6] showing that many patients with SARS-CoV-2 encephalitis exhibited clinical and imaging findings highly consistent with previously reported inflammatorymediated neurotoxicity, 1,2 whereas direct invasion and autoimmune responses appeared to be a rare condition. Despite the interesting insights given by this case report, larger studies are urgently needed to confirm cytokine-induced neuroinflammation as a main driver of SARS-CoV-2 related encephalitis, as this issue has deep consequences for the management and treatment of this growing condition worldwide.…”

“…ICANS is a neuropsychiatric syndrome with heterogeneous clinical manifestations; however, akinetic mutism is a recurrent and specific feature that might help discriminate it from other encephalopathies. 2,3 Interestingly, we observed 3 COVID-19 patients presenting with a similar phenotype to Pilotto et al's case, including transitory akinetic mutism, where other likely causes were reasonably excluded and SARS-CoV-2 real-time polymerase chain reaction in CSF tested negative (unpublished data).…”

“…Diffuse slowing on electroencephalogram, unremarkable brain magnetic resonance imaging, and mildly elevated white blood cell count (WBC) and protein levels in CSF are common findings in ICANS, 2,3 and were also observed in Pilotto et al's case. 1 The authors described elevated CSF interleukin (IL)-8 and tumor necrosis factor (TNF)-α levels that decreased with clinical improvement, whereas WBC remained stable.…”

“…5 ICANS usually resolves on its own; however, corticosteroids are the first-line therapy for severe cases. 2,3 The overlapping features of this case report and neurotoxicity related to CAR-T therapy bring into question the possibility of a shared, cytokine-mediated pathophysiology, which can further inform treatments. Muccioli et al proposed an interesting comparison between the case of encephalitis related to severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2) infection we described and immune effector cell-associated neurotoxicity syndrome (ICANS).…”

Emerging Approaches for Regulation and Control of CAR T Cells: A Mini Review

“…The recent years' success of CAR T cells in the clinic has revealed the serious and potentially lethal side effects associated with the potent treatment, including off-tumor, on-target effects, systemic inflammatory conditions such as CRS and acute neurotoxicity (90,91). More recently it has become clear that cardiovascular and gastrointestinal events can also occur post-CAR-T (92,93).…”