Automated detection of immune effector cell-associated neurotoxicity syndrome via quantitative EEG.

OBJECTIVE: To develop an automated, physiologic metric of immune effector cell-associated neurotoxicity syndrome among patients undergoing chimeric antigen receptor-T cell therapy. METHODS: We conducted a retrospective observational cohort study from 2016 to 2020 at two tertiary care centers among patients receiving chimeric antigen receptor-T cell therapy with a CD19 or B-cell maturation antigen ligand. We determined the daily neurotoxicity grade for each patient during EEG monitoring via chart review and extracted clinical variables and outcomes from the electronic health records. Using quantitative EEG features, we developed a machine learning model to detect the presence and severity of neurotoxicity, known as the EEG immune effector cell-associated neurotoxicity syndrome score. RESULTS: The EEG immune effector cell-associated neurotoxicity syndrome score significantly correlated with the grade of neurotoxicity with a median Spearman's R2 of 0.69 (95% CI of 0.59-0.77). The mean area under receiving operator curve was greater than 0.85 for each binary discrimination level. The score also showed significant correlations with maximum ferritin (R2 0.24, p = 0.008), minimum platelets (R2 -0.29, p = 0.001), and dexamethasone usage (R2 0.42, p < 0.0001). The score significantly correlated with duration of neurotoxicity (R2 0.31, p < 0.0001). INTERPRETATION: The EEG immune effector cell-associated neurotoxicity syndrome score possesses high criterion, construct, and predictive validity, which substantiates its use as a physiologic method to detect the presence and severity of neurotoxicity among patients undergoing chimeric antigen receptor T-cell therapy.

Novel Medical Therapies in Meningiomas.

Meningiomas are the most common primary brain tumor in adults and have been historically managed with surgery and radiation therapy. However, in patients with inoperable, recurrent or high-grade tumors, medical therapy is often needed. Traditional chemotherapy and hormone therapy have been largely ineffective. However, with improved understanding of the molecular drivers in meningioma, there has been increasing interest in targeted molecular and immune therapies. In this chapter, we will discuss recent advances in meningioma genetics and biology and review current clinical trials with targeted molecular treatment and other novel therapies.

Forecasting immune effector cell-associated neurotoxicity syndrome after chimeric antigen receptor t-cell therapy.

BACKGROUND: Immune effector cell-associated neurotoxicity syndrome (ICANS) is a clinical and neuropsychiatric syndrome that can occur days to weeks following administration chimeric antigen receptor (CAR) T-cell therapy. Manifestations of ICANS range from encephalopathy and aphasia to cerebral edema and death. Because the onset and time course of ICANS is currently unpredictable, prolonged hospitalization for close monitoring following CAR T-cell infusion is a frequent standard of care. METHODS: This study was conducted at Brigham and Women's Hospital from April 2015 to February 2020. A cohort of 199 hospitalized patients treated with CAR T-cell therapy was used to develop a combined hidden Markov model and lasso-penalized logistic regression model to forecast the course of ICANS. Model development was done using leave-one-patient-out cross validation. RESULTS: Among the 199 patients included in the analysis 133 were male (66.8%), and the mean (SD) age was 59.5 (11.8) years. 97 patients (48.7%) developed ICANS, of which 59 (29.6%) experienced severe grades 3-4 ICANS. Median time of ICANS onset was day 9. Selected clinical predictors included maximum daily temperature, C reactive protein, IL-6, and procalcitonin. The model correctly predicted which patients developed ICANS and severe ICANS, respectively, with area under the curve of 96.7% and 93.2% when predicting 5 days ahead, and area under the curve of 93.2% and 80.6% when predicting the entire future risk trajectory looking forward from day 5. Forecasting performance was also evaluated over time horizons ranging from 1 to 7 days, using metrics of forecast bias, mean absolute deviation, and weighted average percentage error. CONCLUSION: The forecasting model accurately predicts risk of ICANS following CAR T-cell infusion and the time course ICANS follows once it has begun.Cite Now.

Microenvironmental Landscape of Human Melanoma Brain Metastases in Response to Immune Checkpoint Inhibition.

Melanoma-derived brain metastases (MBM) represent an unmet clinical need because central nervous system progression is frequently an end stage of the disease. Immune checkpoint inhibitors (ICI) provide a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique elements of the MBM TME and correlates of MBM response to ICI, we collected 32 fresh MBM and performed single-cell RNA sequencing of the MBM TME and T-cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity in the MBM TME, most notably multiple distinct neutrophil states, including an IL8-expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. In addition, we observed significant relationships between intracranial T-cell phenotypes and the distribution of T-cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data identify unique features of the MBM TME that may represent potential targets to improve clinical outcomes for patients with MBM.

EEG findings in CAR T-cell-associated neurotoxicity: Clinical and radiological correlations.

BACKGROUND: While EEG is frequently reported as abnormal after chimeric antigen receptor (CAR) T-cell therapy, its clinical significance remains unclear. We aim to systematically describe EEG features in a large single-center cohort and correlate them with clinical and radiological findings. METHODS: We retrospectively identified patients undergoing CAR T-cell therapy who had continuous EEG. Neurotoxicity grades, detailed neurological symptoms, and brain MRI or FDG-PET were obtained. Correlation between clinical and radiological findings and EEG features was assessed. RESULTS: In 81 patients with median neurotoxicity grade 3 (IQR 2-3), diffuse EEG background slowing was the most common finding and correlated with neurotoxicity severity (P <.001). A total of 42 patients had rhythmic or periodic patterns, 16 of them within the ictal-interictal-continuum (IIC), 5 with clinical seizures, and 3 with only electrographic seizures. Focal EEG abnormalities, consisting of lateralized periodic discharges (LPD, n = 1), lateralized rhythmic delta activity (LRDA, n = 6), or focal slowing (n = 19), were found in 22 patients. All patients with LRDA, LPD, and 10/19 patients with focal slowing had focal clinical symptoms concordant with these EEG abnormalities. In addition, these focal EEG changes are often correlated with PET hypometabolism or MRI hypoperfusion, in absence of a structural lesion. CONCLUSION: In adult patients experiencing neurotoxicity after CAR T-cell infusion, EEG degree of background disorganization correlated with neurotoxicity severity. IIC patterns and focal EEG abnormalities are frequent and often correlate with focal clinical symptoms and with PET-hypometabolism/MRI-hypoperfusion, without structural lesion. The etiology of these findings remains to be elucidated.

Neurotoxicity Biology and Management.

ABSTRACT: Chimeric antigen receptor (CAR) T-cell therapy is a highly effective new treatment for relapsed and refractory hematological cancers but is associated with the novel treatment-limiting toxicities of cytokine release syndrome and neurotoxicity. Neurotoxicity, now more commonly referred to as immune effector cell-associated neurotoxicity syndrome (ICANS), is a clinical and neuropsychiatric syndrome that can occur in the days to weeks following CAR T-cell and other T-cell-engaging therapies. While the clinical characteristics of ICANS have been well described, its pathophysiology is poorly understood, and best treatment and preventive strategies remain elusive. Clinical trial experience and animal models suggest a central role for endothelial cell dysfunction, myeloid cells, blood-brain barrier disruption, and elevated central nervous system cytokine levels in the development of ICANS. Here we discuss ICANS incidence, clinical features, risk factors, biomarkers, pathophysiology, and grading and management.

Neurological toxicities associated with chimeric antigen receptor T-cell therapy.

Chimeric antigen receptor T cell therapy has become an important tool in the treatment of relapsed and refractory malignancy; however, it is associated with significant neurological toxicity. We characterized the neurological toxicity associated with chimeric antigen receptor T-cell therapy in a consecutive series of 100 patients up to 2 months post transfusion, 28 of whom were obtained from chart review and the others by prospective observation. The underlying neoplasms were lymphoma (74%), myeloma (14%), leukaemia (10%), and sarcoma (2%). The median age of the cohort was 64.5 years old and 39% of patients were female. The most commonly occurring neurological symptoms were encephalopathy (57%), headache (42%), tremor (38%), aphasia (35%) and focal weakness (11%). Focal neurological deficits are frequently observed after chimeric antigen receptor T-cell therapy and are associated with regional EEG abnormalities, FDG-PET hypometabolism, and elevated velocities on transcranial Doppler ultrasound. In contrast, structural imaging was typically normal. As this form of treatment is more widely adopted, recognition of the frequently encountered symptoms will be of increasing importance for the neurologists and oncologists caring for this growing patient population.

Rhythmic syllable-related activity in a songbird motor thalamic nucleus necessary for learned vocalizations.

Birdsong is a complex behavior that exhibits hierarchical organization. While the representation of singing behavior and its hierarchical organization has been studied in some detail in avian cortical premotor circuits, our understanding of the role of the thalamus in adult birdsong is incomplete. Using a combination of behavioral and electrophysiological studies, we seek to expand on earlier work showing that the thalamic nucleus Uvaeformis (Uva) is necessary for the production of stereotyped, adult song in zebra finch (Taeniopygia guttata). We confirm that complete bilateral lesions of Uva abolish singing in the 'directed' social context, but find that in the 'undirected' social context, such lesions result in highly variable vocalizations similar to early babbling song in juvenile birds. Recordings of neural activity in Uva reveal strong syllable-related modulation, maximally active prior to syllable onsets and minimally active prior to syllable offsets. Furthermore, both song and Uva activity exhibit a pronounced coherent modulation at 10Hz-a pattern observed in downstream premotor areas in adult and, even more prominently, in juvenile birds. These findings are broadly consistent with the idea that Uva is critical in the sequential activation of behavioral modules in HVC.

Hydrogen tunneling steps in cyclooxygenase-2 catalysis.

Cyclooxygenases-1 and -2 are tyrosyl radical (Y·)-utilizing hemoproteins responsible for the biosynthesis of lipid-derived autocoids. COX-2, in particular, is a primary mediator of inflammation and believed to be up-regulated in many forms of cancer. Described here are first-of-a-kind studies of COX-2-catalyzed oxidation of the substrate analogue linoleic acid. Very large (≥20) temperature-independent deuterium kinetic isotope effects (KIEs) on the rate constant for enzyme turnover were observed, due to hydrogen atom abstraction from the bisallylic C-H(D) of the fatty acid. The magnitude of the KIE depends on the O(2) concentration, consistent with reversible H/D tunneling mediated by the catalytic Y·. At physiological levels of O(2), retention of the hydrogen initially abstracted by the catalytic tyrosine results in strongly temperature-dependent KIEs on O-H(D) homolysis, also characteristic of nuclear tunneling.