CLRM-10. THE INTER-RELATIONSHIP BETWEEN MULTI-MODAL LONGITUDINAL BIOMARKERS OF NEURAL DAMAGE, INFLAMMATION, AND COGNITION AFTER CAR T CELLULAR THERAPY: A SINGLE-CENTER PROSPECTIVE OBSERVATIONAL TRIAL (NCT04614987)

Abstract BACKGROUND Immune effector cell associated neurotoxicity syndrome (ICANS) remains a devastating, frequent complication of chimeric antigen receptor (CAR) T cell therapy for advanced-stage hematologic malignancies. Symptoms range from encephalopathy and headaches to aphasia, strokes, and diffuse cerebral edema. Persistent mild cognitive symptoms have also been reported. Unfortunately, the underlying pathophysiology driving ICANS is poorly understood. Current proposed models center on systemic inflammatory changes leading to endothelial dysfunction, blood-brain barrier (BBB) breakdown, and systemic cytokine and/or monocytes infiltration into the central nervous system (CNS). However, these models do not integrate predisposing risk factors for the development of ICANS. We previously demonstrated that pre-infusion plasma neurofilament light chain (NfL), a marker of neurodegeneration, may predict development of ICANS. Early elevations in NfL suggest development of ICANS is also related to pre-existing neuroaxonal injury. The longitudinal relationship between latent neuroaxonal injury, blood brain barrier (BBB) integrity, neuroinflammation, and cognition remains unknown. METHODS This prospective, observational trial examines the relationship between multi-modal (blood, cerebrospinal fluid (CSF), neuroimaging) biomarkers and cognition in a cohort of twenty patients undergoing standard-of-care CAR T cellular therapy. Biomarkers for neural injury include blood and CSF NfL and volumetric measures derived from structural magnetic resonance imaging (MRI). Biomarkers for neuroinflammation include blood and CSF glial fibrillary acidic protein (GFAP) and qualification of white matter hyper-intensity burden on MRI. BBB integrity will be quantified using the serum/CSF albumin ratio. Finally, neuropsychological performance testing will assay cognitive performance across multiple cortical domains including attention, memory, and executive function. Participants will undergo a baseline (pre-infusion) examination, followed by evaluation (blood draw, voluntary lumbar puncture, MRI scan, and cognitive testing) on post-infusion day 3 (D3), D30, D90, and D180. The primary outcome is percent change in a given biomarker level. RESULTS/CONCLUSIONS This ongoing trial has 2 of 20 planned participants enrolled.

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Stem Cell Therapy for Neurodegenerative Diseases: How Do Stem Cells Bypass the Blood-Brain Barrier and Home to the Brain?

Stem Cells International ◽

10.1155/2020/8889061 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Yvonne Cashinn Chia ◽

Clarice Evey Anjum ◽

Hui Rong Yee ◽

Yenny Kenisi ◽

Mike K. S. Chan ◽

...

Keyword(s):

Stem Cells ◽

Neurodegenerative Diseases ◽

Blood Brain Barrier ◽

Cellular Therapy ◽

Immune Cell ◽

Brain Barrier ◽

Normal Brain ◽

Brain Functions ◽

Blood Brain ◽

The Brain

Blood-brain barrier (BBB) is a term describing the highly selective barrier formed by the endothelial cells (ECs) of the central nervous system (CNS) homeostasis by restricting movement across the BBB. An intact BBB is critical for normal brain functions as it maintains brain homeostasis, modulates immune cell transport, and provides protection against pathogens and other foreign substances. However, it also prevents drugs from entering the CNS to treat neurodegenerative diseases. Stem cells, on the other hand, have been reported to bypass the BBB and successfully home to their target in the brain and initiate repair, making them a promising approach in cellular therapy, especially those related to neurodegenerative disease. This review article discusses the mechanism behind the successful homing of stem cells to the brain, their potential role as a drug delivery vehicle, and their applications in neurodegenerative diseases.

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Causes of drug resistance and glioblastoma relapses

Head and neck tumors (HNT) ◽

10.17650/2222-1468-2021-11-1-101-108 ◽

2021 ◽

Vol 11 (1) ◽

pp. 101-108

Author(s):

A. A. Mitrofanov ◽

D. R. Naskhletashvili ◽

V. A. Aleshin ◽

D. M. Belov ◽

A. Kh. Bekyashev ◽

...

Keyword(s):

Drug Resistance ◽

Tumor Progression ◽

Blood Brain Barrier ◽

Evolutionary Dynamics ◽

Checkpoint Inhibitors ◽

Combined Therapy ◽

Response To Therapy ◽

Brain Barrier ◽

T Cell Therapy ◽

Blood Brain

Glioblastoma multiform^ is one of the most aggressive malignancies, wich standard of treatment not changed over the past decade, and the average life expectancy from diagnosis to death does not exceed two years in the most optimistic trials. The review examines the features of the glioblastoma microenvironment, its genetic heterogeneity, the development of recurrent glioblastoma, the formation of drug resistance, the influence of the blood-brain barrier and the brain lymphatic system on the development of immunotherapy and targeted therapy. Molecular subgroups of glioblastomas with an assumed prognostic value were analyzed. It was determined that numerous relationships between glioblastoma cells and the microenvironment are aimed at ensuring tumor progression, and also cause a state of reduced effector function of T cells. Data on the development of future molecular-targeted therapies for four types of cancer cells based on their different properties and response to therapy are summarized: primary GSC, RISC cells, and proliferating and postmitotic non-GSC fractions. The penetration of blood-brain barrier with chemotherapeutic drugs and antibodies currently remains the main limitation in the treatment of glioblastoma. The resulting analysis of the causes is reduced to the following conclusions. A detailed understanding of the evolutionary dynamics of tumor progression can provide insight into the related molecular and genetic mechanisms underlying glioblastoma recurrence. The most promising methods of treatment for glioblastoma are combined therapy using immune checkpoint inhibitors in combination with new treatment methods -vaccine therapy, CAR-T-cell therapy and viral therapy. A deeper study of the mechanisms of drug resistance and acquisition resistance, biology and subcloning clonal populations of glioblastoma and its microenvironment, with active consideration of combined trips to the treatment will increase the survival rate of patients, and may lead to stable remission of the disease.

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Increased Cortical Glycolysis Following CD19 CART Therapy: A Radiographic Surrogate for an Altered Blood-Brain Barrier

Blood ◽

10.1182/blood-2019-125794 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4454-4454 ◽

Cited By ~ 3

Author(s):

Ali Bukhari ◽

Vivek Kesari ◽

Reza Sirous ◽

Noa G. Holtzman ◽

Seung Tae Lee ◽

...

Keyword(s):

Blood Brain Barrier ◽

B Cell Lymphoma ◽

Cortical Activity ◽

Brain Barrier ◽

Cytokine Release ◽

Blood Brain ◽

Glycolytic Activity ◽

Pet Ct ◽

Car T ◽

Post Infusion

Background: Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are known complications of chimeric antigen receptor T-cell (CAR-T) therapy. These clinical syndromes develop as a result of CAR-T activation, proliferation, and tumor lysis with resultant cytokine secretion. In prior reports of CD19 CAR-T therapy patients, those who developed ICANS showed evidence of endothelial activation and disruption of the blood-brain barrier as a result of cytokine release while only approximately one-third demonstrated changes on Brain MRI (Gust et al. Cancer Discov 2017). As such, further predictive markers and studies are needed to identify patients at risk for ICANS to allow for expedited management and improved outcomes. Herein we report a single-center analysis exploring glycolytic activity on PET/CT and the association with clinical outcomes for patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) after CAR-T therapy. Methods: An organ-based evaluation of uninvolved sites was conducted in R/R DLBCL patients (n=32) who underwent CD19 CAR-T therapy with evaluable PET/CT imaging at baseline immediately prior to CAR-T therapy and at 30 days post-infusion (D+30). All patients in this analysis were treated with axicabtagene ciloleucel as standard of care therapy after 2 or more lines of therapy. Tumor metabolic volume (TMV) and mean standard uptake value (SUVmean) of various organs were quantified using ROVER [Region of interest (ROI) visualization, evolution, and image registration] software (ABX advanced biochemical compounds GmbH, Radeberg, Germany). Statistical analysis was completed using STATA 14 (StataCorp. 2015. Stata Statistical Software: Release 14. College Station, TX: StataCorp LP). All tests were performed after testing the normality distribution assumption. Temporal changes were assessed using paired t-tests, and between-group analyses were completed with two-sample t-tests. Results: SUVmean increased significantly after CAR-T therapy in the following organs (D+30 v baseline pre-CAR-T PET/CT): cerebral cortex (8.23 v 7.09, p=0.036), cerebellum (6.26 v 5.56, p=0.024), basal ganglia (9.22 v 7.61, p=0.005), parotid gland (1.61 v 1.42, p=0.004), liver (2.47 v 2.17, p=0.002), spleen (2.08 v 1.84, p=0.043), and pancreas (1.76 v 1.48, p<0.001). No differences in SUVmean were seen in the lung, testes, retroperitoneal or subcutaneous fat, or paraspinal and psoas muscles. A significant increase in cortical activity was seen in patients with CRS grades ≥2 when compared to those with CRS grades 0-1 (Δ2.65 v Δ0.33, p=0.03). No changes in glycolytic activity were observed between patients stratified by CRS in the cerebellum (Δ1.31 v Δ0.36, p=0.12) or liver (Δ0.21 v Δ0.34, p=0.55). In contrast, changes in glycolytic activity were not significantly associated with development of ICANS or with treatment responses. Conclusion: For patients with R/R DLBCL undergoing CD19 CAR-T therapy, significantly increased CNS glycolytic activity is seen on PET/CT at D+30 post-infusion when compared to baseline. Interestingly, these changes do not correlate with development of ICANS or lymphoma response; however, changes in cortical activity were associated with CRS grade ≥2. Overall, our findings illustrate a functional and radiographic link between cytokine release and subsequent disruption of the blood-brain barrier as quantified by increased cortical glycolysis 30 days post-CAR-T therapy. While findings are limited by small sample size, further validation in a larger data set is warranted. Disclosures Hutnick: Kite/Gilead: Other: Yescarta Speakers Bureau, Speakers Bureau. Badros:Celgene Corporation: Consultancy; Amgen: Consultancy.

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NEO100 enables brain delivery of blood‒brain barrier impermeable therapeutics

Neuro-Oncology ◽

10.1093/neuonc/noaa206 ◽

2020 ◽

Author(s):

Weijun Wang ◽

Nagore I Marín-Ramos ◽

Haiping He ◽

Shan Zeng ◽

Hee-Yeon Cho ◽

...

Keyword(s):

Blood Brain Barrier ◽

Cerebral Arteries ◽

Brain Barrier ◽

Clinical Settings ◽

Transport Pathways ◽

Medical Centers ◽

Blood Brain ◽

Car T

Abstract Background Intracarotid injection of mannitol has been applied for decades to support brain entry of therapeutics that otherwise do not effectively cross the blood–brain barrier (BBB). However, the elaborate and high-risk nature of this procedure has kept its use restricted to well-equipped medical centers. We are developing a more straightforward approach to safely open the BBB, based on the intra-arterial (IA) injection of NEO100, a highly purified version of the natural monoterpene perillyl alcohol. Methods In vitro barrier permeability with NEO100 was evaluated by transepithelial/transendothelial electrical resistance and antibody diffusion assays. Its mechanism of action was studied by western blot, microarray analysis, and electron microscopy. In mouse models, we performed ultrasound-guided intracardiac administration of NEO100, followed by intravenous application of Evan’s blue, methotrexate, checkpoint-inhibitory antibodies, or chimeric antigen receptor (CAR) T cells. Results NEO100 opened the BBB in a reversible and nontoxic fashion in vitro and in vivo. It enabled greatly increased brain entry of all tested therapeutics and was well tolerated by animals. Mechanistic studies revealed effects of NEO100 on different BBB transport pathways, along with translocation of tight junction proteins from the membrane to the cytoplasm in brain endothelial cells. Conclusion We envision that this procedure can be translated to patients in the form of transfemoral arterial catheterization and cannulation to the cerebral arteries, which represents a low-risk procedure commonly used in a variety of clinical settings. Combined with NEO100, it is expected to provide a safe, widely available approach to enhance brain entry of any therapeutic.

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