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Publications of the Week

Glial Injury in Neurotoxicity after Pediatric CD19-Directed Chimeric Antigen Receptor T Cell Therapy

By May 31, 2019No Comments

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This week we profile a recent publication in the Annals of Neurology from Dr. Juliane Gust
(pictured, left) at Seattle Children’s Research Institute.

Can you provide a brief overview of your lab’s current research focus?

Dr. Gust works on finding better ways to protect childrens’ developing brains as they undergo therapy for cancer. In the laboratory, she focuses on uncovering the mechanisms of neurotoxicity in cancer immunotherapy patients.

What is the significance of the findings in this publication?

Neurotoxicity remains an important and difficult to predict complication of CAR T cell immunotherapy. About 40% of patients develop some evidence of brain dysfunction, such as confusion or seizures, and, rarely, this neurotoxicity can lead to fatal cerebral edema. We studied a cohort of 43 children and young adults who received CD19-directed CAR T cells for treatment of B cell acute lymphoblastic leukemia, and found that higher levels of systemic cytokines during CAR T cell proliferation are associated with the highest risk of neurotoxicity. In patients with neurotoxicity, very characteristic brain MRI findings can be seen, and on examination of the cerebrospinal fluid, we find evidence of injury to the glia, indicating that there has likely been a disruption of the blood-brain barrier even in patients with relatively mild symptoms.

What are the next steps for this research?

Our next steps on this project will be to develop a mouse model of CAR T cell neurotoxicity to gain a better mechanistic understanding and develop more precise therapeutic targets. In addition, we continue our work on finding patient biomarkers that can predict neurotoxicity risk, develop targeted treatments, and monitor long-term neurocognitive outcomes.

This work was funded by:

Dr. Gust received funding through the Child Neurology Career Development Program K-12 award (1K12NS098482-02).

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