BIOMARKERS TO PREDICT NEUROTOXICITY WITH CAR-T CELL TREATMENT

Although lymphodepletion chemotherapy followed by an infusion of CD19-targeted chimeric antigen receptor (CAR)-modified T cells has produced high response rates in phase I studies of patients with refractory CD19-positive B-cell acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL), most patients develop cytokine-release syndrome. Neurologic adverse events are frequently observed in association with or following cytokine-release syndrome with CD19 CAR T-cell therapy, which can sometimes be fatal; however, the pathogenesis of neurotoxicity is unknown.

Now, a study investigating the clinical, radiologic, and pathologic characterization of neurotoxicity after CD19 CAR T-cell therapy in patients with refractory CD19 B-cell ALL, NHL, or CLL has found that having ALL, high amounts of CD19-positive cells in the bone marrow, high CAR T-cell dose, cytokine-release syndrome, and preexisting neurologic comorbidities were associated with an increased risk for neurologic adverse events. Patients at an increased risk for developing severe neurotoxicity may benefit from early intervention. The study by Gust et al was published in Cancer Discovery.

Study Methodology

The researchers conducted a single-center study of neurologic adverse events in 133 patients with relapsed and/or refractory CD19-positive B-cell ALL, NHL, or CLL who received lymphodepletion chemotherapy and CD19 CAR T cells in a phase I/II CAR T-cell dose escalation/deescalation clinical trial. The patients received lymphodepletion chemotherapy 36 to 96 hours before CAR T-cell infusion.

Neurologic symptoms and signs were prospectively assigned an adverse event term and maximal severity score according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4.03. This study reported on the neurologic adverse events presenting within 28 days after the first CAR T-cell infusion.

The researchers developed a predictive classification tree algorithm based on the side effects, including fever, and high serum interleukin 6 (IL-6), and MCP-1 to identify patients within the first 36 hours after CAR T-cell infusion who are at increased risk for severe neurotoxicity. 

Study Findings

The researchers found that within 28 days of treatment, 53 patients (40%) developed grade 1 or higher neurologic adverse events; of them, 28 (21%) had grade 3 or higher neurotoxicity. Alterations in neurologic status completely resolved in a majority of cases. Of the 133 patients, 4 (3%) developed fatal neurotoxicity.

ALL, a high amount of CD19-positive cells in the bone marrow, high CAR T-cell dose, cytokine-release syndrome, and preexisting neurologic comorbidities were associated with an increased risk for neurologic adverse events. Patients with severe neurotoxicity demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier permeability. The permeable blood-brain barrier failed to protect the cerebrospinal fluid from high concentrations of systemic cytokines, including interferon gamma, 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.

Study Significance

The researchers provided a detailed clinical, radiologic, and pathologic characterization of neurotoxicity after CD19 CAR T-cell infusion and identified risk factors for neurotoxicity. They showed endothelial dysfunction and increased blood-brain barrier permeability in neurotoxicity and found that patients with evidence of endothelial activation before lymphodepletion may be at increased risk for neurotoxicity.

“Additional studies will be required to determine whether preemptive therapy with dexamethasone, IL-6, or IL-6R blockade or endothelial stabilizing agents will prevent severe neurotoxicity in high-risk patients. CD19 CAR T-cell therapy is a promising therapy for patients with refractory B-cell malignancies that can be complicated by neurotoxicity in a subset of patients. Identification of the pathologic characteristics of neurotoxicity, related biomarkers, and risk factors will facilitate further studies of the mechanisms of neurotoxicity and will enhance efforts to safely deliver CAR T-cell immunotherapy,” concluded the study authors.

Cameron J. Turtle, MBBS, PhD, of the Fred Hutchinson Cancer Research Center in Seattle is the corresponding author of this study.

Funding for this study was provided by the National Cancer Institute, Juno Therapeutics, Inc, Life Science Discovery Fund, the Bezos Family, the University of British Columbia Clinical Investigator Program, and Bloodworks Northwest.