If we check certain cytokines in the blood in the first 48 hours after infusion of CAR-T before patients develop full-blown [cytokine-release syndrome] … we have a high likelihood of predicting who will become critically ill and who won’t.
—David T. Teachey, MD
Dramatic advances have been made in using genetically engineered chimeric antigen receptor–modified T cells (CAR-T) with anti-CD19 specificity to treat highly refractory hematologic malignancies. The highest complete remission rates have been achieved in patients with relapsed or refractory acute lymphoblastic leukemia (ALL). However, patients treated with CAR-T infusions, especially those who respond, can develop cytokine-release syndrome, which can be fatal if not treated. Although cytokine-release syndrome is treatable with the interleukin-6 inhibitor tocilizumab (Actemra), ideally, predictive biomarkers could identify which patients are at risk for this serious adverse event, enabling early intervention and resolution of cytokine-release syndrome.
Assay in Development
Researchers at the University of Pennsylvania—one of the hotbeds of CAR-T testing—are developing a rapid assay that can identify patients at risk of developing severe cytokine-release syndrome. Although other centers are working on the problem, these investigators appear to be the furthest along in their research.
At the 2015 American Society of Hematology (ASH) Annual Meeting and Exposition, David T. Teachey, MD, Assistant Professor of Pediatrics at the University of Pennsylvania and Children’s Hospital of Philadelphia, presented a study that identified two predictive biomarkers for cytokine-release syndrome after CAR-T therapy in patients with ALL.1
“If we check certain cytokines in the blood in the first 48 hours after infusion of CAR-T before patients develop full-blown [cytokine-release syndrome]—but they may have fever—we have a high likelihood of predicting who will become critically ill and who won’t,” Dr. Teachey said.
“We can tell early who may need intervention. We could treat with tocilizumab or a different cytokine blocker if the patient is likely to become critically ill—before he or she becomes critically ill. If the patient is not likely to become critically ill with cytokine-release syndrome, you would not necessarily need to monitor him or her as closely and would not need to use empiric cytokine blockade,” he explained.
The investigators studied clinical, laboratory, and biomarker data for 39 children and 12 adults with relapsed/refractory ALL treated with anti-CD19 CAR-T at the University of Pennsylvania. They serially measured 43 cytokines using a multiplex bead array assay. Other biomarkers were tested in a Clinical Laboratory Improvement Amendments/College of American Pathologists (CLIA/CAP)–certified lab.
Of the 51 patients, 48 developed grade 1–5 cytokine-release syndrome. Most cases were mild (grade 1–2) or moderate (grade 3). Fourteen patients developed severe cytokine-release syndrome (grade 4–5). Twenty-one patients were treated with tocilizumab, and most had rapid marked clinical improvement, quick resolution of fever, and weaning of vasoactive medications.
They found that peak levels of two cytokines measured during the first 3 days after CAR-T infusion—interferon-gamma and sgp130—were significant predictors of developing severe cytokine-release syndrome (P < .001). Overall, using regression modeling, they identified a three-cytokine signature that had a positive predictive value of 92%, negative predictive value of 100%, sensitivity of 100%, and specificity of 96%) in children treated with CTL019.
“No test is perfect,” Dr. Teachey remarked. He and his colleagues at the University of Pennsylvania, in collaboration with Novartis, are applying for a patent for this rapid blood assay.
“We believe we are the furthest ahead in developing a rapid clinically usable assay. The plan is to develop a rapid testing kit that would need regulatory approval to be used in the clinic,” he said.
Researchers at Juno Therapeutics and Fred Hutchinson Cancer Center are also working on a predictive blood assay for cytokine-release syndrome. ■
Disclosure: Dr. Teachey has received research funding from Novartis.
1. Teachey DT, Lacey SF, Shaw PA, et al: Biomarkers accurately predict cytokine release syndrome after chimeric antigen receptor (CAR) T cell therapy for acute lymphoblastic leukemia. 2015 ASH Annual Meeting. Abstract 1334. Presented December 5, 2015.