Journal
CLINICAL CANCER RESEARCH
Volume 28, Issue 17, Pages 3804-3813Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-22-0822
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Funding
- Leukemia and Lymphoma Society
- NIH [R01CA193776, R01CA264837, R03CA256550, U10CA180886, U24CA196173, X01HD100702, P01CA214278]
- Cookies for Kids Cancer
- Alex's Lemonade Stand Foundation
- Children's Hospital of Philadelphia Immune Dysregulation Frontier Program
- CIHR
- ASCO Conquer Cancer Young Investigator Award
- Thrasher Research Fund [15351]
- CHOP Research Institute
- Department of Anesthesiology and Critical Care
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In this study, we used proteomic profiling to identify predictive biomarkers for severe CRS and found that IFN gamma pathway plays a fundamental role in driving CRS. We also identified a potentially targetable cytokine associated with ICANS. These findings have important implications for disease treatment.
Purpose: To study the biology and identify markers of severe cytokine release syndrome (CRS) and immune effector cell- associated neurotoxicity syndrome (ICANS) in children after chimeric antigen receptor T-cell (CAR T) treatment. Experimental Design: We used comprehensive proteomic pro-filing to measure over 1,400 serum proteins at multiple serial timepoints in a cohort of patients with B-cell acute lymphoblastic leukemia treated with the CD19-targeted CAR T CTL019 on two clinical trials. Results: We identified fms-like tyrosine kinase 3 (FLT3) and mast cell immunoglobulin-like receptor 1 (MILR1) as preinfusion predictive biomarkers of severe CRS. We demonstrated that CRS is an IFN gamma-driven process with a protein signature overlapping with hemophagocytic lymphohistiocytosis (HLH). We identified IL18 as a potentially targetable cytokine associated with the development of ICANS. Conclusions: We identified preinfusion biomarkers that can be used to predict severe CRS with a sensitivity, specificity, and accuracy superior to the current gold standard of disease burden. We demonstrated the fundamental role of the IFN gamma pathway in driving CRS, suggesting CRS and carHLH are overlapping rather than distinct phenomena, an observation with important treatment implications. We identified IL18 as a possible targetable cytokine in ICANS, providing rationale for IL18 blocking therapies to be translated into clinical trials in ICANS.
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