title: Identification of Predictive Biomarkers for Cytokine Release Syndrome after Chimeric Antigen Receptor T-cell Therapy for Acute Lymphoblastic Leukemia.
abstract: Chimeric antigen receptor (CAR)-modified T cells with anti-CD19 specificity are a highly effective novel immune therapy for relapsed/refractory acute lymphoblastic leukemia. Cytokine release syndrome (CRS) is the most significant and life-threatening toxicity. To improve understanding of CRS, we measured cytokines and clinical biomarkers in 51 CTL019-treated patients. Peak levels of 24 cytokines, including IFNγ, IL6, sgp130, and sIL6R, in the first month after infusion were highly associated with severe CRS. Using regression modeling, we could accurately predict which patients would develop severe CRS with a signature composed of three cytokines. Results were validated in an independent cohort. Changes in serum biochemical markers, including C-reactive protein and ferritin, were associated with CRS but failed to predict development of severe CRS. These comprehensive profiling data provide novel insights into CRS biology and, importantly, represent the first data that can accurately predict which patients have a high probability of becoming critically ill.
  
  
  
  CRS is the most common severe toxicity seen after CAR T-cell treatment. We developed models that can accurately predict which patients are likely to develop severe CRS before they become critically ill, which improves understanding of CRS biology and may guide future cytokine-directed therapy. Cancer Discov; 6(6); 664-79. ©2016 AACR.See related commentary by Rouce and Heslop, p. 579This article is highlighted in the In This Issue feature, p. 561.
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. Department of Pediatrics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Abramson Cancer Center, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. teacheyd@email.chop.edu.
authors.forename: David T
authors.initials: DT
authors.lastname: Teachey
authors.affiliation: Abramson Cancer Center, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Department of Pathology and Laboratory Medicine, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Center for Cellular Immunotherapies, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Simon F
authors.initials: SF
authors.lastname: Lacey
authors.affiliation: Department of Biostatistics and Epidemiology, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Shaw
authors.affiliation: Abramson Cancer Center, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Department of Pathology and Laboratory Medicine, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Center for Cellular Immunotherapies, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: J Joseph
authors.initials: JJ
authors.lastname: Melenhorst
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. Department of Pediatrics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Abramson Cancer Center, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Maude
authors.affiliation: Abramson Cancer Center, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Department of Medicine, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Division of Hematology-Oncology, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Noelle
authors.initials: N
authors.lastname: Frey
authors.affiliation: Abramson Cancer Center, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Department of Pathology and Laboratory Medicine, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Center for Cellular Immunotherapies, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Edward
authors.initials: E
authors.lastname: Pequignot
authors.affiliation: Abramson Cancer Center, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Department of Pathology and Laboratory Medicine, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Vanessa E
authors.initials: VE
authors.lastname: Gonzalez
authors.affiliation: Abramson Cancer Center, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Department of Pathology and Laboratory Medicine, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Center for Cellular Immunotherapies, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Fang
authors.initials: F
authors.lastname: Chen
authors.affiliation: Abramson Cancer Center, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Department of Pathology and Laboratory Medicine, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Center for Cellular Immunotherapies, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Finklestein
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. Department of Pediatrics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Abramson Cancer Center, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: David M
authors.initials: DM
authors.lastname: Barrett
authors.affiliation: Department of Anesthesia and Critical Care Medicine, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Weiss
authors.affiliation: Department of Anesthesia and Critical Care Medicine, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Julie C
authors.initials: JC
authors.lastname: Fitzgerald
authors.affiliation: Department of Anesthesia and Critical Care Medicine, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Berg
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. Department of Pediatrics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Abramson Cancer Center, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Richard
authors.initials: R
authors.lastname: Aplenc
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Colleen
authors.initials: C
authors.lastname: Callahan
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. Department of Pediatrics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Abramson Cancer Center, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Rheingold
authors.affiliation: Abramson Cancer Center, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Department of Pathology and Laboratory Medicine, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Center for Cellular Immunotherapies, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Institute of Biochemistry, CAU Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Fort Belvoir Community Hospital, Fort Belvoir, Virginia.
authors.forename: Jason C
authors.initials: JC
authors.lastname: White
authors.affiliation: Abramson Cancer Center, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Department of Pathology and Laboratory Medicine, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Center for Cellular Immunotherapies, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Farzana
authors.initials: F
authors.lastname: Nazimuddin
authors.affiliation: Abramson Cancer Center, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Department of Pathology and Laboratory Medicine, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Gerald
authors.initials: G
authors.lastname: Wertheim
authors.affiliation: Abramson Cancer Center, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Department of Pathology and Laboratory Medicine, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Center for Cellular Immunotherapies, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Levine
authors.affiliation: Abramson Cancer Center, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Department of Pathology and Laboratory Medicine, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Center for Cellular Immunotherapies, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
authors.affiliation: Abramson Cancer Center, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Department of Medicine, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Division of Hematology-Oncology, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: David L
authors.initials: DL
authors.lastname: Porter
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. Department of Pediatrics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Abramson Cancer Center, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Department of Pathology and Laboratory Medicine, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Grupp
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D018941:Antigens, CD19 / Q000276:immunology / Q000378:metabolism; D015415:Biomarkers; D064987:Cell- and Tissue-Based Therapy / Q000009:adverse effects* / Q000379:methods; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects* / Q000379:methods; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications* / Q000628:therapy; D011379:Prognosis; D012372:ROC Curve; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012720:Severity of Illness Index; D016896:Treatment Outcome; D015275:Tumor Lysis Syndrome / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018941:Antigens, CD19; D015415:Biomarkers; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; C502936:tocilizumab