Identification of Predictive Biomarkers for Cytokine Release Syndrome after Chimeric Antigen Receptor T-cell Therapy for Acute Lymphoblastic Leukemia.

TitleIdentification of Predictive Biomarkers for Cytokine Release Syndrome after Chimeric Antigen Receptor T-cell Therapy for Acute Lymphoblastic Leukemia.
Publication TypeJournal Article
Year of Publication2016
AuthorsTeachey DT, Lacey SF, Shaw PA, J Melenhorst J, Maude SL, Frey N, Pequignot E, Gonzalez VE, Chen F, Finklestein J, Barrett DM, Weiss SL, Fitzgerald JC, Berg RA, Aplenc R, Callahan C, Rheingold SR, Zheng Z, Rose-John S, White JC, Nazimuddin F, Wertheim G, Levine BL, June CH, Porter DL, Grupp SA
JournalCancer Discov
Volume6
Issue6
Pagination664-79
Date Published2016 06
ISSN2159-8290
KeywordsAdolescent, Adult, Aged, Antibodies, Monoclonal, Humanized, Antigens, CD19, Biomarkers, Cell- and Tissue-Based Therapy, Child, Child, Preschool, Cytokines, Female, Humans, Immunotherapy, Male, Middle Aged, Phenotype, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Prognosis, Receptors, Antigen, T-Cell, ROC Curve, Severity of Illness Index, Treatment Outcome, Tumor Lysis Syndrome, Young Adult
Abstract

UNLABELLED: 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.

SIGNIFICANCE: 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.

DOI10.1158/2159-8290.CD-16-0040
Alternate JournalCancer Discov
PubMed ID27076371
Grant ListP30 CA016520 / CA / NCI NIH HHS / United States
R01 CA102646 / CA / NCI NIH HHS / United States
R01 CA116660 / CA / NCI NIH HHS / United States
R01 CA193776 / CA / NCI NIH HHS / United States
R01 CA165206 / CA / NCI NIH HHS / United States
K23 GM110496 / GM / NIGMS NIH HHS / United States