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

By D. Teachey, S. Lacey, Pamela A. Shaw, J. Melenhorst, S. Maude, N. Frey, E. Pequignot, V. Gonzalez, Fang Chen, J. Finklestein and 16 more. Cancer Discovery, 2016

965 citations recorded by the source corpus.

Chimeric antigen receptor (CAR)-modified T cells with anti-CD19 specificity are a highly effective novel immune therapy for relapsed/refractory acute lymphoblastic leukemia (ALL). 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 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.

Subfields: Oncology, Pathology and Forensic Medicine, Public Health, Environmental and Occupational Health

View Paper: https://www.semanticscholar.org/paper/ad224480c5ec31f56fb8b33af57f42df11f67619

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Citations in the corpus

• Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma (2017, neutral): “Febrile neutropenia 35 (35) 4 (4) 31 (31)”
• Cytokine release syndrome (2018, background): “They subsequently validated these findings in 12 pediatric patients [62].”
• B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. (2019, background): “Peak foldincrease in IL-6 was strongly associated with both severe CRS and neurotoxicity (Supplemental Table 8, Supplemental Table 9); however, tocilizumab and siltuximab administration can artificially elevate serum IL-6 levels (17).”
• CRISPR-engineered T cells in patients with refractory cancer (2020, background): “We chose to redirect specificity of the T cells with a T cell receptor, rather than a CAR, to avoid the CAR-associated potential toxicities such as cytokine release syndrome (31).”
• Recent advances in CAR T-cell toxicity: Mechanisms, manifestations and management (2018, background): “Tocilizumab has in many cases resulted in rapid and complete resolution of hemodynamic instability [7,26,46].”
• ASBMT Consensus Grading for Cytokine Release Syndrome and Neurological Toxicity Associated with Immune Effector Cells (2018, background): “Hemophagocytic lymphohistiocytosis or macrophage activation syndrome (HLH/MAS) overlaps substantially with CRS, as illustrated by ferritin elevations seen in many CAR T cell recipients during CRS [2,12,20,22,27].”
• FDA Approval Summary: Tocilizumab for Treatment of Chimeric Antigen Receptor T Cell‐Induced Severe or Life‐Threatening Cytokine Release Syndrome (2018, background): “High-dose corticosteroids can moderate toxicity in some cases, but corticosteroids may also reduce the clinical effectiveness of the CAR T-cell therapy by blocking T-cell activation, function, and proliferation [8, 11].”
• The Principles of Engineering Immune Cells to Treat Cancer (2017, background): “Infusional toxicities have been limited to cytokine release syndrome (Fitzgerald et al., 2016; Teachey et al., 2016) and a poorly understood neurological syndrome.”