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Cited by 1,102CAR-T cell therapy researchImmunotherapy and Immune ResponsesCancer Immunotherapy and Biomarkers

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

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Teachey, David T., Lacey, Simon F., Shaw, Pamela A., Melenhorst, J. Joseph, Maude, Shannon L., Frey, Noelle, Pequignot, Edward, Gonzalez, Vanessa E. +18 more·2016·Cancer Discovery
DOI 10.1158/2159-8290.cd-16-0040PMC PMC5448406

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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. 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. 579. This article is highlighted in the In This Issue feature, p. 561

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  • Cytokine release syndrome and neurotoxicity are the most serious immune-related adverse events, and they are most prominently reported in patients given CAR-T cells.

    “The most severe of these immune-related adverse events (irAEs) are cytokine release syndrome (CRS) and neurotoxicity, most prominently described in patients treated with CAR-T-cells [6–11].”

    From Immune reconstitution and clinical recovery following anti-CD28 antibody (TGN1412)-induced cytokine storm (2021) · cites this paper as [7]

    The Introduction calls CRS the most common potentially severe toxicity associated with CAR T cells, and the Results report encephalopathy in some children with severe CRS. The paper does not identify neurotoxicity as a separate one of the most severe immune-related adverse events or establish that these two events are most prominently reported with CAR-T cells compared with other treatments. The Introduction notes that CRS also occurs with other T-cell-engaging therapies. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • In some cancer patients, immune checkpoint blockade produces immune-related adverse events during short-term follow-up, but reliable immune biomarkers for these effects remain under study.

    “Immune checkpoint blockade induces irAEs during short-term follow-up of some patients with cancer, though robust immune biomarkers correlating with adverse effects of therapy are still being investigated [1, 4, 7, 20–25].”

    From Immune reconstitution and clinical recovery following anti-CD28 antibody (TGN1412)-induced cytokine storm (2021) · cites this paper as [7]

    The Introduction and Results describe cytokine release syndrome after CAR T-cell therapy, not immune-related adverse events after checkpoint blockade. A search for checkpoint blockade and irAEs found no passage addressing those effects or their biomarkers; the Discussion’s biomarker findings concern CAR T-cell–associated cytokine release syndrome. (LLM, conf=0.79)

    Experimental — accuracy not yet measured

  • Serum biomarkers, including glycoprotein 130 (gp130), interferon-γ, and interleukin-1-receptor antagonist (IL1RA), can be used to predict the severity of cytokine storm induced by CAR T-cell therapy.

    “Serum biomarkers, including glycoprotein 130 (gp130), interferon-γ, and interleukin-1–receptor antagonist (IL1RA), can be used to predict the severity of cytokine storm induced by CAR T-cell therapy”

    From Cytokine storm (2020) · cites this paper as [13]

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Authors
Teachey, D. T., Lacey, S. F., Shaw, P. A., Melenhorst, J. J., Maude, S. L., Frey, N., Pequignot, E., Gonzalez, V. E., Chen, F., Finklestein, J., Barrett, D. M., Weiss, S. L., Fitzgerald, J. C., Berg, R. A., Aplenc, R., Callahan, C., Rheingold, S. R., Zheng, Z., Rose-John, S., White, J. C., Nazimuddin, F., Wertheim, G., Levine, B. L., June, C. H., Porter, D. L., & Grupp, S. A.
Affiliations
  • Children's Hospital of Philadelphia (US)
  • University of Pennsylvania (US)
  • 10Institute of Biochemistry, CAU Kiel, Germany.
  • Alexander T. Augusta Military Medical Center (US)
Corresponding author
Teachey, David T.
ORCID
Venue
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Published
2016-06-01
Volume
6
Issue
6
Pages
664-679
ISSN
  • 2159-8274 (ISSN-L)
  • 2159-8290
DOI
10.1158/2159-8290.cd-16-0040
PMC
PMC5448406
OpenAlex
W2340435799
Cited by
1,102
References
35
Citations by year
2026: 72 · 2025: 116 · 2024: 94 · 2023: 110 · 2022: 102 · 2021: 142 · 2020: 181 · 2019: 103 · 2018: 93 · 2017: 64 · 2016: 22 · 2013: 1
FWCI
50.70
Type
journal article
Language
en
Open access
Locations
  • Cancer Discovery (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Cancer Institute (R01CA165206, R01CA102646, R01CA116660, R01CA193776, P30CA016520)
  • National Institute of General Medical Sciences (K23GM110496)
Topics
  • Health Sciences › Medicine › Oncology › CAR-T cell therapy research
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
cytokine release syndrome, CAR T-cell therapy, acute lymphoblastic leukemia, CD19 CAR T cells, tisagenlecleucel, predictive biomarkers, cytokine profiling, interferon-gamma, interleukin-6, soluble gp130, C-reactive protein, ferritin, relapsed/refractory leukemia, toxicity prediction
MeSH terms
Adolescent, Adult, Aged, Child, Child, Preschool, Female, Humans, Immunotherapy, Male, Middle Aged, Phenotype, Prognosis, Receptors, Antigen, T-Cell, ROC Curve, Severity of Illness Index, Tumor Lysis Syndrome, Biomarkers, Cytokines, Treatment Outcome, Antigens, CD19, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Young Adult, Antibodies, Monoclonal, Humanized, Cell- and Tissue-Based Therapy

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