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Identification of Predictive Biomarkers for Cytokine Release Syndrome after Chimeric Antigen Receptor T-cell Therapy for Acute Lymphoblastic Leukemia
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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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“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]
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“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]
Experimental — accuracy not yet measuredIn the citing paper
“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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Metadata
- 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
- Teachey, David T.
- Lacey, Simon F.
- Shaw, Pamela A.
- Melenhorst, J. Joseph
- Maude, Shannon L.
- Frey, Noelle
- Gonzalez, Vanessa E.
- Chen, Fang
- Barrett, David M.
- Weiss, Scott L.
- Fitzgerald, Julie C.
- Berg, Robert A.
- Aplenc, Richard
- Callahan, Colleen
- Rheingold, Susan R.
- Zheng, Zhaohui
- Wertheim, Gerald
- Levine, Bruce L.
- June, Carl H.
- Porter, David L.
- Grupp, Stephan A.
- Venue
- Cancer Discovery
- Published
- 2016-06-01
- Volume
- 6
- Issue
- 6
- Pages
- 664-679
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- 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
- FWCI
- 50.70
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- 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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