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Identification of Predictive Biomarkers for Cytokine Release Syndrome after Chimeric Antigen Receptor T-cell Therapy for Acute Lymphoblastic Leukemia
Open accessPublished version of a preprint
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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Cites
A Simple Sequentially Rejective Multiple Test Procedure
(1979) · Scandinavian Journal of Statistics · doi:10.2307/4615733 · Cited by 21,526
Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia
Maude, S. L., Frey, N., Shaw, P. A., Aplenc, R., Barrett, D. M., Bunin, N. J., Chew, A., Gonzalez, V. E., Zheng, Z., Lacey, S. F., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1407222 · Cited by 5,413
Self-citationChimeric antigen receptor–modified T cells in chronic lymphoid leukemia
Porter, D. L., Levine, B. L., Kalos, M., Bagg, A., & June, C. H. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1103849 · Cited by 3,565
Self-citationChimeric Antigen Receptor–Modified T Cells for Acute Lymphoid Leukemia
Grupp, S. A., Kalos, M., Barrett, D., Aplenc, R., Porter, D. L., Rheingold, S. R., Teachey, D. T., Chew, A., Hauck, B., Wright, J. F., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1215134 · Cited by 3,509
Self-citationLee, D. W., Kochenderfer, J. N., Stetler-Stevenson, M., Cui, Y. K., Delbrook, C., Feldman, S. A., Fry, T. J., Orentas, R., Sabatino, M., Shah, N. N., et al. (2015) · The Lancet · doi:10.1016/s0140-6736(14)61403-3 · Cited by 2,898
Current concepts in the diagnosis and management of cytokine release syndrome.
Lee, D. W., Gardner, R., Porter, D. L., Louis, C. U., Ahmed, N., Jensen, M., Grupp, S. A., & Mackall, C. L. (2014) · Blood · doi:10.1182/blood-2014-05-552729 · Cited by 2,806
Self-citationEfficacy and Toxicity Management of 19-28z CAR T Cell Therapy in B Cell Acute Lymphoblastic Leukemia
Davila, M. L., Rivière, I., Wang, X., Bartido, S. M., Park, J. H., Curran, K. J., Chung, S. S., Stefanski, J., Bórquez-Ojeda, O., Olszewska, M., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3008226 · Cited by 2,514
Porter, D. L., Hwang, W.-T., Frey, N. V., Lacey, S. F., Shaw, P. A., Loren, A. W., Bagg, A., Marcucci, K. T., Shen, A., Gonzalez, V., et al. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aac5415 · Cited by 1,729
Self-citationRose-John, S. (2012) · International Journal of Biological Sciences · doi:10.7150/ijbs.4989 · Cited by 1,040 · cited 3×
“In other IL6-mediated diseases, IL6 levels often go up and sIL6R levels either increase or decrease after treatment as the interaction between IL6R and IL6 is blocked (21, 23, 24).”
BackgroundSelf-citationBorowitz, M. J., Devidas, M., Hunger, S. P., Bowman, W. P., Carroll, A. J., Carroll, W. L., Linda, S. B., Martin, P. L., Pullen, D. J., Viswanatha, D. S., et al. (2008) · Blood · doi:10.1182/blood-2008-01-132837 · Cited by 841
Nishimoto, N., Terao, K., Mima, T., Nakahara, H., Takagi, N., & Kakehi, T. (2008) · Blood · doi:10.1182/blood-2008-05-155846 · Cited by 781
Soluble receptors for cytokines and growth factors: generation and biological function
Rose‐John, S., & Heinrich, P. C. (1994) · Biochemical Journal · doi:10.1042/bj3000281 · Cited by 777
Self-citationHighly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis
Allen, C. E., Yu, X., Kozinetz, C. A., & McClain, K. L. (2007) · Pediatric Blood & Cancer · doi:10.1002/pbc.21423 · Cited by 637
Teachey, D. T., Rheingold, S. R., Maude, S. L., Zugmaier, G., Barrett, D. M., Seif, A. E., Nichols, K. E., Suppa, E. K., Kalos, M., Berg, R. A., et al. (2013) · Blood · doi:10.1182/blood-2013-02-485623 · Cited by 613
Self-citationHypercytokinemia in familial hemophagocytic lymphohistiocytosis
Henter, J., Elinder, G., Soder, O., Hansson, M., Andersson, B., & Andersson, U. (1991) · Blood · doi:10.1182/blood.v78.11.2918.2918 · Cited by 505
Klinger, M., Brandl, C., Zugmaier, G., Hijazi, Y., Bargou, R. C., Topp, M. S., Gökbuget, N., Neumann, S., Goebeler, M., Viardot, A., et al. (2012) · Blood · doi:10.1182/blood-2012-01-400515 · Cited by 475
The IL-6/gp130/STAT3 signaling axis: recent advances towards specific inhibition
Garbers, C., Aparicio-Siegmund, S., & Rose‐John, S. (2015) · Current Opinion in Immunology · doi:10.1016/j.coi.2015.02.008 · Cited by 432
Self-citationCytokine Production Regulating Th1 and Th2 Cytokines in Hemophagocytic Lymphohistiocytosis
Osugi, Y., Hara, J., Tagawa, S., Takai, K., Hosoi, G., Matsuda, Y., Ohta, H., Fujisaki, H., Kobayashi, M., Sakata, N., et al. (1997) · Blood · doi:10.1182/blood.v89.11.4100 · Cited by 366
Cytokine Levels in the Serum of Healthy Subjects
Kleiner, G., Marcuzzi, A., Zanin, V., Monasta, L., & Zauli, G. (2013) · Mediators of Inflammation · doi:10.1155/2013/434010 · Cited by 358
IL-6 biology: implications for clinical targeting in rheumatic disease
Calabrese, L., & Rose-John, S. (2014) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2014.127 · Cited by 329
Self-citationCytokines as Biomarkers in Rheumatoid Arthritis
Burska, A. N., Boissinot, M., & Ponchel, F. (2014) · Mediators of Inflammation · doi:10.1155/2014/545493 · Cited by 231
Diagnostic Accuracy of a Specific Cytokine Pattern in Hemophagocytic Lymphohistiocytosis in Children
Xu, X., Tang, Y., Song, H., Yang, S.-L., Xu, W., Zhao, N., Shi, S., Shen, H., Mao, J., Zhang, L., et al. (2012) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2011.11.046 · Cited by 227
Familial and Acquired Hemophagocytic Lymphohistiocytosis
Janka, G., & Stadt, U. Z. (2005) · Hematology · doi:10.1182/asheducation-2005.1.82 · Cited by 203
Tang, Y., Xu, X., Song, H., Yang, S., Shi, S., Wei, J., Pan, B., Zhao, F., Liao, C., & Luo, C. (2008) · British Journal of Haematology · doi:10.1111/j.1365-2141.2008.07298.x · Cited by 186
Cutting Edge: Soluble IL-6R Is Produced by IL-6R Ectodomain Shedding in Activated CD4 T Cells
Briso, E. M., Dienz, O., & Rincón, M. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.11.7102 · Cited by 165
Weir, E., Cowan, K., Lebeau, P., & Borowitz, M. J. (1999) · Leukemia · doi:10.1038/sj.leu.2401364 · Cited by 145
Koehne, G., Hasan, A. N., Doubrovina, E. S., Prockop, S. E., Tyler, E. M., Wasilewski, G., & O’Reilly, R. J. (2015) · Transplantation and Cellular Therapy · doi:10.1016/j.bbmt.2015.05.015 · Cited by 92
Cytokine Production Differs in Children and Adults
Lilić, D., Cant, A. J., Abinun, M., Calvert, J. E., & Spickett, G. P. (1997) · Pediatric Research · doi:10.1203/00006450-199708000-00018 · Cited by 84
TAKADA, H., Takahata, Y., Nomura, A., Ohga, S., Mizuno, Y., & Hara, T. (2003) · Clinical & Experimental Immunology · doi:10.1046/j.1365-2249.2003.02237.x · Cited by 68
Maney, S. K., McIlwain, D. R., Polz, R., Pandyra, A. A., Sundaram, B., Wolff, D., Ohishi, K., Maretzky, T., Brooke, M. A., Evers, A., et al. (2015) · Science Signaling · doi:10.1126/scisignal.aac5356 · Cited by 60
Tamura, K., Kanazawa, T., Tsukada, S., Kobayashi, T., Kawamura, M., & Morikawa, A. (2008) · Pediatric Blood & Cancer · doi:10.1002/pbc.21660 · Cited by 43
Age-Specific Analysis of Normal Cytokine Levels in Healthy Infants
Berdat, P. A., Wehrle, T. J., Küng, A., Achermann, F., Sutter, M., Carrel, T. P., & Nydegger, U. E. (2003) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm.2003.204 · Cited by 37
Uno, K., Yoshizaki, K., Iwahashi, M., Yamana, J., Yamana, S., Tanigawa, M., & Yagi, K. (2015) · PLoS ONE · doi:10.1371/journal.pone.0132055 · Cited by 36
Switala, J. R., Hendricks, M. G., & Davidson, A. (2012) · Journal of Pediatric Hematology/Oncology · doi:10.1097/mph.0b013e31824227b9 · Cited by 28
Hemophagoctic lymphohistiocytosis--recent concept.
Bhattacharyya, M., & Ghosh, M. (2008) · PubMed · Cited by 27
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Neelapu, S. S., Locke, F. L., Bartlett, N. L., Lekakis, L. J., Miklos, D. B., Jacobson, C. A., Braunschweig, I., Oluwole, O. O., Siddiqi, T., Lin, Y., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1707447 · Cited by 6,030
Lee, D. W., Santomasso, B. D., Locke, F. L., Ghobadi, A., Turtle, C. J., Brudno, J. N., Maus, M. V., Park, J. H., Mead, E., Pavletic, S., et al. (2019) · Biology of Blood and Marrow Transplantation · doi:10.1016/j.bbmt.2018.12.758 · Cited by 3,675
Self-citationFajgenbaum, D. C., & June, C. H. (2020) · New England Journal of Medicine · doi:10.1056/nejmra2026131 · Cited by 3,196
Self-citationChimeric antigen receptor T-cell therapy—assessment and management of toxicities
Neelapu, S. S., Tummala, S., Kebriaei, P., Wierda, W., Gutierrez, C., Locke, F. L., Komanduri, K. V., Lin, Y., Jain, N., Daver, N., et al. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2017.148 · Cited by 2,438
Chimeric Antigen Receptor Therapy
June, C. H., & Sadelain, M. (2018) · New England Journal of Medicine · doi:10.1056/nejmra1706169 · Cited by 2,411
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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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