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Cited by 2,438CAR-T cell therapy researchImmunotherapy and Immune ResponsesCancer Immunotherapy and Biomarkers

Chimeric antigen receptor T-cell therapy—assessment and management of toxicities

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Neelapu, Sattva S., Tummala, Sudhakar, Kebriaei, Partow, Wierda, William, Gutierrez, Cristina, Locke, Frederick L., Komanduri, Krishna V., Lin, Yi +11 more·2018·Nature Reviews Clinical Oncology
DOI 10.1038/nrclinonc.2017.148PMC PMC6733403
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Abstract

Immunotherapy using T cells genetically engineered to express a chimeric antigen receptor (CAR) is rapidly emerging as a promising new treatment for haematological and non-haematological malignancies. CAR-T-cell therapy can induce rapid and durable clinical responses, but is associated with unique acute toxicities, which can be severe or even fatal. Cytokine-release syndrome (CRS), the most commonly observed toxicity, can range in severity from low-grade constitutional symptoms to a high-grade syndrome associated with life-threatening multiorgan dysfunction; rarely, severe CRS can evolve into fulminant haemophagocytic lymphohistiocytosis (HLH). Neurotoxicity, termed CAR-T-cell-related encephalopathy syndrome (CRES), is the second most-common adverse event, and can occur concurrently with or after CRS. Intensive monitoring and prompt management of toxicities is essential to minimize the morbidity and mortality associated with this potentially curative therapeutic approach; however, algorithms for accurate and consistent grading and management of the toxicities are lacking. To address this unmet need, we formed a CAR-T-cell-therapy-associated TOXicity (CARTOX) Working Group, comprising investigators from multiple institutions and medical disciplines who have experience in treating patients with various CAR-T-cell therapy products. Herein, we describe the multidisciplinary approach adopted at our institutions, and provide recommendations for monitoring, grading, and managing the acute toxicities that can occur in patients treated with CAR-T-cell therapy.

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  • The anti-IL-6R antibodies tocilizumab and sarilumab are used to treat RA, Castleman's disease and CAR-T-induced CRS.

    “The anti-IL-6R antibodies tocilizumab and sarilumab are used to treat RA, Castleman’s disease and CAR-T-induced CRS (71–75, 352, 364) and have promise for treating the severe form of COVID-19 (365–367).”

    From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [352]

    The “IL-6 and IL-6R antagonists” section (page unavailable) identifies tocilizumab as an anti-IL-6R antibody used for rheumatoid arthritis and CAR-T-induced CRS. It does not mention sarilumab; for multicentric Castleman disease, it names siltuximab, which it describes as an anti-IL-6 antibody rather than an anti-IL-6R antibody. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • The anti-IL-6R antibody tocilizumab is effective at treating patients with CAR-T-induced cytokine release syndrome.

    “The anti-IL-6R antibody tocilizumab is effective at treating patients with CAR-T-induced cytokine release syndrome (CRS) (352, 364) and is being considered for treating ARDS in COVID-19 patients (365–368).”

    From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [352]

  • CAR-T cytokine storm is triggered by the activation of CAR-T cells that recognize cognate antigens expressed by tumor cells, leading to the release of cytokines and chemokines, including IL-6, in parallel with the release of pro-inflammatory cytokines and chemokines by monocytes and/or macrophages.

    “It is triggered by the activation of CAR-T cells that recognize cognate antigens expressed by tumor cells, leading to the release of cytokines and chemokines, including IL-6 in parallel with the release of pro-inflammatory cytokines and chemokines by monocytes and/or macrophages (351, 352).”

    From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [352]

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Authors
Neelapu, S. S., Tummala, S., Kebriaei, P., Wierda, W., Gutierrez, C., Locke, F. L., Komanduri, K. V., Lin, Y., Jain, N., Daver, N., Westin, J., Gulbis, A. M., Loghin, M. E., de Groot, J. F., Adkins, S., Davis, S. E., Rezvani, K., Hwu, P., & Shpall, E. J.
Affiliations
  • The University of Texas MD Anderson Cancer Center (US)
  • Moffitt Cancer Center (US)
  • University of Miami (US)
  • Mayo Clinic (US)
Corresponding author
Neelapu, Sattva S.
ORCID
Venue
Nature Reviews Clinical Oncology
Publisher
Springer Science and Business Media LLC
Published
2017-09-19
Volume
15
Issue
1
Pages
47-62
ISSN
  • 1759-4774 (ISSN-L)
  • 1759-4782
DOI
10.1038/nrclinonc.2017.148
PMC
PMC6733403
OpenAlex
W2754562068
Cited by
2,438
References
10
Citations by year
2026: 241 · 2025: 243 · 2024: 265 · 2023: 276 · 2022: 332 · 2021: 343 · 2020: 341 · 2019: 231 · 2018: 149 · 2017: 9 · 2013: 1 · 2012: 1
FWCI
20.94
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Reviews Clinical Oncology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Bristol-Myers Squibb
  • Eli Lilly and Company (P30 CA016672)
  • Pfizer
  • AstraZeneca (CA016672)
  • Sanofi
  • Gilead Sciences
  • Celgene
  • Celldex Therapeutics
  • Sunesis
  • Five Prime Therapeutics
  • Adaptive Biotechnologies
  • Deciphera Pharmaceuticals
  • Incyte (CA016672)
  • Kiadis Pharma
  • Servier
  • National Institutes of Health (CA- 016672)
  • Genentech
  • University of Texas MD Anderson Cancer Center ((CA016672), P30-CA-016672)
  • Kite Pharma
  • Pharmacyclics
  • Juno Therapeutics
  • Foundation Medicine
  • National Cancer Institute (K23CA201594, P30CA016672)
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
CAR T-cell therapy, cytokine release syndrome, hemophagocytic lymphohistiocytosis, macrophage activation syndrome, toxicity grading, toxicity management, neurotoxicity, B-cell malignancies, hematologic malignancies
MeSH terms
Adult, Brain Diseases, Female, Humans, Receptors, Antigen, T-Cell, Syndrome, Cytokines, Immunotherapy, Adoptive

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