Monocyte lineage–derived IL-6 does not affect chimeric antigen receptor T-cell function
Open accessAbstract
Background aims Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 has demonstrated remarkable success in targeting B-cell malignancies but is often complicated by serious systemic toxicity in the form of cytokine release syndrome (CRS). CRS symptoms are primarily mediated by interleukin 6 (IL-6), and clinical management has focused on inhibition of IL-6 signaling. The cellular source and function of IL-6 in CRS remain unknown.Methods Using co-culture assays and data from patients on our clinical CAR T-cell trials, we investigated the cellular source of IL-6, as well as other CRS-associated cytokines, during CAR T-cell activation. We also explored the effect that IL-6 has on T-cell function.Results We demonstrated that IL-6 is secreted by monocyte-lineage cells in response to CAR T-cell activation in a contact-independent mechanism upon T-cell engagement of target leukemia. We observed that the presence of antigen-presenting cell-derived IL-6 has no impact on CAR T-cell transcriptional profiles or cytotoxicity. Finally, we confirm that CAR T cells do not secrete IL-6 in vivo during clinical CRS.Discussion These findings suggest that IL-6 blockade will not affect CD19 CAR T-cell-driven anti-leukemic cytotoxicity, permitting enhanced control of CRS while maintaining CAR T-cell efficacy.
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Recent studies in mice suggest that cytokines and factors mediating the severity of CAR T-cell-induced cytokine storm are produced by macrophages, not CAR T cells, and can be reversed by interleukin-6 and interleukin-1 blockade.
“recent studies in mice suggest that the cytokines and factors mediating the severity of cytokine storm are produced not by the CAR T cells but by macrophages and can be reversed by interleukin-6 and interleukin-1 blockade.52-54”
From Cytokine storm (2020) · cites this paper as [52]
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- Authors
- Singh, N., Hofmann, T. J., Gershenson, Z., Levine, B. L., Grupp, S. A., Teachey, D. T., & Barrett, D. M.
- Affiliations
- University of Pennsylvania (US)
- Children's Hospital of Philadelphia (US)
- Corresponding author
- Singh, Nathan
- ORCID
- Venue
- Cytotherapy
- Publisher
- Elsevier BV
- Published
- 2017-07
- Volume
- 19
- Issue
- 7
- Pages
- 867-880
- ISSN
- 1465-3249 (ISSN-L)
- PMC
- PMC6676485
- OpenAlex
- W2612001965
- Cited by
- 151
- References
- 26
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 14 · 2023: 10 · 2022: 16 · 2021: 27 · 2020: 29 · 2019: 22 · 2018: 19 · 2017: 2
- FWCI
- 8.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cytotherapy (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Stand Up To Cancer–St. Baldrick's Pediatric Dream Team Translational Research (SU2C-AACR-DT1113)
- Pennsylvania Department of Health
- St. Baldrick's Foundation
- Gabrielle's Angel Foundation for Cancer Research
- First Annual Immuno-oncology Forum
- Topics
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- interleukin-6, cytokine release syndrome, CAR T-cell therapy, CD19, monocytes, antigen-presenting cells, T cell activation, IL-6 inhibition, B-cell malignancies, T cell cytotoxicity, cytokine signaling
- MeSH terms
- Animals, Antigen-Presenting Cells, Humans, Lymphocyte Activation, Monocytes, Receptors, Antigen, T-Cell, Recombinant Proteins, T-Lymphocytes, Interleukin-6, Cytokines, Mice, Inbred NOD, Coculture Techniques, Antigens, CD19, Cell Lineage, Xenograft Model Antitumor Assays
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