Understanding and treating the inflammatory adverse events of cancer immunotherapy
Open accessAbstract
During the past decade, immunotherapies have made a major impact on the treatment of diverse types of cancer. Inflammatory toxicities are not only a major concern for Food and Drug Administration (FDA)-approved checkpoint blockade and chimeric antigen receptor (CAR) T cell therapies, but also limit the development and use of combination therapies. Fundamentally, these adverse events highlight the intricate balance of pro- and anti-inflammatory pathways that regulate protective immune responses. Here, we discuss the cellular and molecular mechanisms of inflammatory adverse events, current approaches to treatment, as well as opportunities for the design of immunotherapies that limit such inflammatory toxicities while preserving anti-tumor efficacy.
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ICI myocarditis occurs in less than 1% of patients.
“Despite occurring in <1% of patients”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [179]
The Overview of checkpoint blockade toxicities (page not provided) says cardiac toxicities from immunotherapy are rare, consistent with the claim’s general point. It does not give a myocarditis incidence or substantiate the specific figure of less than 1% of patients. (LLM, conf=0.84)
Experimental — accuracy not yet measuredICI myocarditis has a fatality rate of up to 50%.
“ICI myocarditis has a high fatality rate of up to 50%.”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [179]
The Overview of checkpoint blockade toxicities says cardiac toxicities account for a substantial fraction of fatal checkpoint-blockade toxicities, and the Introduction identifies myocarditis as a severe toxicity. Neither passage gives a case-fatality rate for ICI myocarditis or supports the figure of up to 50%. (LLM, conf=0.78)
Experimental — accuracy not yet measuredActivation or re-activation of tissue-resident autoreactive T cells is thought to be a dominant factor in the development of immune-related adverse events.
“Activation or re-activation of tissue-resident autoreactive T cells is thought to be a dominant factor in the development of irAEs”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Dougan et al., 2021
Targeting CTLA-4 could theoretically cause Treg dysfunction or depletion, as shown in mice, though human data are not all supportive.
“CTLA-4 is also expressed on Tregs; targeting CTLA-4 could theoretically lead to Treg cell dysfunction or depletion as has been demonstrated in mice (Simpson et al., 2013), though not all data support this notion in humans”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Dougan et al., 2021
Nearly 25% of melanoma patients develop new autoantibodies after immune checkpoint blockade, but typical autoimmune antibody targets are not always seen in immune-related adverse events even when the same target is affected.
“Nearly 25% of patients developed new autoantibodies following treatment with ICB for melanoma; however, the typical antibody targets observed in autoimmune disease are not always seen in irAEs even when the same target is affected”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Dougan et al., 2021
TCR analysis shows that a large fraction of cytotoxic effector cells in immune checkpoint blockade-induced colitis derive from tissue-resident CD8+ T cells.
“TCR analysis demonstrates that a large fraction of the cytotoxic effector cells found in ICB-induced colitis derive from tissue-resident CD8+ T cells”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Dougan et al., 2021
Immune checkpoint blockade-associated colitis and myocarditis show robust macrophage infiltrates, and macrophages play a prominent role in ICB-induced diabetes.
“Patients with ICB-associated colitis and myocarditis exhibit a robust, active macrophage infiltrate (Dougan et al., 2021; Luoma et al., 2020)s; macrophages also play a prominent role in ICB-induced diabetes”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Dougan et al., 2021
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Tsang, V., McGrath, R. T., Clifton-Bligh, R. J., Scolyer, R. A., Jakrot, V., Guminski, A. D., Long, G. V., & Menzies, A. M. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2019-00423 · Cited by 141 · see citing works
Badran, Y. R., Cohen, J. V., Brastianos, P. K., Parikh, A. R., Hong, T. S., & Dougan, M. L. (2019) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-019-0711-0 · Cited by 138 · see citing works
Self-citationThrombocytopenia in patients with melanoma receiving immune checkpoint inhibitor therapy
Shiuan, E. F., Beckermann, K. E., Özgün, A., Kelly, C. M., McKean, M. A., McQuade, J. L., Thompson, M. A., Puzanov, I. J., Greer, J. P., Rapisuwon, S., et al. (2017) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-017-0210-0 · Cited by 134 · see citing works
Diagnosis and Management of Hepatitis in Patients on Checkpoint Blockade
Reynolds, K. L., Thomas, M. F., & Dougan, M. L. (2018) · The Oncologist · doi:10.1634/theoncologist.2018-0174 · Cited by 111 · see citing works
Self-citationBudesonide treatment for microscopic colitis from immune checkpoint inhibitors
Hughes, M. S., Molina, G. E., Chen, S. T., Zheng, H., Deshpande, V., Fadden, R. M., Sullivan, R. J., & Dougan, M. L. (2019) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-019-0756-0 · Cited by 100 · see citing works
Self-citationLiver biopsy findings in patients on immune checkpoint inhibitors
Cohen, J. V., Dougan, M. L., Zubiri, L., Reynolds, K. L., Sullivan, R. J., & Misdraji, J. (2020) · Modern Pathology · doi:10.1038/s41379-020-00653-1 · Cited by 86 · see citing works
Self-citationMucosal inflammation predicts response to systemic steroids in immune checkpoint inhibitor colitis
Mooradian, M. J., Wang, D. Y., Coromilas, A. J., Lumish, M. A., Chen, T., Giobbie‐Hurder, A., Johnson, D. B., Sullivan, R. J., & Dougan, M. L. (2020) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2019-000451 · Cited by 76 · see citing works
Self-citationT cell receptor recognition of self and foreign antigens in the induction of autoimmunity
Wucherpfennig, K. W., & Sethi, D. K. (2011) · Seminars in Immunology · doi:10.1016/j.smim.2011.01.007 · Cited by 73 · see citing works
Self-citationTargeting Immunotherapy to the Tumor Microenvironment
Dougan, M. L., & Dougan, S. K. (2017) · Journal of Cellular Biochemistry · doi:10.1002/jcb.26005 · Cited by 53 · see citing works
Self-citationThe Emergence of T-Bodies/CAR T Cells
Eshhar, Z., Waks, T., & Gross, G. (2014) · The Cancer Journal · doi:10.1097/ppo.0000000000000027 · Cited by 50 · see citing works
Integrating resident memory into T cell differentiation models
Rosato, P. C., Wijeyesinghe, S., Stolley, J. M., & Masopust, D. (2020) · Current Opinion in Immunology · doi:10.1016/j.coi.2020.01.001 · Cited by 39 · see citing works
Deyà‐Martínez, À., Alonso‐Saladrigues, A., García, A. P., et al. (2020) · Bone Marrow Transplantation · doi:10.1038/s41409-020-01027-6 · Cited by 21 · see citing works
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Sorted by citations
Hallmarks of response, resistance, and toxicity to immune checkpoint blockade
Morad, G., Helmink, B. A., Sharma, P., & Wargo, J. A. (2021) · Cell · doi:10.1016/j.cell.2021.09.020 · Cited by 1,648 · see citing works
Autoimmune Myocarditis, Old Dogs and New Tricks.
Won, T., Song, E. J., Kalinoski, H. M., Moslehi, J. J., & Čiháková, D. (2024) · Circulation Research · doi:10.1161/circresaha.124.323816 · Cited by 51 · see citing works
Groenewegen, B., Terveer, E. M., Joosse, A., Barnhoorn, M. C., & Zwittink, R. D. (2023) · Journal of Immunotherapy · doi:10.1097/cji.0000000000000474 · Cited by 24 · see citing works
- Authors
- Dougan, M., Luoma, A. M., Dougan, S. K., & Wucherpfennig, K. W.
- Affiliations
- Harvard University (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Dougan, Michael
- Wucherpfennig, Kai W.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2021-03
- Volume
- 184
- Issue
- 6
- Pages
- 1575-1588
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC7979511
- OpenAlex
- W3134238388
- Cited by
- 319
- References
- 84
- Citations by year
- 2026: 53 · 2025: 72 · 2024: 87 · 2023: 66 · 2022: 30 · 2021: 10 · 2015: 1
- FWCI
- 5.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 383 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Melanoma Research Alliance
- National Institutes of Health
- American Cancer Society
- American Gastroenterological Association
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- cancer immunotherapy, immune checkpoint inhibitors, CAR T-cell therapy, immune-related adverse events, immunotherapy toxicity management, combination immunotherapy, antitumor immunity
- MeSH terms
- Immune Checkpoint Inhibitors, Animals, Humans, Immunotherapy, Inflammation, Neoplasms, T-Lymphocytes, Cytokines
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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