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Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab
Abstract
Monoclonal antibodies directed against the immune checkpoint protein cytotoxic T-lymphocyte antigen-4 (CTLA-4; CD152)—ipilimumab and tremelimumab—have been investigated in metastatic melanoma and other cancers and have shown promising results. Recently, ipilimumab was approved by the US Food and Drug Administration for the treatment of metastatic melanoma. We review the literature on managing the adverse effects and kinetics of tumor regression with ipilimumab and provide guidelines on their management. During treatment with these antibodies, a unique set of adverse effects may occur, called immune-related adverse events (irAEs). These include rashes, which may rarely progress to life-threatening toxic epidermal necrolysis, and colitis, characterized by a mild to moderate, but occasionally also severe and persistent diarrhea. Hypophysitis, hepatitis, pancreatitis, iridocyclitis, lymphadenopathy, neuropathies, and nephritis have also been reported with ipilimumab. Early recognition of irAEs and initiation of treatment are critical to reduce the risk of sequelae. Interestingly, irAEs correlated with treatment response in some studies. Unique kinetics of response have been observed with CTLA-4 blockade with at least four patterns: (1) response in baseline lesions by week 12, with no new lesions seen; (2) stable disease, followed by a slow, steady decline in total tumor burden; (3) regression of tumor after initial increase in total tumor burden; and (4) reduction in total tumor burden during or after the appearance of new lesion(s) after week 12. We provide a detailed description of irAEs and recommendations for practicing oncologists who are managing them, along with the unusual kinetics of response associated with ipilimumab therapy.
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“We observed an association between irAEs and improved PFS using a landmark analysis, in agreement with previous studies58–60, and uncovered that baseline gut microbiome composition segregated PD-1-treated patients who developed irAEs from those who did not.”
From Intestinal microbiota signatures of clinical response and immune-related adverse events in melanoma patients treated with anti-PD-1 (2022) · cites this paper as [60]
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“cineurin inhibitors, also appear to be relevant for anti-PD-1 and anti-PD-L1 agents.(46,47)”
BackgroundAbdallah, A.-O. A., Herlopian, A., Ravilla, R., Bansal, M., Chandra-Reddy, S., Mahmoud, F. A., Ong, S., Gökden, M., & Hutchins, L. F. (2015) · Journal of Oncology Pharmacy Practice · doi:10.1177/1078155215572932 · Cited by 43
“For severe (grade 3 and 4) neurological toxicity, ipilimumab should be permanently discontinued, and one should initiate systemic corticosteroids at a dose of prednisone (or equivalent) 1 to 2 mg/kg once per day tapering over at least 30 days.(32,33) Some patients responded to infliximab suggesting that cytokine relea…”
BackgroundPD-1 as an emerging therapeutic target in renal cell carcinoma: current evidence
Tykodi, S. S. (2014) · OncoTargets and Therapy · doi:10.2147/ott.s48443 · Cited by 43
Management of Brain Metastases in Patients With Melanoma
Chukwueke, U. N., Batchelor, T. T., & Brastianos, P. K. (2016) · Journal of Oncology Practice · doi:10.1200/jop.2016.011882 · Cited by 43
Cancer immunotherapy-induced rheumatic diseases emerge as new clinical entities
Cappelli, L. C., Shah, A. A., & Bingham, C. O. (2016) · RMD Open · doi:10.1136/rmdopen-2016-000321 · Cited by 43
“damage of tissues, collectively referred to as immune-related adverse events (IRAEs).(8) IRAEs have been described that affect nearly”
BackgroundEmerging role of immunotherapy in urothelial carcinoma—Advanced disease
Zibelman, M. R., Ramamurthy, C., & Plimack, E. R. (2016) · Urologic Oncology Seminars and Original Investigations · doi:10.1016/j.urolonc.2016.10.017 · Cited by 43
“Shared experiences from early clinical trials with checkpoint inhibitors have led to the development of algorithmic guidelines for management, which have minimized treatment-related morbidity and mortality [30].”
A case of severe encephalitis while on PD-1 immunotherapy for recurrent clear cell ovarian cancer
Burke, M. P., Hardesty, M. M., & Downs, W. (2018) · Gynecologic Oncology Reports · doi:10.1016/j.gore.2018.03.007 · Cited by 43
“These effects often vary in severity from mild transient peripheral neuropathies that resolve spontaneously, to persistent conditions that require prolonged steroid treatment (Weber et al., 2012, 2016; Linardou and Gogas, 2016; Friedman et al., 2016).”
BackgroundInfluentialRecent advances in immunotherapies: from infection and autoimmunity, to cancer, and back again
Bucktrout, S. L., Bluestone, J. A., & Ramsdell, F. (2018) · Genome Medicine · doi:10.1186/s13073-018-0588-4 · Cited by 47
Improving safety of cancer immunotherapy via delivery technology
Hu, D., Zhang, W., Tang, J., Zhou, Z., Liu, X., & Shen, Y. (2020) · Biomaterials · doi:10.1016/j.biomaterials.2020.120407 · Cited by 43
Ziogas, D. C., Gkoufa, A., Cholongitas, Ε., Diamantopoulos, P. T., Anastasopoulou, A. N., Ascierto, P. A., & Gogas, H. J. (2020) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-001322 · Cited by 43
Castro, M. A., Corrales, E. P., Molina‐Cerrillo, J., & Alonso‐Gordoa, T. (2021) · Biomedicines · doi:10.3390/biomedicines9030304 · Cited by 43
“Hepatitis and hypophysitis may develop later in time [99].”
BackgroundCancer Immunotherapy: Whence and Whither
Stambrook, P. J., Maher, J. F., & Farzaneh, F. (2017) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-16-0427 · Cited by 43
“These neoantigens can likely contribute to recognition by tumor-reactive T cells (160) when unleashed by inhibition of immune blockade (161, 162), suggesting that a heavier mutation load may predict a more successful outcome following inhibition of a PD-1 or CTLA-4 blockade.”
BackgroundInfluentialCurrent challenges in designing GBM trials for immunotherapy
Weathers, S.-P. S., & Gilbert, M. R. (2015) · Journal of Neuro-Oncology · doi:10.1007/s11060-015-1716-2 · Cited by 44
Update on benefit of immunotherapy and targeted therapy in melanoma: the changing landscape
McDermott, D. F., & Srivastava, N. (2014) · Cancer Management and Research · doi:10.2147/cmar.s64979 · Cited by 43
Isolated recto-sigmoid colitis: a new imaging pattern of ipilimumab-associated colitis
Barina, A. R., Bashir, M. R., Howard, B. A., Hanks, B. A., Salama, A. K. S., & Jaffe, T. A. (2015) · Abdominal Radiology · doi:10.1007/s00261-015-0560-3 · Cited by 42
Lerner, S. P., Bajorin, D. F., Dinney, C. P., Efstathiou, J. A., Groshen, S. G., Hahn, N. M., Hansel, D. E., Kwiatkowski, D. J., O’Donnell, M. A., Rosenberg, J. E., et al. (2016) · Bladder Cancer · doi:10.3233/blc-160053 · Cited by 42
“Although generally tolerable, combined CTLA-4/PD-1 blockade is associated with a high rate of Grade III and IV immune related adverse events; these events necessitate intervention with corticosteroids and occasionally with drugs that block tumor necrosis factor (TNF) [76].”
BackgroundImmune-related adverse events by immune checkpoint inhibitors
Kadono, T. (2017) · Japanese Journal of Clinical Immunology · doi:10.2177/jsci.40.83 · Cited by 42
Grávalos, C., Sanmartín, O., Gúrpide, A., España, A., Majem, M., Oh, H. J. S., Aragón, I., Segura, S., Beato, C., & Botella, R. (2018) · Clinical & Translational Oncology · doi:10.1007/s12094-018-1953-x · Cited by 43
Treatment- and immune-related adverse events of immune checkpoint inhibitors in advanced lung cancer
Shao, J., Wang, C., Ren, P., Jiang, Y., Tian, P., & Li, W. (2020) · Bioscience Reports · doi:10.1042/bsr20192347 · Cited by 46
Zhou, Y., Wang, Y., Xia, R.-L., Liu, J., & Ma, X. (2022) · International Journal of Ophthalmology · doi:10.18240/ijo.2022.04.19 · Cited by 42
Marlier, J., Cocquyt, V., Brochez, L., Belle, S. V., & Krüse, V. (2014) · Endocrine · doi:10.1007/s12020-014-0199-9 · Cited by 41
Rozera, C., Cappellini, G. A., D’Agostino, G., Santodonato, L., Castiello, L., Urbani, F., Macchia, I., Aricò, E., Casorelli, I., Sestili, P., et al. (2015) · Journal of Translational Medicine · doi:10.1186/s12967-015-0473-5 · Cited by 41
Dermatological Toxicity Associated with Targeted Therapies in Cancer: Optimal Management
Peuvrel, L., & Dréno, B. (2014) · American Journal of Clinical Dermatology · doi:10.1007/s40257-014-0088-2 · Cited by 41
Ipilimumab-induced acute generalized exanthematous pustulosis in a patient with metastatic melanoma
Hwang, S. J. E., Carlos, G., Wakade, D., Sharma, R. N., & Fernández‐Peñas, P. (2016) · Melanoma Research · doi:10.1097/cmr.0000000000000261 · Cited by 41
Checkpoint inhibitors and gastrointestinal immune-related adverse events
Pernot, S., Ramtohul, T., & Taı̈eb, J. (2016) · Current Opinion in Oncology · doi:10.1097/cco.0000000000000292 · Cited by 40
“Rectosigmoidoscopy should be performed without delay for grade 3–4 diarrhea or any symptom persisting for more than 7 days [18].”
BackgroundCardiovascular and Cancer Risk: The Role of Cardio-oncology
Coviello, J. S. (2018) · Journal of the Advanced Practitioner in Oncology · doi:10.6004/jadpro.2018.9.2.3 · Cited by 41
Pembrolizumab-induced Sarcoid-like Reactions during Treatment of Metastatic Melanoma
Cheshire, S., Ruth E. Board, Lewis, A. R., Gudur, L., & Dobson, M. J. (2018) · Radiology · doi:10.1148/radiol.2018180572 · Cited by 41
Central nervous system toxicities of anti-cancer immune checkpoint blockade
Conry, R. M. (2016) · Journal of Neurology and Neuromedicine · doi:10.29245/2572.942x/2016/4.1040 · Cited by 41
Immune Checkpoint Inhibitors-Induced Hepatitis
Tian, Y., Abu‐Sbeih, H., & Wang, Y. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-02505-2_8 · Cited by 41
Metadata
- Authors
- Weber, J. S., Kähler, K. C., & Hauschild, A.
- Affiliations
- Moffitt Cancer Center (US)
- Venue
- Journal of Clinical Oncology
- Published
- 2012-07-20
- Volume
- 30
- Issue
- 21
- Pages
- 2691-2697
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2109653150
- Cited by
- 1,415
- References
- 33
- Citations by year
- 2026: 24 · 2025: 35 · 2024: 59 · 2023: 79 · 2022: 84 · 2021: 117 · 2020: 129 · 2019: 123 · 2018: 146 · 2017: 153 · 2016: 152 · 2015: 145 · 2014: 94 · 2013: 65 · 2012: 9
- FWCI
- 10.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Keywords
- ipilimumab, immune-related adverse events, CTLA-4 blockade, metastatic melanoma, immune checkpoint inhibitors, toxic epidermal necrolysis, colitis, hypophysitis, hepatitis, iridocyclitis, neuropathy, nephritis, adverse event management
- MeSH terms
- Ipilimumab, Antibodies, Monoclonal, Antineoplastic Agents, Colitis, Drug Eruptions, Diarrhea, Humans, Liver, Lymphatic Diseases, Melanoma, Mucous Membrane, Pancreatitis, Peripheral Nervous System Diseases, Pituitary Gland, Skin, Skin Neoplasms, Stevens-Johnson Syndrome, Uveitis, Scleritis, Chemical and Drug Induced Liver Injury, CTLA-4 Antigen, Antibodies, Monoclonal, Humanized
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