Sex and Interleukin-6 Are Prognostic Factors for Autoimmune Toxicity Following Treatment with Anti-CTLA4 Blockade

Overview

Journal J Transl Med

Publisher Biomed Central

Specialties Biomedical Engineering
General Medicine

Date 2018 Apr 13

PMID 29642948

Citations 99

Authors

Sara Valpione

Sandro Pasquali

Luca Giovanni Campana

Luisa Piccin

Simone Mocellin

Jacopo Pigozzo

Vanna Chiarion-Sileni

Affiliations

Soon will be listed here.

Abstract

Background: Ipilimumab is a licensed immunotherapy for metastatic melanoma patients and, in the US, as adjuvant treatment for high risk melanoma radically resected. The use of ipilimumab is associated with a typical but unpredictable pattern of side effects. The purpose of this study was to identify clinical features and blood biomarkers capable of predicting ipilimumab related toxicity.

Methods: We performed a prospective study aimed at analyzing potential clinical and biological markers associated with immune-related toxicity in patients treated with ipilimumab (3 mg/kg, q3w). We enrolled 140 consecutive melanoma patients treated with ipilimumab for metastatic disease. The following prospectively collected data were utilized: patient characteristics, previous therapies, level of circulating biomarkers associated with tumour burden or immune-inflammation status (lactic dehydrogenase, C-reactive protein, β2-microglobulin, vascular endothelial growth factor, interleukin-2, interleukin-6, S-100, alkaline phosphatase, transaminases) and blood cells subsets (leukocyte and lymphocyte subpopulations). Logistic regression was used for multivariate analysis of data.

Results: Out of 140 patients, 36 (26%) experienced a severe adverse event, 33 (24%) discontinued treatment for severe toxicity. Among the immune-profile biomarkers analyzed, only interleukin-6 was associated with the risk of toxicity. Female patients had a further increase of immune-related adverse events. Low baseline interleukin-6 serum levels (OR = 2.84, 95% CI 1.34-6.03, P = 0.007) and sex female (OR = 1.5, 95% CI 1.06-2.16 P = 0.022) and were significant and independent risk factors for immune related adverse events.

Conclusions: Baseline IL6 serum levels and female sex were significantly and independently associated with higher risk of severe toxicity and could be exploited in clinical practice to personalize toxicity surveillance in patients treated with ipilimumab.

Citing Articles

Revolutionary Cancer Therapy for Personalization and Improved Efficacy: Strategies to Overcome Resistance to Immune Checkpoint Inhibitor Therapy.

Almawash S Cancers (Basel). 2025; 17(5).

PMID: 40075727 PMC: 11899125. DOI: 10.3390/cancers17050880.

Analysis of risk factors for immune checkpoint inhibitor-associated liver injury: a retrospective analysis based on clinical study and real-world data.

Wang B, Zhuang S, Lin S, Lin J, Zeng W, Du B Hepatol Int. 2025; .

PMID: 40019709 DOI: 10.1007/s12072-025-10783-w.

Yan T, Long M, Liu C, Zhang J, Wei X, Li F Front Pharmacol. 2025; 16:1519082.

PMID: 39959424 PMC: 11825824. DOI: 10.3389/fphar.2025.1519082.

Osimertinib exacerbates immune checkpoint inhibitor-related severe adverse events by activating the IL-6/JAK/STAT3 pathway in macrophages.

Li Y, Chen Y, Meng Y, Shen M, Yang F, Ren X Cancer Biol Med. 2024; 21(12.

PMID: 39651787 PMC: 11745090. DOI: 10.20892/j.issn.2095-3941.2024.0269.

Kao C, Charmsaz S, Alden S, Brancati M, Li H, Balaji A J Clin Invest. 2024; 134(20).

PMID: 39403935 PMC: 11473156. DOI: 10.1172/JCI176567.

References

Lebbe C, Weber J, Maio M, Neyns B, Harmankaya K, Hamid O . Survival follow-up and ipilimumab retreatment of patients with advanced melanoma who received ipilimumab in prior phase II studies. Ann Oncol. 2014; 25(11):2277-2284. PMC: 4990834. DOI: 10.1093/annonc/mdu441. View

Agostino N, Saraceni C, Kincaid H, Shi W, Nevala W, Markovic S . A prospective evaluation of the role of Vascular Endothelial Growth Factor (VEGF) and the immune system in stage III/IV melanoma. Springerplus. 2015; 4:186. PMC: 4411400. DOI: 10.1186/s40064-015-0951-5. View

Valpione S, Martinoli C, Fava P, Mocellin S, Campana L, Quaglino P . Personalised medicine: Development and external validation of a prognostic model for metastatic melanoma patients treated with ipilimumab. Eur J Cancer. 2015; 51(14):2086-94. DOI: 10.1016/j.ejca.2015.06.130. View

McDermott D, Haanen J, Chen T, Lorigan P, ODay S . Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20). Ann Oncol. 2013; 24(10):2694-2698. DOI: 10.1093/annonc/mdt291. View

Patel S, Gooderham N . IL6 Mediates Immune and Colorectal Cancer Cell Cross-talk via miR-21 and miR-29b. Mol Cancer Res. 2015; 13(11):1502-8. DOI: 10.1158/1541-7786.MCR-15-0147. View

Barzey V, Atkins M, Garrison L, Asukai Y, Kotapati S, Penrod J . Ipilimumab in 2nd line treatment of patients with advanced melanoma: a cost-effectiveness analysis. J Med Econ. 2012; 16(2):202-12. DOI: 10.3111/13696998.2012.739226. View

Roth I, Campbell H, Rubio C, Vennin C, Wilson M, Wiles A . The Δ133p53 isoform and its mouse analogue Δ122p53 promote invasion and metastasis involving pro-inflammatory molecules interleukin-6 and CCL2. Oncogene. 2016; 35(38):4981-9. DOI: 10.1038/onc.2016.45. View

Weinstein D, Leininger J, Hamby C, Safai B . Diagnostic and prognostic biomarkers in melanoma. J Clin Aesthet Dermatol. 2014; 7(6):13-24. PMC: 4086529. View

Zelenay S, van der Veen A, Bottcher J, Snelgrove K, Rogers N, Acton S . Cyclooxygenase-Dependent Tumor Growth through Evasion of Immunity. Cell. 2015; 162(6):1257-70. PMC: 4597191. DOI: 10.1016/j.cell.2015.08.015. View

10.

Sansone P, Ceccarelli C, Berishaj M, Chang Q, Rajasekhar V, Perna F . Self-renewal of CD133(hi) cells by IL6/Notch3 signalling regulates endocrine resistance in metastatic breast cancer. Nat Commun. 2016; 7:10442. PMC: 4748123. DOI: 10.1038/ncomms10442. View

11.

Kim H, Jeon J, Yoon J, Suh C . Beta 2-microglobulin can be a disease activity marker in systemic lupus erythematosus. Am J Med Sci. 2010; 339(4):337-40. DOI: 10.1097/MAJ.0b013e3181d26dfb. View

12.

Mocellin S, Mandruzzato S, Bronte V, Lise M, Nitti D . Part I: Vaccines for solid tumours. Lancet Oncol. 2004; 5(11):681-9. DOI: 10.1016/S1470-2045(04)01610-9. View

13.

Amedei A, Prisco D, D Elios M . The use of cytokines and chemokines in the cancer immunotherapy. Recent Pat Anticancer Drug Discov. 2012; 8(2):126-42. View

14.

Berman D, Parker S, Siegel J, Chasalow S, Weber J, Galbraith S . Blockade of cytotoxic T-lymphocyte antigen-4 by ipilimumab results in dysregulation of gastrointestinal immunity in patients with advanced melanoma. Cancer Immun. 2010; 10:11. PMC: 2999944. View

15.

Ernstoff M . Self-recognition and tumor response to immunotherapy. J Clin Oncol. 2005; 23(25):5875-7. DOI: 10.1200/JCO.2005.95.029. View

16.

Postow M, Chesney J, Pavlick A, Robert C, Grossmann K, McDermott D . Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015; 372(21):2006-17. PMC: 5744258. DOI: 10.1056/NEJMoa1414428. View

17.

Kim M, Lee W, Jeong J, Kim S, Jin W . Induction of metastatic potential by TrkB via activation of IL6/JAK2/STAT3 and PI3K/AKT signaling in breast cancer. Oncotarget. 2015; 6(37):40158-71. PMC: 4741886. DOI: 10.18632/oncotarget.5522. View

18.

Bender C, Dimitrakopoulou-Strauss A, Enk A, Hassel J . Safety of the PD-1 antibody pembrolizumab in patients with high-grade adverse events under ipilimumab treatment. Ann Oncol. 2016; 27(7):1353-4. DOI: 10.1093/annonc/mdw128. View

19.

Ahmad S, Qian W, Ellis S, Mason E, Khattak M, Gupta A . Ipilimumab in the real world: the UK expanded access programme experience in previously treated advanced melanoma patients. Melanoma Res. 2015; 25(5):432-42. PMC: 4560270. DOI: 10.1097/CMR.0000000000000185. View

20.

Boussiotis V . Somatic mutations and immunotherapy outcome with CTLA-4 blockade in melanoma. N Engl J Med. 2014; 371(23):2230-2. PMC: 4456677. DOI: 10.1056/NEJMe1413061. View