Soluble CTLA-4 as a favorable predictive biomarker in metastatic melanoma patients treated with ipilimumab: an Italian melanoma intergroup study: Cancer Immunology, Immunotherapy

M.P. Pistillo, V. Fontana, A. Morabito, B. Dozin, S. Laurent, R. Carosio, B. Banelli, F. Ferrero, L. Spano, E. Tanda, P.F. Ferrucci, C. Martinoli, E. Cocorocchio, M. Guida, S. Tommasi, F. De Galitiis, E. Pagani, G.C. Antonini Cappellini, P. Marchetti, P. QuaglinoP. Fava, S. Osella-Abate, P.A. Ascierto, M. Capone, E. Simeone, M. Romani, F. Spagnolo, P. Queirolo, On behalf of the Italian Melanoma Intergroup (IMI)

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CTLA-4 blockade by means of ipilimumab (IPI) potentiates the immune response and improves overall survival (OS) in a minority of metastatic melanoma (MM) patients. We investigated the role of soluble CTLA-4 (sCTLA-4) as a possible biomarker for identifying this subset of patients. sCTLA-4 levels were analyzed at baseline in sera from 113 IPI-treated MM patients by ELISA, and the median value (200 pg/ml) was used to create two equally sized subgroups. Associations of sCTLA-4 with best overall response (BOR) to IPI and immune-related adverse events (irAEs) were evaluated through logistic regression. Kaplan–Meier and Cox regression methods were used to analyze OS. A remarkable association between sCTLA-4 levels and BOR was found. Specifically, the proportion of patients with sCTLA-4 > 200 pg/ml in irSD or irPD (immune-related stable or progressive disease) was, respectively, 80% (OR = 0.23; 95%CL = 0.03–1.88) and 89% (OR = 0.11; 95%CL = 0.02–0.71) and was lower than that observed among patients in irCR/irPR (immune-related complete/partial response). sCTLA-4 levels increased during IPI treatment, since the proportion of patients showing sCTLA > 200 pg/ml after 3 cycles was 4 times higher (OR = 4.41, 95%CL = 1.02–19.1) than that after 1 cycle. Moreover, a significantly lower death rate was estimated for patients with sCTLA-4 > 200 pg/ml (HR = 0.61, 95%CL = 0.39–0.98). Higher baseline sCTLA-4 levels were also associated with the onset of any irAE (p value = 0.029), in particular irAEs of the digestive tract (p value = 0.041). In conclusion, our results suggest that high sCTLA-4 serum levels might predict favorable clinical outcome and higher risk of irAEs in IPI-treated MM patients. © 2018, Springer-Verlag GmbH Germany, part of Springer Nature.
Original languageEnglish
Pages (from-to)97-107
Number of pages11
JournalCancer Immunol. Immunother.
Issue number1
Publication statusPublished - 2019


  • Adverse events
  • Best response
  • Ipilimumab
  • Overall survival
  • Soluble CTLA-4
  • aminotransferase
  • amylase
  • B Raf kinase inhibitor
  • biological marker
  • cytotoxic T lymphocyte antigen 4
  • gilvetmab
  • ipilimumab
  • melanoma antigen 3
  • mitogen activated protein kinase kinase inhibitor
  • recombinant interferon
  • recombinant interleukin 2
  • triacylglycerol lipase
  • immunological antineoplastic agent
  • tumor marker
  • adult
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  • correlation analysis
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  • enzyme linked immunosorbent assay
  • female
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  • hypophysitis
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  • Italy
  • Kaplan Meier method
  • liver disease
  • logistic regression analysis
  • major clinical study
  • male
  • metastatic melanoma
  • mortality rate
  • nausea and vomiting
  • overall survival
  • pancreas disease
  • predictive value
  • priority journal
  • proportional hazards model
  • pruritus
  • rash
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  • blood
  • melanoma
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  • middle aged
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  • solubility
  • very elderly
  • young adult
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents, Immunological
  • Biomarkers, Tumor
  • CTLA-4 Antigen
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Melanoma
  • Middle Aged
  • Neoplasm Metastasis
  • Predictive Value of Tests
  • Solubility
  • Young Adult


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