Soluble CTLA-4 as a favorable predictive biomarker in metastatic melanoma patients treated with ipilimumab: an Italian melanoma intergroup study
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.
KeywordsSoluble CTLA-4 Ipilimumab Best response Adverse events Overall survival
Absolute neutrophil count
Best overall response
Cytotoxic T lymphocyte antigen-4
Derived lymphocyte count
Derived neutrophil–lymphocyte ratio
Expanded access program
Immune-related adverse events
Immune-related complete response
Immune-related progressive disease
Immune-related partial response
Immune-related stable disease
Multinomial logistic regression
Single nucleotide variants
Conventional T cells
Regulatory T cells
The authors would like to thank the patients and investigators who participated in the Italian Expanded Access Program (EAP). This work was supported by the Italian Melanoma Intergroup (IMI). The authors also thank the blood donors and staff of all centers, in particular the Transfusion Center of the IRCCS Ospedale Policlinico San Martino, Genoa, Italy, and the research nurse P. Peirano for collection of blood samples from melanoma patients.
Study concept and design, and study supervision: MPP and Paola Queirolo. Recruitment and management of metastatic melanoma patients: Paola Queirolo, FF, LS, ET, PFF, EC, MG, FDG, GCAC, PM, Pietro Quaglino, PAA, ES, and FS. ELISA assay for detection of sCTLA-4: AM, SL, RC, and BB. SNV genotyping: AM, RC, BB, and MR. Acquisition, analysis, or interpretation of data: MPP, VF, AM, BD, MR, FS, and Paola Queirolo. Drafting of the manuscript: MPP, VF, BD, FS, and Paola Queirolo. Statistical analyses: VF and BD. Administrative, technical, or material support: AM, BB, PFF, CM, ST, EP, PF, SO-A, and MC. Critical revision of the manuscript for important intellectual content: MPP, VF, BD, PFF, MR, FS, and Paola Queirolo. All authors read and approved the final manuscript.
This work was supported by grants from the Italian Ministry of Health (5 × 1000 funds 2013 and 2014 to Pistillo), Italy. This work was supported by the Italian Melanoma Intergroup (IMI). The Expanded Access Program (EAP) was sponsored by Bristol-Myers Squibb.
Compliance with ethical standards
Conflict of interest
Queirolo is member of the advisory board and consultant of Roche, Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Amgen. Ferrucci participated to Bristol-Myers Squibb, Novartis and Roche advisory boards, has served as consultant and received travel support from Bristol-Myers Squibb, Roche, Novartis, Merck Sharp & Dohme. Ascierto has/had a consultant/advisory role for Bristol-Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Ventana, Amgen, Array. He received also research grants from Bristol-Myers Squibb, Roche-Genentech, Ventana, Array. All other authors have declared no conflict of interest. The Expanded Access Program (EAP) was sponsored by Bristol-Myers Squibb.
Patients were recruited in six Italian centers. The study was approved by the local Ethics Committee (EC) of the Liguria Region (CE-IST OMA07.024 emended on 2 January 2011) and by the EC of each participating center. All procedures performed in the study were in accordance with the Helsinki declaration.
All patients provided signed informed consent before enrolment. Additional informed consent was obtained from healthy blood donors in compliance with the Institutional regulations.
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