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

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Abstract

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.

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Abbreviations

ANC:

Absolute neutrophil count

BOR:

Best overall response

CTLA-4:

Cytotoxic T lymphocyte antigen-4

dALC:

Derived lymphocyte count

dNLR:

Derived neutrophil–lymphocyte ratio

EAP:

Expanded access program

flCTLA-4:

Full-length CTLA-4

HR:

Hazard ratio

IPI:

Ipilimumab

irAE:

Immune-related adverse events

irCR:

Immune-related complete response

irPD:

Immune-related progressive disease

irPR:

Immune-related partial response

irSD:

Immune-related stable disease

MLR:

Multinomial logistic regression

MM:

Metastatic melanoma

OR:

Odds ratio

sCTLA-4:

Soluble CTLA-4

SNV:

Single nucleotide variants

Tconv:

Conventional T cells

Treg:

Regulatory T cells

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Acknowledgements

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.

Funding

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.

Author information

Authors and Affiliations

  1. Unit of Tumor Epigenetics, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132, Genoa, Italy

    Maria Pia Pistillo, Anna Morabito, Roberta Carosio, Barbara Banelli & Massimo Romani

  2. Unit of Clinical Epidemiology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy

    Vincenzo Fontana & Beatrice Dozin

  3. Department of Internal Medicine, University of Genoa, Genoa, Italy

    Stefania Laurent

  4. Department of Health Sciences, University of Genoa, Genoa, Italy

    Barbara Banelli

  5. Department of Medical Oncology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy

    Francesca Ferrero, Laura Spano, Enrica Tanda, Francesco Spagnolo & Paola Queirolo

  6. Oncology of Melanoma Unit, European Institute of Oncology, Milan, Italy

    Pier Francesco Ferrucci, Chiara Martinoli & Emilia Cocorocchio

  7. iTeos Therapeutics, Gosselies, Belgium

    Chiara Martinoli

  8. Department of Medical Oncology and Molecular Genetics Laboratory, IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, Italy

    Michele Guida & Stefania Tommasi

  9. Istituto Dermopatico dell’Immacolata IDI-IRCCS, Rome, Italy

    Federica De Galitiis, Elena Pagani, Gian Carlo Antonini Cappellini & Paolo Marchetti

  10. Sapienza University of Rome, Rome, Italy

    Paolo Marchetti

  11. Department of Medical Sciences, Dermatologic Clinic, University of Turin, Turin, Italy

    Pietro Quaglino & Paolo Fava

  12. Department of Medical Sciences, Section of Surgical Pathology, University of Turin, Turin, Italy

    Simona Osella-Abate

  13. Melanoma, Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione’G. Pascale’, Naples, Italy

    Paolo Antonio Ascierto, Mariaelena Capone & Ester Simeone

Authors
  1. Maria Pia Pistillo
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  2. Vincenzo Fontana
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  3. Anna Morabito
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  4. Beatrice Dozin
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  5. Stefania Laurent
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  8. Francesca Ferrero
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  9. Laura Spano
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  16. Federica De Galitiis
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  26. Massimo Romani
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  27. Francesco Spagnolo
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  28. Paola Queirolo
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Consortia

On behalf of the Italian Melanoma Intergroup (IMI)

Contributions

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.

Corresponding author

Correspondence to Maria Pia Pistillo.

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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.

Ethical approval

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.

Informed consent

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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Pistillo, M.P., Fontana, V., Morabito, A. et al. Soluble CTLA-4 as a favorable predictive biomarker in metastatic melanoma patients treated with ipilimumab: an Italian melanoma intergroup study. Cancer Immunol Immunother 68, 97–107 (2019). https://doi.org/10.1007/s00262-018-2258-1

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