Advertisement

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

  • Maria Pia Pistillo
  • Vincenzo Fontana
  • Anna Morabito
  • Beatrice Dozin
  • Stefania Laurent
  • Roberta Carosio
  • Barbara Banelli
  • Francesca Ferrero
  • Laura Spano
  • Enrica Tanda
  • Pier Francesco Ferrucci
  • Chiara Martinoli
  • Emilia Cocorocchio
  • Michele Guida
  • Stefania Tommasi
  • Federica De Galitiis
  • Elena Pagani
  • Gian Carlo Antonini Cappellini
  • Paolo Marchetti
  • Pietro Quaglino
  • Paolo Fava
  • Simona Osella-Abate
  • Paolo Antonio Ascierto
  • Mariaelena Capone
  • Ester Simeone
  • Massimo Romani
  • Francesco Spagnolo
  • Paola Queirolo
  • On behalf of the Italian Melanoma Intergroup (IMI)
Original Article

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.

Keywords

Soluble CTLA-4 Ipilimumab Best response Adverse events Overall survival 

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

Notes

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.

Authors’ 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.

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.

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.

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.

Supplementary material

262_2018_2258_MOESM1_ESM.pdf (164 kb)
Supplementary material 1 (PDF 164 KB)

References

  1. 1.
    Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723CrossRefGoogle Scholar
  2. 2.
    Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C et al (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517–2526CrossRefGoogle Scholar
  3. 3.
    Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O et al (2015) Pooled analysis of long-term survival data from Phase II and Phase III trials of Ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 33:1889–1894CrossRefGoogle Scholar
  4. 4.
    Peggs KS, Quezada SA, Korman AJ, Allison JP (2006) Principles and use of anti-CTLA-4 antibody in human cancer immunotherapy. Curr Opin Immunol 18:206–231CrossRefGoogle Scholar
  5. 5.
    Tarhini AA, Edington H, Butterfield LH, Lin Y, Shuai Y, Tawbi H et al (2014) Immune monitoring of the circulation and the tumor microenvironment in patients with regionally advanced melanoma receiving neoadjuvant ipilimumab. PLoS One 9:e87705CrossRefGoogle Scholar
  6. 6.
    Brunner MC, Chambers CA, Chan FK, Hanke J, Winoto A, Allison JP (1999) CTLA-4-mediated inhibition of early events of T cell proliferation. J Immunol 162:5813–5820PubMedGoogle Scholar
  7. 7.
    Walker LS, Sansom DM (2011) The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nat Rev Immunol 11:852–863CrossRefGoogle Scholar
  8. 8.
    Walker SK, Sansom DM (2015) Confusing signals: recent progress in CTLA-4 biology. Trends Immunol 36:63–70CrossRefGoogle Scholar
  9. 9.
    Oaks MK, Hallett KM (2000) Cutting edge: a soluble form of CTLA-4 in patients with autoimmune thyroid disease. J Immunol 164:5015–5018CrossRefGoogle Scholar
  10. 10.
    Magistrelli G, Jeannin P, Herbault N, Benoit De Coignac A, Gauchat JF et al (1999) A soluble form of CTLA-4 generated by alternative splicing is expressed by nonstimulated human T cells. Eur J Immunol 29:3596–3602CrossRefGoogle Scholar
  11. 11.
    Simone R, Pesce G, Antola P, Rumbullaku M, Bagnasco M, Bizzaro N, Saverino D (2014) The soluble form of CTLA-4 from serum of patients with autoimmune diseases regulates T-cell responses. Biomed Res Int 2014:215763PubMedPubMedCentralGoogle Scholar
  12. 12.
    Simone R, Tenca C, Fais F, Luciani M, De Rossi G, Pesce G et al (2012) A soluble form of CTLA-4 is present in paediatric patients with acute lymphoblastic leukaemia and correlates with CD1d + expression. PLoS One 7:e44654CrossRefGoogle Scholar
  13. 13.
    Erfani N, Razmkhah M, Ghaderi A (2010) Circulating soluble CTLA4 (sCTLA4) is elevated in patients with breast cancer. Cancer Invest 28:828–832CrossRefGoogle Scholar
  14. 14.
    Liu Q, Hu P, Deng G, Zhang J, Liang N, Xie J et al (2017) Soluble cytotoxic T-lymphocyte antigen 4: a favorable predictor in malignant tumors after therapy. Onco Targets Ther 10:2147–2154CrossRefGoogle Scholar
  15. 15.
    Ward FJ, Dahal LN, Wijesekera SK, Abdul-Jawad SK, Kaewarpai T, Xu H et al (2013) The soluble isoform of CTLA-4 as a regulator of T-cell responses. Eur J Immunol 43:1274–1285CrossRefGoogle Scholar
  16. 16.
    Rydén A, Bolmeson C, Jonson CO, Cilio CM, Faresjö M (2012) Low expression and secretion of circulating soluble CTLA-4 in peripheral blood mononuclear cells and sera from type 1 diabetic children. Diabetes Metab Res Rev 28:84–96CrossRefGoogle Scholar
  17. 17.
    Sato S, Fujimoto M, Hasegawa M, Komura K, Yanaba K, Hayakawa I al (2004) Serum soluble CTLA-4 levels are increased in diffuse cutaneous systemic sclerosis. Rheumatology 43:1261–1266CrossRefGoogle Scholar
  18. 18.
    Zaragoza J, Caille A, Beneton N, Bens G, Christiann F, Maillard H, Machet L (2016) High neutrophil to lymphocyte ratio measured before starting ipilimumab treatment is associated with reduced overall survival in patients with melanoma. Br J Dermatol 174:146–151CrossRefGoogle Scholar
  19. 19.
    Seremet T, Koch A, Jansen Y, Schreuer M, Wilgenhof S, Del Marmol VJ et al (2016) Molecular and epigenetic features of melanomas and tumor immune microenvironment linked to durable remission to ipilimumab-based immunotherapy in metastatic patients. J Transl Med 14(1):232CrossRefGoogle Scholar
  20. 20.
    Queirolo P, Dozin B, Morabito A, Banelli B, Piccioli P, Fava C et al (2017) Association of CTLA-4 gene variants with response to therapy and long-term survival in metastatic melanoma patients treated with ipilimumab: an Italian melanoma intergroup study. Front Immunol 8:386CrossRefGoogle Scholar
  21. 21.
    Queirolo P, Dozin B, Morabito A, Banelli B, Carosio R, Fontana V et al (2018) CTLA-4 gene variant—1661A> G may predict the onset of endocrine adverse events in metastatic melanoma patients treated with ipilimumab. Eur J Cancer 97:59–61CrossRefGoogle Scholar
  22. 22.
    Ascierto PA, Simeone E, Sileni VC, Pigozzo J, Maio M, Altomonte M et al (2014) Clinical experience with ipilimumab 3 mg/kg: real-world efficacy and safety data from an expanded access program cohort. J Transl Med 12:116CrossRefGoogle Scholar
  23. 23.
    Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbé C et al (2009) Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 15:7412–7420CrossRefGoogle Scholar
  24. 24.
    National Cancer Institute (2006) Common terminology criteria for adverse events v3.0 (CTCAE). http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. Accessed 30 Dec 2015
  25. 25.
    Ferrucci PF, Ascierto PA, Pigozzo J, Del Vecchio M, Maio M, Antonini Cappellini GC et al (2016) Baseline neutrophils and derived neutrophil-to-lymphocyte ratio: prognostic relevance in metastatic melanoma patients receiving ipilimumab. Ann Oncol 27:732–738CrossRefGoogle Scholar
  26. 26.
    Proctor MJ, McMillan DC, Morrison DS, Fletcher CD, Horgan PG, Clarke SJ (2012) A derived neutrophil to lymphocyte ratio predicts survival in patients with cancer. Br J Cancer 107:695–699CrossRefGoogle Scholar
  27. 27.
    Kleinbaum DG, Klein M (2010) Logistic regression, 3rd edn. Springer, New YorkCrossRefGoogle Scholar
  28. 28.
    Kleinbaum DG, Klein M (2005) Survival analysis, 2nd edn. Springer, New YorkGoogle Scholar
  29. 29.
    Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G et al (2003) Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423:506–511CrossRefGoogle Scholar
  30. 30.
    Leung AM, Lee AF, Ozao-Choy J, Ramos RI, Hamid O, O’Day SJ et al (2014) Clinical benefit from ipilimumab therapy in melanoma patients may be associated with serum CTLA4 levels. Front Oncol 4:110PubMedPubMedCentralGoogle Scholar
  31. 31.
    Masuda A, Arai K, Nishihara D, Mizuno T, Yuki H, Kambara T et al (2014) Clinical significance of serum soluble T cell regulatory molecules in clear cell renal cell carcinoma. Biomed Res Int 2014:396064PubMedPubMedCentralGoogle Scholar
  32. 32.
    Kucukhuseyin O, Turan S, Yanar K, Arikan S, Duzkoylu Y, Aydin S et al (2015) Individual and combined effects of CTLA4-cd28 variants and oxidant-antioxidant status on the development of colorectal cancer. Anticancer Res 35:5391–5400PubMedGoogle Scholar
  33. 33.
    Laurent S, Queirolo P, Boero S, Salvi S, Piccioli P, Boccardo S et al (2013) The engagement of CTLA-4 on primary melanoma cell lines induces antibody-dependent cellular cytotoxicity and TNF-α production. J Transl Med 11:108CrossRefGoogle Scholar
  34. 34.
    Weber JS, Kähler KC, Hauschild A (2012) Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 30:2691–2697CrossRefGoogle Scholar
  35. 35.
    Chen Z, Zhou F, Huang S, Jiang T, Chen L, Ge L, Xia B (2011) Association of cytotoxic T lymphocyte associated antigen-4 gene (rs60872763) polymorphism with Crohn’s disease and high levels of serum sCTLA-4 in Crohn’s disease. J Gastroenterol Hepatol 26:924–930CrossRefGoogle Scholar
  36. 36.
    Jiang T, Ge LQ, Chen ZT, Li C, Zhou F, Luo Y, Xia B (2010) Effect of cytotoxic T lymphocyte-associated molecule 4 1661 gene polymorphism on its expression and transcription in ulcerative colitis. J Dig Dis 11:369–375CrossRefGoogle Scholar
  37. 37.
    Cao J, Zhang L, Huang S, Chen P, Zou L, Chen H et al (2011) Aberrant production of soluble co-stimulatory molecules CTLA-4 and CD28 in patients with chronic hepatitis B. Microb Pathog 51:262–267CrossRefGoogle Scholar
  38. 38.
    Umemura T, Ota M, Hamano H, Katsuyama Y, Muraki T, Arakura N et al (2008) Association of autoimmune pancreatitis with cytotoxic T-lymphocyte antigen 4 gene polymorphisms in Japanese patients. Am J Gastroenterol 103:588–594CrossRefGoogle Scholar
  39. 39.
    Kelderman S, Heemskerk B, van Tinteren H, van den Brom RR, Hospers GA, van den Eertwegh AJ et al (2014) Lactate dehydrogenase as a selection criterion for ipilimumab treatment in metastatic melanoma. Cancer Immunol Immunother 63:449–458PubMedGoogle Scholar
  40. 40.
    Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman DR et al (2017) IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest 127:2930–2940CrossRefGoogle Scholar
  41. 41.
    Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L et al (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:568–571CrossRefGoogle Scholar
  42. 42.
    Weide B, Martens A, Hassel JC, Berking C, Postow MA, Bisschop K et al (2016) Baseline biomarkers for outcome of melanoma patients treated with pembrolizumab. Clin Cancer Res 22:5487–5496CrossRefGoogle Scholar
  43. 43.
    Roncella S, Laurent S, Fontana V, Ferro P, Franceschini MC, Salvi S et al (2016) CTLA-4 in mesothelioma patients: tissue expression, body fluid levels and possible relevance as a prognostic factor. Cancer Immunol Immunother 65:909–917CrossRefGoogle Scholar
  44. 44.
    Salvi S, Fontana V, Boccardo S, Merlo DF, Margallo E, Laurent S, Morabito A et al (2012) Evaluation of CTLA-4 expression and relevance as a novel prognostic factor in patients with non-small cell lung cancer. Cancer Immunol Immunother 61:1463–1472CrossRefGoogle Scholar
  45. 45.
    Hu P, Liu Q, Deng G, Zhang J, Liang N, Xie J, Zhang J (2017) The prognostic value of cytotoxic T-lymphocyte antigen 4 in cancers: a systematic review and meta-analysis. Sci Rep 7:42913CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Maria Pia Pistillo
    • 1
  • Vincenzo Fontana
    • 2
  • Anna Morabito
    • 1
  • Beatrice Dozin
    • 2
  • Stefania Laurent
    • 3
  • Roberta Carosio
    • 1
  • Barbara Banelli
    • 1
    • 4
  • Francesca Ferrero
    • 5
  • Laura Spano
    • 5
  • Enrica Tanda
    • 5
  • Pier Francesco Ferrucci
    • 6
  • Chiara Martinoli
    • 6
    • 7
  • Emilia Cocorocchio
    • 6
  • Michele Guida
    • 8
  • Stefania Tommasi
    • 8
  • Federica De Galitiis
    • 9
  • Elena Pagani
    • 9
  • Gian Carlo Antonini Cappellini
    • 9
  • Paolo Marchetti
    • 9
    • 10
  • Pietro Quaglino
    • 11
  • Paolo Fava
    • 11
  • Simona Osella-Abate
    • 12
  • Paolo Antonio Ascierto
    • 13
  • Mariaelena Capone
    • 13
  • Ester Simeone
    • 13
  • Massimo Romani
    • 1
  • Francesco Spagnolo
    • 5
  • Paola Queirolo
    • 5
  • On behalf of the Italian Melanoma Intergroup (IMI)
  1. 1.Unit of Tumor EpigeneticsIRCCS Ospedale Policlinico San MartinoGenoaItaly
  2. 2.Unit of Clinical EpidemiologyIRCCS Ospedale Policlinico San MartinoGenoaItaly
  3. 3.Department of Internal MedicineUniversity of GenoaGenoaItaly
  4. 4.Department of Health SciencesUniversity of GenoaGenoaItaly
  5. 5.Department of Medical OncologyIRCCS Ospedale Policlinico San MartinoGenoaItaly
  6. 6.Oncology of Melanoma UnitEuropean Institute of OncologyMilanItaly
  7. 7.iTeos TherapeuticsGosseliesBelgium
  8. 8.Department of Medical Oncology and Molecular Genetics LaboratoryIRCCS Istituto Tumori “Giovanni Paolo II”BariItaly
  9. 9.Istituto Dermopatico dell’Immacolata IDI-IRCCSRomeItaly
  10. 10.Sapienza University of RomeRomeItaly
  11. 11.Department of Medical Sciences, Dermatologic ClinicUniversity of TurinTurinItaly
  12. 12.Department of Medical Sciences, Section of Surgical PathologyUniversity of TurinTurinItaly
  13. 13.Melanoma, Cancer Immunotherapy and Innovative Therapy UnitIstituto Nazionale Tumori Fondazione’G. Pascale’NaplesItaly

Personalised recommendations