Cancer Immunology, Immunotherapy

, Volume 62, Issue 6, pp 1021–1028

Long-term survival and immunological parameters in metastatic melanoma patients who responded to ipilimumab 10 mg/kg within an expanded access programme

  • Anna Maria Di Giacomo
  • Luana Calabrò
  • Riccardo Danielli
  • Ester Fonsatti
  • Erica Bertocci
  • Isabella Pesce
  • Carolina Fazio
  • Ornella Cutaia
  • Diana Giannarelli
  • Clelia Miracco
  • Maurizio Biagioli
  • Maresa Altomonte
  • Michele Maio
Original Article



Ipilimumab can result in durable clinical responses among patients with advanced melanoma. However, no predictive marker of clinical activity has yet been identified. We provide preliminary data describing the correlation between immunological parameters and response/survival among patients with advanced melanoma who received ipilimumab 10 mg/kg in an expanded access programme.


Patients received ipilimumab 10 mg/kg every 3 weeks (Q3W) for four doses (induction) and Q12W from week 24 (W24) as maintenance therapy. Tumor assessments were conducted Q12W. Expression of inducible T cell costimulator (ICOS) on CD4+ and CD8+ T cells was assessed at baseline, W7, W12 and W24, and the ratio between absolute neutrophils (N) and lymphocytes (L) determined at baseline, W4, W7 and W10.


Median overall survival among 27 patients was 9.6 months (95 % CI 3.2–16.1), with 3- and 4-year survival rates of 20.4 %. Five patients survived >4 years. Patients with an increase in the number of circulating ICOS+ T cells at W7 were more likely to experience disease control and have improved survival. An N/L ratio below the median at W7 and W10 was also associated with better survival compared with an N/L ratio above the median.


Ipilimumab can induce long-term survival benefits in heavily pretreated patients with metastatic melanoma. Changes in the number of circulating ICOS+ T cells or N/L ratio during ipilimumab treatment may represent early markers of response. However, given the limited sample size, further investigation is required.


Biomarker Expanded access programme Ipilimumab Long-term survival Metastatic melanoma 


  1. 1.
    Ferlay J, Parkin DM, Steliarova-Foucher E (2010) Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer 46:765–781PubMedCrossRefGoogle Scholar
  2. 2.
    Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60:277–300PubMedCrossRefGoogle Scholar
  3. 3.
    Korn EL, Liu PY, Lee SJ, Chapman JA, Niedzwiecki D, Suman VJ, Moon J, Sondak VK, Atkins MB, Eisenhauer EA, Parulekar W, Markovic SN, Saxman S, Kirkwood JM (2008) Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials. J Clin Oncol 26:527–534PubMedCrossRefGoogle Scholar
  4. 4.
    Tarhini AA, Agarwala SS (2006) Cutaneous melanoma: available therapy for metastatic disease. Dermatol Ther 19:19–25PubMedCrossRefGoogle Scholar
  5. 5.
    Eggermont AM (2010) Advances in systemic treatment of melanoma. Ann Oncol 21(Suppl 7):vii339–vii344PubMedCrossRefGoogle Scholar
  6. 6.
    Serrone L, Zeuli M, Sega FM, Cognetti F (2000) Dacarbazine-based chemotherapy for metastatic melanoma: thirty-year experience overview. J Exp Clin Cancer Res 19:21–34PubMedGoogle Scholar
  7. 7.
    Peggs KS, Quezada SA, Korman AJ, Allison JP (2006) Principles and use of anti-CTLA4 antibody in human cancer immunotherapy. Curr Opin Immunol 18:206–213PubMedCrossRefGoogle Scholar
  8. 8.
    Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723PubMedCrossRefGoogle Scholar
  9. 9.
    Robert C, Thomas L, Bondarenko I, O’Day S, Garbe JWC, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517–2526PubMedCrossRefGoogle Scholar
  10. 10.
    Hamid O, Schmidt H, Nissan A, Ridolfi L, Aamdal S, Hansson J, Guida M, Hyams DM, Gomez H, Bastholt L, Chasalow SD, Berman D (2011) A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Transl Med 9:204PubMedCrossRefGoogle Scholar
  11. 11.
    Wang W, Yu D, Sarnaik AA, Yu B, Hall M, Morelli D, Zhang Y, Zhao X, Weber JS (2012) Biomarkers on melanoma patient T cells associated with ipilimumab treatment. J Transl Med 10:146PubMedCrossRefGoogle Scholar
  12. 12.
    Yuan J, Adamow M, Ginsberg BA, Rasalan TS, Ritter E, Gallardo HF, Xu Y, Pogoriler E, Terzulli SL, Kuk D, Panageas KS, Ritter G, Sznol M, Halaban R, Jungbluth AA, Allison JP, Old LJ, Wolchok JD, Gnjatic S (2011) Integrated NY-ESO-1 antibody and CD8 + T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab. Proc Natl Acad Sci USA 108:16723–16728PubMedCrossRefGoogle Scholar
  13. 13.
    Di Giacomo AM, Danielli R, Calabro L, Bertocci E, Nannicini C, Giannarelli D, Balestrazzi A, Vigni F, Riversi V, Miracco C, Biagioli M, Altomonte M, Maio M (2011) Ipilimumab experience in heavily pretreated patients with melanoma in an expanded access program at the university hospital of Siena (Italy). Cancer Immunol Immunother 60:467–477PubMedCrossRefGoogle Scholar
  14. 14.
    Ku GY, Yuan J, Page DB, Schroeder SE, Panageas KS, Carvajal RD, Chapman PB, Schwartz GK, Allison JP, Wolchok JD (2010) Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates with survival. Cancer 116:1767–1775PubMedCrossRefGoogle Scholar
  15. 15.
    Simeone E, Gentilcore G, Romano A, Daponte A (2012) Immunological and biological changes during ipilimumab (Ipi) treatment and their correlation with clinical response and survival. J Clin Oncol 30(Suppl): abstract 8573Google Scholar
  16. 16.
    Berrocal A, Lopez-Martin JA, Arance AM, Soriano VEE (2012) Spanish experience with the ipilimumab Expanded Access Program. J Clin Oncol 30(Suppl): abstract e19023Google Scholar
  17. 17.
    Danielli R, Ridolfi R, Chiarion-Sileni V, Queirolo P, Testori A, Plummer R, Boitano M, Calabro L, Rossi CD, Di Giacomo AM, Ferrucci PF, Ridolfi L, Altomonte M, Miracco C, Balestrazzi A, Maio M (2012) Ipilimumab in pretreated patients with metastatic uveal melanoma: safety and clinical efficacy. Cancer Immunol Immunother 61:41–48PubMedCrossRefGoogle Scholar
  18. 18.
    Wilgenhof S, Four SD, Everaert H, Neyns B (2012) Patterns of response in patients with pretreated metastatic melanoma who received ipilimumab 3 mg/kg in a European expanded access program: five illustrative case reports. Cancer Invest 30:712–720PubMedCrossRefGoogle Scholar
  19. 19.
    Di Giacomo AM, Calabrò L, Danielli R, Fonsatti E, Bertocci E, Pesce I, Giannarelli D, Biagioli M, Altomonte M, Maio M (2012) Long term survival and immunological correlates in metastatic melanoma treated with ipilimumab at 10 mgs within an expanded access program. Ann Oncol 23(Suppl 9):abstract 1117PDGoogle Scholar
  20. 20.
    Lebbe C, Weinberg AD, Maio M, Neyns B, Harmankaya K, Chin K, Opatt McDowell D, Cykowski L, McHenry MB, Wolchok JD (2012) Five-year survival rates for patients (Pts) with metastatic melanoma (MM) treated with ipilimumab (Ipi) in phase II trials. Ann Oncol 23(Suppl 9):abstract 1116PDGoogle Scholar
  21. 21.
    Prieto PA, Yang JC, Sherry RM, Hughes MS, Kammula US, White DE, Levy CL, Rosenberg SA, Phan GQ (2012) CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma. Clin Cancer Res 18:2039–2047PubMedCrossRefGoogle Scholar
  22. 22.
    Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbe C, Maio M, Binder M, Bohnsack O, Nichol G, Humphrey R, Hodi FS (2009) Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 15:7412–7420PubMedCrossRefGoogle Scholar
  23. 23.
    Weber J (2007) Review: anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse events. Oncologist 12:864–872PubMedCrossRefGoogle Scholar
  24. 24.
    YERVOY™ Summary of Product Characteristics (2012) Available at: Accessed December 2012
  25. 25.
    Weber JS, Kahler KC, Hauschild A (2012) Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 30:2691–2697PubMedCrossRefGoogle Scholar
  26. 26.
    Hutloff A, Dittrich AM, Beier KC, Eljaschewitsch B, Kraft R, Anagnostopoulos I, Kroczek RA (1999) ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 397:263–266PubMedCrossRefGoogle Scholar
  27. 27.
    Schenk AD, Gorbacheva V, Rabant M, Fairchild RL, Valujskikh A (2009) Effector functions of donor-reactive CD8 memory T cells are dependent on ICOS induced during division in cardiac grafts. Am J Transplant 9:64–73PubMedCrossRefGoogle Scholar
  28. 28.
    Yoshinaga SK, Whoriskey JS, Khare SD, Sarmiento U, Guo J, Horan T, Shih G, Zhang M, Coccia MA, Kohno T, Tafuri-Bladt A, Brankow D, Campbell P, Chang D, Chiu L, Dai T, Duncan G, Elliott GS, Hui A, McCabe SM, Scully S, Shahinian A, Shaklee CL, Van G, Mak TW, Senaldi G (1999) T-cell co-stimulation through B7RP-1 and ICOS. Nature 402:827–832PubMedCrossRefGoogle Scholar
  29. 29.
    An X, Ding PR, Li YH, Wang FH, Shi YX, Wang ZQ, He YJ, Xu RH, Jiang WQ (2010) Elevated neutrophil to lymphocyte ratio predicts survival in advanced pancreatic cancer. Biomarkers 15:516–522PubMedCrossRefGoogle Scholar
  30. 30.
    Sarraf KM, Belcher E, Raevsky E, Nicholson AG, Goldstraw P, Lim E (2009) Neutrophil/lymphocyte ratio and its association with survival after complete resection in non-small cell lung cancer. J Thorac Cardiovasc Surg 137:425–428PubMedCrossRefGoogle Scholar
  31. 31.
    Walsh SR, Cook EJ, Goulder F, Justin TA, Keeling NJ (2005) Neutrophil-lymphocyte ratio as a prognostic factor in colorectal cancer. J Surg Oncol 91:181–184PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Anna Maria Di Giacomo
    • 1
  • Luana Calabrò
    • 1
  • Riccardo Danielli
    • 1
  • Ester Fonsatti
    • 1
  • Erica Bertocci
    • 1
  • Isabella Pesce
    • 1
  • Carolina Fazio
    • 1
  • Ornella Cutaia
    • 1
  • Diana Giannarelli
    • 2
  • Clelia Miracco
    • 3
  • Maurizio Biagioli
    • 4
  • Maresa Altomonte
    • 1
  • Michele Maio
    • 1
  1. 1.Division of Medical Oncology and Immunotherapy, Department of Oncology, Istituto Toscano TumoriUniversity Hospital of SienaSienaItaly
  2. 2.Statistical UnitRegina Elena National Cancer InstituteRomeItaly
  3. 3.Department of PathologyUniversity Hospital of SienaSienaItaly
  4. 4.Department of DermatologyUniversity Hospital of SienaSienaItaly

Personalised recommendations