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Checkpoint Modulation in Melanoma: An Update on Ipilimumab and Future Directions

  • Melanoma (KB Kim, Section Editor)
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Abstract

Ipilimumab, an anti-cytotoxic T-lymphocyte antigen 4 antibody, was the first therapy demonstrated to improve overall survival in melanoma. Since ipilimumab’s approval by the FDA in 2011, a wealth of data has amassed, helping clinicians to optimize its use. We have learned how to mitigate the adverse effects of ipilimumab, identified its effects in melanoma subpopulations such as those with brain metastases, uveal melanoma, and mucosal melanoma, discovered potential biomarkers of activity, and investigated its use in combination with other therapeutic modalities. These discoveries have paved the way for rapid development of second-generation immunomodulatory antibodies such as inhibitors of the programmed cell death 1 receptor axis. These new agents hold promise as monotherapy, but perhaps the greatest allure lies in the possibility of combining these agents in synergistic multidrug regimens.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17(7):2105–16.

    PubMed  CAS  Google Scholar 

  2. Serrone L, Zeuli M, Sega FM, Cognetti F. Dacarbazine-based chemotherapy for metastatic melanoma: thirty-year experience overview. J Exp Clin Cancer Res. 2000;19(1):21–34.

    PubMed  CAS  Google Scholar 

  3. •• Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23. This was the first phase III study to demonstrate an overall survival benefit with therapy in metastatic melanoma.

  4. •• Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364(26):2517–26. This is a phase III study showing improved overall survival with ipilimumab plus dacarbazine compared with a previous standard of care, dacarbazine.

  5. •• Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507–16. This is a phase III trial establishing vemurafenib as a standard of care for metastatic melanoma patients harboring the V600E BRAF mutation.

  6. •• Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54. This is a sentinel phase I trial demonstrating safety and clinical activity for PD-1 blockade.

  7. •• Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65. This is a sentinel phase I trial demonstrating safety and clinical activity for PD-L1 blockade.

  8. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365–76.

    Article  PubMed  CAS  Google Scholar 

  9. Revicki DA, van den Eertwegh AJ, Lorigan P, et al. Health related quality of life outcomes for unresectable stage III or IV melanoma patients receiving ipilimumab treatment. Health Qual Life Outcome. 2012;10:66.

    Article  Google Scholar 

  10. Prieto PA, Yang JC, Sherry RM, et al. CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma. Clin Cancer Res. 2012;18(7):2039–47.

    Article  PubMed  CAS  Google Scholar 

  11. Phan GQ, Yang JC, Sherry RM, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A. 2003;100(14):8372–7.

    Article  PubMed  CAS  Google Scholar 

  12. Maker AV, Phan GQ, Attia P, et al. Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study. Ann Surg Oncol. 2005;12(12):1005–16.

    Article  PubMed  Google Scholar 

  13. Maker AV, Yang JC, Sherry RM, et al. Intrapatient dose escalation of anti-CTLA-4 antibody in patients with metastatic melanoma. J Immunother. 2006;29(4):455–63.

    Article  PubMed  CAS  Google Scholar 

  14. Postow MA, Callahan MK, Wolchok JD. The antitumor immunity of ipilimumab: (T-cell) memories to last a lifetime? Clin Cancer Res. 2012;18(7):1821–3.

    Article  PubMed  CAS  Google Scholar 

  15. Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11(2):155–64.

    Article  PubMed  CAS  Google Scholar 

  16. Robert C, Schadendorf D, Messina M, et al. Efficacy and safety of retreatment with ipilimumab in patients with pretreated advanced melanoma who progressed after initially achieving disease control. Clin Cancer Res. 2013;19(8):2232–9.

    Article  PubMed  CAS  Google Scholar 

  17. Ackerman A, McDermott D, Lawrence D, et al. Outcomes of patients with malignant melanoma treated with immunotherapy prior to or after vemurafenib. Paper presented at: 2012 ASCO Annual Meeting; 2012 Jun 1–5; Chicago.

  18. Wolchok J. How recent advances in immunotherapy are changing the standard of care for patients with metastatic melanoma. Ann Oncol. 2012;23 Suppl 8:viii15-21.

    Article  PubMed  Google Scholar 

  19. Boni A, Cogdill AP, Dang P, et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res. 2010;70(13):5213–9.

    Article  PubMed  CAS  Google Scholar 

  20. Comin-Anduix B, Chodon T, Sazegar H, et al. The oncogenic BRAF kinase inhibitor PLX4032/RG7204 does not affect the viability or function of human lymphocytes across a wide range of concentrations. Clin Cancer Res. 2010;16(24):6040–8.

    Article  PubMed  CAS  Google Scholar 

  21. Wilmott JS, Long GV, Howle JR, et al. Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma. Clin Cancer Res. 2012;18(5):1386–94.

    Article  PubMed  CAS  Google Scholar 

  22. Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012;12(4):237–51.

    Article  PubMed  CAS  Google Scholar 

  23. Yang DH, Park JS, Jin CJ, et al. The dysfunction and abnormal signaling pathway of dendritic cells loaded by tumor antigen can be overcome by neutralizing VEGF in multiple myeloma. Leuk Res. 2009;33(5):665–70.

    Article  PubMed  CAS  Google Scholar 

  24. Ribas A, Hodi FS, Callahan M, et al. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2013;368(14):1365–6.

    Article  PubMed  CAS  Google Scholar 

  25. Harding JJ, Pulitzer M, Chapman PB. Vemurafenib sensitivity skin reaction after ipilimumab. N Engl J Med. 2012;366(9):866–8.

    Article  PubMed  CAS  Google Scholar 

  26. Bafaloukos D, Gogas H. The treatment of brain metastases in melanoma patients. Cancer Treat Rev. 2004;30(6):515–20.

    Article  PubMed  CAS  Google Scholar 

  27. Barth A, Wanek LA, Morton DL. Prognostic factors in 1,521 melanoma patients with distant metastases. J Am Coll Surg. 1995;181(3):193–201.

    PubMed  CAS  Google Scholar 

  28. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012;13(5):459–65.

    Article  PubMed  CAS  Google Scholar 

  29. Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological aspects of cancer chemotherapy. Nat Rev Immunol. 2008;8(1):59–73.

    Article  PubMed  CAS  Google Scholar 

  30. Carson 3rd WE, Shapiro CL, Crespin TR, et al. Cellular immunity in breast cancer patients completing taxane treatment. Clin Cancer Res. 2004;10(10):3401–9.

    Article  PubMed  CAS  Google Scholar 

  31. Suzuki E, Kapoor V, Jassar AS, et al. Gemcitabine selectively eliminates splenic Gr-1+/CD11b + myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res. 2005;11(18):6713–21.

    Article  PubMed  CAS  Google Scholar 

  32. Hersh EM, O'Day SJ, Powderly J, et al. A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naive patients with advanced melanoma. Invest New Drugs. 2011;29(3):489–98.

    Article  PubMed  CAS  Google Scholar 

  33. Avril MF, Aamdal S, Grob JJ, et al. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol. 2004;22(6):1118–25.

    Article  PubMed  CAS  Google Scholar 

  34. Di Giacomo AM, Ascierto PA, Pilla L, et al. Ipilimumab and fotemustine in patients with advanced melanoma (NIBIT-M1): an open-label, single-arm phase 2 trial. Lancet Oncol. 2012;13(9):879–86.

    Article  PubMed  Google Scholar 

  35. Wang J, Patel SG, Hwu WJ, et al. Development of brain metastases in patients with metastatic melanoma treated with ipilimumab plus temozolomide. Paper presented at: 2012 Annual ASCO Meeting; 2012 Jun 1–5; Chicago.

  36. Patel SP, Hwu WJ, Kim KB, et al. Phase II study of the frontline combination of ipilimumab and temozolomide in patients with metastatic melanoma. Paper presented at: 2012 Annual ASCO Meeting; 2012 Jun 1–5; Chicago.

  37. Kingsley DP. An interesting case of possible abscopal effect in malignant melanoma. Br J Radiol. 1975;48(574):863–6.

    Article  PubMed  CAS  Google Scholar 

  38. • Stamell EF, Wolchok JD, Gnjatic S, et al. The abscopal effect associated with a systemic anti-melanoma immune response. Int J Radiat Oncol Biol Phys. 2013;85(2):293–5. This is a case report demonstrating immune correlates of the abscopal effect in a patient treated with ipilimumab and external beam radiotherapy.

  39. Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366(10):925–31.

    Article  PubMed  CAS  Google Scholar 

  40. Seung SK, Curti BD, Crittenden M, et al. Phase 1 study of stereotactic body radiotherapy and interleukin-2—tumor and immunological responses. Sci Transl Med. 2012;4(137):137ra74.

    Article  PubMed  CAS  Google Scholar 

  41. Dewan MZ, Galloway AE, Kawashima N, et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res. 2009;15(17):5379–88.

    Article  PubMed  CAS  Google Scholar 

  42. Augsburger JJ, Correa ZM, Shaikh AH. Effectiveness of treatments for metastatic uveal melanoma. Am J Ophthalmol. 2009;148(1):119–27.

    Article  PubMed  Google Scholar 

  43. Van Raamsdonk CD, Griewank KG, Crosby MB, et al. Mutations in GNA11 in uveal melanoma. N Engl J Med. 2010;363(23):2191–9.

    Article  PubMed  Google Scholar 

  44. Khan S, Callahan M, Postow MA et al. Ipilimumab in the treatment of uveal melanoma: The Memorial Sloan-Kettering Cancer Center experience. Paper presented at: 2012 ASCO Annual Meeting; 2012 Jun 1–5; Chicago.

  45. Khattak MA, Fisher R, Hughes P, et al. Ipilimumab activity in advanced uveal melanoma. Melanoma Res. 2013;23(1):79–81.

    Article  PubMed  CAS  Google Scholar 

  46. Danielli R, Ridolfi R, Chiarion-Sileni V, et al. Ipilimumab in pretreated patients with metastatic uveal melanoma: safety and clinical efficacy. Cancer Immunol Immunother. 2012;61(1):41–8.

    Article  PubMed  CAS  Google Scholar 

  47. Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a therapeutic target in metastatic melanoma. JAMA. 2011;305(22):2327–34.

    Article  PubMed  CAS  Google Scholar 

  48. Del Vecchio M, Simeone E, Chiarion Sileni V, et al. Efficacy and safety of ipilimumab in patients with pretreated, mucosal melanoma: experience from Italian clinics participating in the European expanded access programme (EAP). Paper presented at: ESMO 2012 Congress; 2012 Sep 28-October 2; Vienna.

  49. Kirkwood JM, Lorigan P, Hersey P, et al. Phase II trial of tremelimumab (CP-675,206) in patients with advanced refractory or relapsed melanoma. Clin Cancer Res. 2010;16(3):1042–8.

    Article  PubMed  CAS  Google Scholar 

  50. Ribas A, Kefford R, Marshall MA, et al. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013;31(5):616–22.

    Article  PubMed  CAS  Google Scholar 

  51. Tarhini AA, Cherian J, Moschos SJ, et al. Safety and efficacy of combination immunotherapy with interferon alfa-2b and tremelimumab in patients with stage IV melanoma. J Clin Oncol. 2012;30(3):322–8.

    Article  PubMed  CAS  Google Scholar 

  52. Ku GY, Yuan J, Page DB, et al. Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates with survival. Cancer. 2010;116(7):1767–75.

    Article  PubMed  CAS  Google Scholar 

  53. Postow MA, Yuan J, Panageas KS ,et al. Evaluation of the absolute lymphocyte count as a biomarker for melanoma patients treated with the commercially available dose of ipilimumab (3mg/kg). Paper presented at: 2012 ASCO Annual Meeting. 2012 Jun 1–5; Chicago.

  54. Carthon BC, Wolchok JD, Yuan J, et al. Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial. Clin Cancer Res. 2010;16(10):2861–71.

    Article  PubMed  CAS  Google Scholar 

  55. Yuan J, Adamow M, Ginsberg BA, et al. 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 U S A. 2011;108(40):16723–8.

    Article  PubMed  CAS  Google Scholar 

  56. Yuan J, Ginsberg B, Page D, et al. CTLA-4 blockade increases antigen-specific CD8+ T cells in prevaccinated patients with melanoma: three cases. Cancer Immunol Immunother. 2011;60(8):1137–46.

    Article  PubMed  CAS  Google Scholar 

  57. Hamid O, Schmidt H, Nissan A, et al. A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Transl Med. 2011;9:204.

    Article  PubMed  CAS  Google Scholar 

  58. Ji RR, Chasalow SD, Wang L, et al. An immune-active tumor microenvironment favors clinical response to ipilimumab. Cancer Immunol Immunother. 2012;61(7):1019–31.

    Article  PubMed  CAS  Google Scholar 

  59. Kitano S, Postow MA, Cortez C, et al. Myeloid-derived suppressor cell quantity prior to treatment with ipilimumab at 10mg/kg to predict for overall survival in patients with metastatic melanoma. Paper presented at: 2012 ASCO Annual Meeting; 2012 Jun 1–5; Chicago.

  60. Ellis SG, Wheater M, Tier K, et al. Biomarker for benefit from ipilimumab: correlation of breadth of humor tumor-antigen-specific immunity with outcome. Paper presented at: 2012 ASCO Annual Meeting; 2012 Jun 1–5; Chicago.

  61. Shahabi V, Berman D, Chasalow SD, et al. Gene expression profiling of whole blood in ipilimumab-treated patients for identification of potential biomarkers of immune-mediated gastrointestinal adverse events. Paper presented at: 2012 ASCO Annual Meeting; 2012 Jun 1–5; Chicago.

  62. Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol. 2012;24(2):207–12.

    Article  PubMed  CAS  Google Scholar 

  63. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027–34.

    Article  PubMed  CAS  Google Scholar 

  64. Topalian SL, Brahmer JR, Hodi FS, et al. Anti-programmed death-1 (PD-1) (BMS-936558/MDX-1106/ONO-4538) in patients with advanced solid tumors: clinical activity, safety, and molecular markers. Paper presented at: ESMO 2012 Congress; 2012 Sep 28-Oct 2; Vienna.

  65. Lipson EJ, Sharfman WH, Drake CG, et al. Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody. Clin Cancer Res. 2013.

  66. Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691–7.

    Article  PubMed  CAS  Google Scholar 

  67. Hamid O, Daud A, Robert C, et al. Preliminary clinical efficacy and safety of MK-3475 (anti-PD-1 monoclonal antibody) in patients with advanced melanoma. Pigment Cell Melanoma Res. 2012;25(6):836–903.

    Article  Google Scholar 

  68. Park JJ, Omiya R, Matsumura Y, et al. B7-H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance. Blood. 2010;116(8):1291–8.

    Article  PubMed  CAS  Google Scholar 

  69. Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15(23):7412–20.

    Article  PubMed  CAS  Google Scholar 

  70. Melero I, Grimaldi AM, Perez-Gracia JL, Ascierto PA. Clinical development of immunostimulatory monoclonal antibodies and opportunities for combination. Clin Cancer Res. 2013;19(5):997–1008.

    Article  PubMed  CAS  Google Scholar 

  71. Curran MA, Kim M, Montalvo W, et al. Combination CTLA-4 blockade and 4-1BB activation enhances tumor rejection by increasing T-cell infiltration, proliferation, and cytokine production. PLoS One. 2011;6(4):e19499.

    Article  PubMed  CAS  Google Scholar 

  72. Fourcade J, Sun Z, Pagliano O, et al. CD8+ T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1. Cancer Res. 2012;72(4):887–96.

    Article  PubMed  CAS  Google Scholar 

  73. Ngiow SF, von Scheidt B, Akiba H, et al. Anti-TIM3 antibody promotes T cell IFN-gamma-mediated antitumor immunity and suppresses established tumors. Cancer Res. 2011;71(10):3540–51.

    Article  PubMed  CAS  Google Scholar 

  74. Atkins MB, Hsu J, Lee S, et al. Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (E3695): a trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2008;26(35):5748–54.

    Article  PubMed  CAS  Google Scholar 

  75. Chi M, Dudek AZ. Vaccine therapy for metastatic melanoma: systematic review and meta-analysis of clinical trials. Melanoma Res. 2011;21(3):165–74.

    Article  PubMed  CAS  Google Scholar 

  76. Bernatchez C, Radvanyi LG, Hwu P. Advances in the treatment of metastatic melanoma: adoptive T-cell therapy. Semin Oncol. 2012;39(2):215–26.

    Article  PubMed  CAS  Google Scholar 

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Conflict of Interest

Margaret K. Callahan has received a research grant from Bristol-Myers Squibb.

Michael A. Postow has served on a nonpaid advisory board for Bristol-Myers Squibb and has received a research grant and travel reimbursement from Bristol-Myers Squibb.

Jedd D. Wolchok has been a consultant for Bristol-Myers Squibb and Merck, has received grants from Bristol-Myers Squibb, Merck, and AstraZeneca, and has received travel accommodation from Bristol-Myers Squibb.

David B. Page declares no conflict of interest.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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Correspondence to Jedd D. Wolchok.

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Page, D.B., Postow, M.A., Callahan, M.K. et al. Checkpoint Modulation in Melanoma: An Update on Ipilimumab and Future Directions. Curr Oncol Rep 15, 500–508 (2013). https://doi.org/10.1007/s11912-013-0337-1

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