Abstract
Clinical and laboratory observations suggest that host immunity may influence the course of melanoma progression, rationalizing the investigation of immunotherapeutic approaches in this disease. Areas of active investigation have included the use of recombinant cytokines, either alone or in combination with other biologic response modifiers, cancer vaccines, gene therapy, adoptive immunotherapy, or monoclonal antibodies. Although cytokine therapies of interferon alpha (IFN) and interleukin-2 (IL-2) are effective in only a small percentage of patients, the results can be quite dramatic and durable.
Resistance to immunotherapy has been documented to result from a number of immunoevasive maneuvers used by cancer cells. The most effective defense mounted by cancer cells is accomplished through hijacking the host’s complex check and balance system governing peripheral tolerance—the mechanism operated by numerous immune checkpoint molecules to prevent autoimmune attacks on normal tissues. The strategy of using monoclonal antibodies to block the inhibitory immune checkpoint receptors of cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed cell death-1 (PD-1), and programmed cell death ligand-1 (PD-L1) has been shown to restore effective host immunity against melanoma.
This chapter will focus on the use of cytokines and immune checkpoint-targeted antibodies in the management of patients with advanced melanoma.
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References
Kalialis LV, Drzewiecki KT, Klyver H (2009) Spontaneous regression of metastases from melanoma: review of the literature. Melanoma Res 19:275–282
Kubica AW, Brewer JD (2012) Melanoma in immunosuppressed patients. Mayo Clin Proc 87:991–1003
Platanias LC (2005) Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat Rev Immunol 5:375–386
Jonasch E, Haluska FG (2001) Interferon in oncological practice: review of interferon biology, clinical applications, and toxicities. Oncologist 6:34–55
Balch CM, Soong SJ, Atkins MD et al (2004) An evidence-based staging system for cutaneous melanoma. CA Cancer J Clin 54:131–149
Kirkwood JM, Strawderman MH, Ernstoff MS et al (1996) Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the eastern cooperative oncology group trial EST 1684. J Clin Oncol 14:7–17
Kirkwood JM, Ibrahim JG, Sondak VK et al (2000) High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 18:2444–2458
Kleeberg UR, Suciu S, Brocker EB et al (2004) Final results of the EORTC 18871/DKG 80-1 randomised phase III trial. rIFN-alpha2b versus rIFN-gamma versus ISCADOR M versus observation after surgery in melanoma patients with either high-risk primary (thickness >3 mm) or regional lymph node metastasis. Eur J Cancer 40:390–402
Eggermont AM, Suciu S, Mackie R et al (2005) Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial. Lancet 366:1189–1196
Hansson J, Aamdal S, Bastholt L et al (2011) Two different duration of adjuvant therapy with intermediate-dose interferon alfa-2b in patients with high-risk melanoma (Nordic IFN trial): a randomised phase III trial. Lancet Oncol 12:144–152
Pectasides D, Dafni U, Bafaloukos D et al (2009) Randomized phase III study of 1 month versus 1 year of adjuvant high-dose interferon alfa-2b in patients with resected high-risk melanoma. J Clin Oncol 27:939–944
Agarwala SS, Lee SJ, Flaherty LE et al (2011) Randomized phase III study of high-dose interferon alfa-2b (HDI) for 4 weeks induction only in patients with intermediate- and high-risk melanoma (intergroup trial E 1697). J Clin Oncol 29:Abstract 8505
Merck Sharp and Dohme Corp. (2012) SylatronTM US prescribing information. http://www.sylatron.com/peginterferon/sylatron/hcp/index.jsp. Accessed 28 Jun 2013
Eggermont AM, Suciu S, Testori A et al (2012) Long-term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma. J Clin Oncol 30:3810–3818
Wheatley K, Ives N, Eggermont AMM et al (2007) Interferon-α as adjuvant therapy for melanoma: an individual patient meta-analysis of randomised trials. J Clin Oncol 25:Abstract 8526
Mocelin S, Pasquali S, Rossi CR et al (2010) Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst 102:492–501
Gogas H, Ioannovich J, Dafni U et al (2006) Prognostic significance of autoimmunity during treatment of melanoma with interferon. N Engl J Med 354:709–718
Krauze MT, Tarhini A, Gogas H et al (2011) Prognostic significance of autoimmunity during treatment of melanoma with interferon. Semin Immunopathol 33:385–391
Eggermont AM, Suciu S, Testori A et al (2012) Ulceration and stage are predictive of interferon efficacy in melanoma: results of the phase III adjuvant trials EORTC 18952 and EORTC 18991. Eur J Cancer 48:218–225
Prometheus Laboratories Inc. (2012) Proleukin® US prescribing information. http://www.proleukin.com. Accessed 28 Jun 2013
Atkins MB, Lotze MT, Dutcher JP et al (1999) High-dose recombinant interleukin-2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17:2105–2116
Rudd CE, Taylor A, Schneider H (2009) CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol Rev 229:12–26
Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264
Graziani G, Tentori L, Navarra P (2012) Ipilimumab: a novel immunostimulatory monoclonal antibody for the treatment of cancer. Pharmacol Res 65:9–22
Leach DR, Krummel MF, Allison JP (1996) Enhancement of antitumor immunity by CTLA-4 blockade. Science 271:1734–1736
Hodi FS, O’Day SJ, McDermott DF et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723
Robert C, Thomas L, Bondarenko I et al (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517–2526
Schadendorf D, Hodi FS, Robert C 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(17):1889–1994
Callahan MK, Wolchok JD, Allison JP (2010) Anti-CTLA-4 antibody therapy: immune monitoring during clinical development of a novel immunotherapy. Semin Oncol 37:473–484
Ku GY, Yuan J, Page DB et al (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(7):1767–1775
Yuan J, Adamow M, Ginsberg BA et al (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 108:16723–16728
Hamid O, Schmidt H, Nissan A et al (2011) A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Transl Med 9:204
Bristol-Myers Squibb (2013) YervoyTM US prescribing information. http://packageinserts.bms.com/pi/pi_yervoy.pdf. Accessed 28 Jun 2013
Datapharm Communications Limited (2013) YERVOY™ (ipilimumab) summary of product characteristics. http://www.medicines.org.uk/emc/medicine/24779. Accessed 29 Jun 2013
Robert C, Schadendorf D, Messina M et al (2013) Efficacy and safety of retreatment with ipilimumab in patients with pretreated advanced melanoma who progressed after initially achieving disease control. Clin Cancer Res 19:2232–2239
Bronstein Y, Ng CS, Hwu P et al (2011) Radiologic manifestations of immune-related adverse events in patients with metastatic melanoma undergoing anti-CTLA-4 antibody therapy. AJR Am J Roentgenol 197:W992–W1000
Wolchok JD, Hoos A, O’Day S et al (2009) Guidelines for the evaluation of immune therapy in solid tumors: immune-related response criteria. Clin Cancer Res 15:7412–7420
Ribas A, Chmielowski B, Glaspy JA (2009) Do we need a different set of response assessment criteria for tumor immunotherapy? Clin Cancer Res 15:7116–7118
Eggermont AM, Chiarion-Sileni V, Grob JJ et al (2015) Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol 16(5):522–530
Margolin K, Ernstoff MS, Hamid O et al (2012) Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol 13:459–465
Di Giacomo AM, Ascierto PA, Pilla L et al (2012) Ipilimumab and fotemustine in patients with advanced melanoma (NIBIT-M1): an open-label, single-arm phase 2 trial. Lancet Oncol 13:879–886
Kähler KC, Hauschild A (2011) Treatment and side effect management of CTLA-4 antibody therapy in metastatic melanoma. J Dtsch Dermatol Ges 9:277–286
Bristol-Myers Squibb (2013) YervoyTM US prescribing information: risk evaluation and mitigation strategy. http://www.yervoy.com/hcp/rems.aspx. Accessed 29 Aug 2015
Amin A, de Pril V, Hamid O et al (2009) Evaluation of the effect of systemic corticosteroids for the treatment of immune-related adverse events (irAEs) on the development or maintenance of ipilimumab clinical activity. J Clin Oncol 27:Abstract 9037
Horvat TZ, Adel NG, Dang TO et al (2015) Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at memorial Sloan Kettering cancer center. J Clin Oncol 33:3193–3198
Bristol-Myers Squibb (2015) Opdivo® Prescribing information. http://packageinserts.bms.com/pi/pi_opdivo.pdf. Accessed 1 Sept 2015
Camacho LH, Antonia S, Sosman J et al (2009) Phase I/II trial of tremelimumab in patients with metastatic melanoma. J Clin Oncol 27:1075–1081
Kirkwood JM, Lorigan P, Hersey P et al (2010) Phase II trial of tremelimumab (CP-675,206) in patients with advanced refractory or relapsed melanoma. Clin Cancer Res 16:1042–1048
Ribas A, Kefford R, Marshall MA et al (2013) Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol 31:616–622
Flies DB, Sandler BJ, Sznol M et al (2011) Blockade of the B7-H1/PD-1 pathway for cancer immunotherapy. Yale J Biol Med 84:409–421
Sznol M, Chen L (2013) Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. Clin Cancer Res 19:1021–1034
Okudaira K, Hokari R, Tsuzuki Y et al (2009) Blockade of B7-H1 or B7-DC induces an anti-tumor effect in a mouse pancreatic cancer model. Int J Oncol 35:741–749
Zhou Q, Xiao H, Liu Y et al (2010) Blockade of programmed death-1 pathway rescues the effector function of tumor-infiltrating T cells and enhances the antitumor efficacy of lentivector immunization. J Immunol 185:5082–5092
Brahmer JR, Drake CG, Wollner I et al (2010) Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 28:3167–3175
Topalian SL, Hodi FS, Brahmer JR et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454
Topalian SL, Sznol M, Mcdermott DF et al (2014) Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 32(10):1020–1030
Weber JS, D’Angelo SP, Minor D et al (2015) Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 16(4):375–384
Robert C, Long GV, Brady B et al (2015) Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372(4):320–330
Larkin J, Chiarion-Sileni V, Gonzalez R et al (2015) Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373(1):23–34
Daud A, Ribas A, Robert C (2015) Long-term efficacy of pembrolizumab in a pooled analysis of 655 patients with advanced melanoma enrolled in KEYNOTE-001. J Clin Oncol 33:Abstract 9005
Hamid O, Robert C, Daud A et al (2013) Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 369(2):134–144
Ribas A, Puzanov I, Dummer R et al (2015) Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol 16(8):908–918
Robert C, Schachter J, Long GV et al (2015) Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 372(26):2521–2532
Merck Sharp and Dohme (2014) Keytruda® prescribing information. http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf. Accessed 1 Sept 2015
Berger R, Rotem-Yehudar R, Slama G et al (2008) Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res 14:3044–3051
Atkins MB, Kudchadkar RR, Sznol M et al (2014) Phase 2, multicenter, safety and efficacy study of pidilizumab in patients with metastatic melanoma. J Clin Oncol 32:Abstract 9001
Brahmer JR, Tykodi SS, Chow LQ et al (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366:2455–2465
Herbst RS, Gordon MS, Fine GD et al (2013) A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors. J Clin Oncol 31:Abstract 3000
Gilboa E (2004) The promise of cancer vaccines. Nat Rev Cancer 4:401–411
Melero I, Grimaldi AM, Perez-Gracia JL et al (2013) Clinical development of immunostimulatory monoclonal antibodies and opportunities for combination. Clin Cancer Res 19:997–1008
Fonsatti E, Maio M, Altomonte M et al (2010) Biology and clinical applications of CD40 in cancer treatment. Semin Oncol 37:517–523
Vonderheide RH, Glennie MJ (2013) Agonistic CD40 antibodies and cancer therapy. Clin Cancer Res 19:1035–1043
von Leoprechting A, van der Bruggen P, Pahl HL et al (1999) Stimulation of CD40 on immunogenic human malignant melanomas augments their cytotoxic T lymphocyte-mediated lysis and induces apoptosis. Cancer Res 59:1287–1294
Ghamande S, Hylander BL, Oflazoglu E et al (2001) Recombinant CD40 ligand therapy has significant antitumor effects on CD40-positive ovarian tumor xenografts grown in SCID mice and demonstrates an augmented effect with cisplatin. Cancer Res 61:7556–7562
Funakoshi S, Longo DL, Beckwith M et al (1994) Inhibition of human B-cell lymphoma growth by CD40 stimulation. Blood 83:2787–2794
Schultze JL, Michalak S, Seamon MJ et al (1997) CD40-activated human B cells: an alternative source of highly efficient antigen presenting cells to generate autologous antigen-specific T cells for adoptive immunotherapy. J Clin Invest 100:2757–2765
Vonderheide RH, Flaherty KT, Khalil M et al (2007) Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody. J Clin Oncol 25:876–883
Slupsky JR, Kalbas M, Willuweit A et al (1998) Activated platelets induce tissue factor expression on human umbilical vein endothelial cells by ligation of CD40. Thromb Haemost 80:1008–1014
Rüter J, Antonia SJ, Burris HA et al (2010) Immune modulation with weekly dosing of an agonist CD40 antibody in a phase I study of patients with advanced solid tumors. Cancer Biol Ther 10:983–993
Melero I, Hirschhorn-Cymerman D, Morales-Kastresana A et al (2013) Agonist antibodies to TNFR molecules that costimulate T and NK cells. Clin Cancer Res 19:1044–1053
Sznol M, Hodi FS, Margolin K et al (2008) Phase I study of BMS-663513, a fully human anti-CD137 agonist monoclonal antibody, in patients with advanced cancer. J Clin Oncol 26:Abstract 3007
Hwu WJ (2010) Targeted therapies for melanoma: from bench to bedside. HemOnc Today (published online 25 Jun 2010). http://www.healio.com/hematology-oncology/melanoma-skin-cancer/news/print/hematology-oncology/%7B77E71A11-1FD1-4193-A2F7-7C50C6121C1F%7D/Targeted-therapy-for-metastatic-melanoma-From-bench-to-bedside. Accessed 29 Jun 2013
Postow MA, Callahan MK, Barker CA et al (2012) Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med 366:925–931
Ribas A, Hodi FS, Callahan M et al (2013) Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med 368:1365–1366
Puzanov I, Callahan MK, Linette GP et al (2014) Phase 1 study of the BRAF inhibitor dabrafenib with or wihout the MEK inhibitor trametinib in combination with ipilimumab for V600E/K mutation-positive unresectable or metastatic melanoma. J Clin Oncol 32:Abstract 2511
Prieto PA, Yang JC, Sherry RM et al (2012) CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma. Clin Cancer Res 18:2039–2047
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Trinh, V.A., Ahn, Y., Hwu, WJ. (2016). Immunotherapy in Melanoma. In: Torres-Cabala, C., Curry, J. (eds) Genetics of Melanoma. Cancer Genetics. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-3554-3_10
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