Published: 2018-04-25

Advances in biological treatment of melanoma

Qazi Syed Irfanullah Shah, Xuefeng Wan, Akebaier Sulaiman, Paride Abliz, Yasir Ali Butt, Lu Jin


Biological therapy involves the use of living organisms, substances derived from living organisms, or laboratory-produced versions of such substances to treat disease. Metastatic disease have a grave prognosis in comparison to early stage metastatic cancer where surgical treatment can benefit the patients thus traditional chemotherapy regimens have been found to offer relatively little survival benefit. Treatment of advanced or metastatic melanoma includes involvement of biological modalities such as immunotherapeutic approaches, targeted therapies and epigenetic modification therapies. The goal of immunotherapy for cancer is to provide an effective anticancer immune response. These biological therapies restore or increase the activities of specific immune-system components and counteract immunosuppressive signals produced by cancer cells. Monoclonal antibodies, are laboratory-produced antibodies that bind to specific antigens expressed by cells, such as a protein that is present on the surface of cancer cells but is absent from normal cells. They interfere with the action of proteins that are necessary for tumor growth. When bound to bevacizumab, VEGF cannot interact with its cellular receptor, preventing the signaling that leads to the growth of new blood vessels. MAb’s that bind to cell surface growth factor receptors prevent the targeted receptors from sending their normal growth-promoting signals. The targeted therapeutic agents modulate specific pro-oncogenic mutations such as v-Raf murine sarcoma viral oncogene homolog B (BRAF), MEK inhibitors and CDK4/CDK6, PTEN and GNAQ/GNA11 genes. This review summarizes the biological agents and newer modalities of treatments, and their recent advancements and contributions in the treatment of patients with metastatic melanoma.


Biological therapy, Metastatic melanoma, Targeted therapeutic agents

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Tsao H, Chin L, Garraway LA and Fisher DE: Melanoma: From mutations to medicine. Genes Dev. 2012;26(11):1131-55.

Pratilas CA, Solit DB. Targeting the mitogen-activated protein kinase pathway: physiological feedback and drug response. J Am Association Cancer Res. 2010;16(13):3329-34.

Morales-Espinosa D, García-Román S, Teixidó C, Karachaliou N, Rosell R. Immunotherapy meets targeted therapy: will this team end the war against cancer? Translational Lung Cancer Res. 2015;4(6):752-5.

Menzies AM, Long GV. Recent advances in melanoma systemic therapy. BRAF inhibitors, CTLA4 antibodies and beyond. European J Cancer. 2013;49:3229–41.

Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Current Opinion Immunol. 2012;24(2):207–212.

Ribas A. Tumor immunotherapy directed at PD-1. New England J Med. 2012;366:2517–9.

Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011;17(13):4550-7.

Kaur B, Cripe TP, Chiocca EA. Buy one get one free: armed viruses for the treatment of cancer cells and their microenvironment. Curr Gene Ther. 2009;9:341–55.

Montagut C, Sharma SV, Shioda T, McDermott U, Ulman M, Ulkus LE, et al. Elevated CRAF as a Potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res. 2008;68(12):4853-61.

Hu-Lieskovan S, Robert L, Homet Moreno B, Ribas A. Combining targeted therapy With immunotherapy in BRAF mutant melanoma: Promise and challenges. J Clin Oncol. 2014;32(21):2248-54.

Tsai J, Lee JT, Wang W, Zhang J, Cho H, Mamo S, et al. Discovery of a selective inhibitor of oncogenic BRAF kinase with potent antimelanoma activity. Proc Natl Acad Sci USA. 2008;105(8):3041-6.

Robert C, Arnault JP, Mateus C. RAF inhibition and induction of cutaneous squamous cell carcinoma. Curr Opin Oncol. 2011;23:177-82.

Glaxo Smith Kline. Highlights of Prescribing Information of Tafinlar (Dabrafenib Capsules), Glaxo SmithKline, Brentford, UK, 2014.

GlaxoSmithKline, Two New GSK Oral Oncology Treatments BRAF-Inhibitor Tafinlar (Dabrafenib) Capsules and the First MEK-InhibitorMekinist (Trametinib) Tablets, Approved by FDA as Single-Agent Therapies, GlaxoSmithKline, 2014.

Lemech C, Infante J, Arkenau HT. Combination molecularly targeted drug therapy in metastatic melanoma: progress to date. Drugs. 2013;73(8):767–77.

Sullivan RJ, Flaherty KT. Resistance to BRAF-targeted therapy in melanoma. European J Cancer. 2013;49(6):1297–304.

Sauter ER, Yeo UC, Von Stemm A, Zhu W, Litwin S, Tichansky DS, et al. Cyclin D1 is a candidate oncogene in cutaneous melanoma. Cancer Res. 2002;62(11):3200–6.

Paraiso KHT, Xiang Y, Rebecca VW, Abel EV, Chen YA, Munko AC, et al. PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Res. 2011;71(7):2750–60.

Wright CJM, McCormack PL. Trametinib: first global approval. Drugs. 2013;73(11):1245–54.

Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, et al. Improved survival with MEK inhibition in BRAF mutated melanoma, New England J Med. 2012;367(2):107–14.

Ascierto PA, Schadendorf D, Berking C, Agarwala SS, van Herpen CM, Queirolo P, et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAFmutations: a non-randomised, open-label phase 2 study. Lancet Oncol. 2013;14(3):249–56.

Carvajal RD, Lawrence DP, Weber JS, Gajewski TF, Gonzalez R, Lutzky J, et al. Phase II study of nilotinib in melanoma arboring KIT alterations following progression to prior KIT inhibition. Clin Cancer Res. 2015;21(10):2289-96.

Guo J, Si L, Kong Y, Flaherty KT, Xu X, Zhu Y, et al. Phase II, open-label, single-arm trial of Imatinib mesylate in patients with metastatic melanoma harboring c-KIT mutation or amplification. J Clin Oncol. 2011;29(21):2904-9.

Carvajal RD, Antonescu CR, Wolchok JD, Chapman PB, Roman RA, Teitcher J, et al. KIT as a therapeutic target in metastatic melanoma. JAMA. 2011;305:2327-34.

Hanahan D, Weinberg RA. Hallmarks of cancer: the Next generation. Cell. 2011;144(5):646–74.

Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, et al. Mutational heterogeneity in cancer and the search for new cancer associated genes. Nature. 2013;499(7457):214–8.

Vogelstein JT, GrayRoncal W, Vogelstein RJ, Priebe CE. Graph classification using Signal subgraphs: applications in statistical connectomics. IEEE Trans Pattern Anal Mach Intell. 2013;35(7):1539–51.

Yadav M, Jhunjhunwala S, Phung QT, Lupardus P, Tanguay J, Bumbaca S, et al. Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing. Nature. 2014;515 (7528):572–6.

Castle JC, Kreiter S, Diekmann J, Löwer M, van de Roemer N, de Graaf J, et al. Exploiting the mutanome for tumor vaccination. Cancer Res. 2012;72(5):1081–91.

Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature. 2014;515(7528):577–81.

Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371(23):2189–99.

Walunas TL, Bakker CY, Bluestone JA. CTLA-4 ligation blocks CD28- dependent T cell activation. J Exp Med. 1996;183:2541–50.

Chambers CA, Krummel MF, Boitel B, Hurwitz A, Sullivan TJ, Fournier S, et al. The role of CTLA-4 in the regulation and initiation of T-cell responses. Immunol Rev. 1996;153:27–46.

Graziani G, Tentori L, Navarra P. Ipilimumab: a novel immunostimulatory monoclonal antibody for the treatment of cancer. Pharmacol Res. 2012;65:9-22.

Traynor K. Ipilimumab approved for metastatic melanoma. Am J Health Syst Pharm. 2011;68:768.

Danielli R, Ridolfi R, Chiarion-Sileni V, Queirolo P, Testori A, Plummer R, et al. Ipilimumab in pretreated patients with metastatic uveal melanoma: safety and clinical efficacy. Cancer Immunother. 2012;61:41-8.

Eggermont AM, Robert C. New drugs in melanoma: it's a whole new world. Eur J Cancer. 2011;47:2150-7.

38. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-23

Ribas A. Tumor immunotherapy directed at PD-1. New England J Med. 2012;366(26):2517–9.

Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2008;30(8):643–72.

Poust J. Targeting metastatic melanoma. Am J Health Syst Pharm. 2008;65(24): 9–15.

US Food and Drug Administration, FDA Approves Opdivo for Advanced Melanoma, US Food and Drug Administration, 2014.

Nivolumab Label. Last updated Nov 2015.

Johnson DB, Peng C, Sosman JA. Nivolumab in melanoma: latest evidence and clinical potential. Ther Adv Med Oncol. 2015;7(2): 97–106.

Hamid O, Sosman JA, Lawrence DP, Sullivan RJ, Ibrahim N, Kluger HM, et al. Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PDL1 antibody in patients with locally advanced or metastatic melanoma. J Clin Oncol. 2013;31:9010,

Genentech. A phase 1 study of MPDL3280A (an engineered anti-PDL1 antibody) in patients with locally advanced or metastatic solid tumors. NCT01375842, 2014.

Roche HL. A study to assess the safety and tolerability of MPDL3280A in combination with other immune modulating therapies in patients with locally advanced or metastatic solid tumors. NCT02174172, 2015.