Immune Checkpoint Inhibitors in Melanoma: Review and Update

  • Eugénia Matos Pires Interna do Internato Complementar de Dermatologia e Venereologia / Resident, Dermatology and Venereology, Centro Hospitalar de Lisboa Central, Hospital de Santo António dos Capuchos, Lisboa, Portugal
  • Cecília Moura Assistente Hospitalar Sénior de Dermatologia / Senior Consultant Dermatology, Instituto Português de Oncologia de Lisboa, Francisco Gentil, Lisboa, Portugal
Keywords: Antibodies, Monoclonal, Cell Cycle Checkpoints, CTLA-4 Antigen, Immunotherapy, Ipilimumab, Melanoma, Nivolumab, Programmed Cell Death 1 Receptor


The overall increasing incidence of melanoma will very probably be the trend over the next two decades. This data stresses the need for new therapeutic resources, other than classic chemotherapy. Nevertheless, the treatment of advanced melanoma has been changed in the last decade due to novel therapeutic strategies, including immunotherapy with immune checkpoint inhibitors targeting cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). Inhibition of these targets enhances immune host response against cancer and results in durable objective responses, establishing immunotherapy as standard treatment for BRAF wild-type melanoma patients in advanced stages (III – unresectable and IV – metastases at distant sites). Anti-CTLA-4, ipilimumab, was the first–in-class immune checkpoint inhibitor to show improvement in overall survival in advanced melanoma. Latter, anti-PD-1 agents, nivolumab and pembrolizumab, have improved tumour response and tolerability in comparison with ipilimumab. Differences in outcome are expected considering the distinct target of checkpoint inhibition pathways. In this setting, it is of utmost importance the assessment of efficacy by combined therapy and the identification of biomarkers capable of predicting response to anti-CTLA-4 and anti-PD-1. After a previous review on cancer biology and mechanisms of action of immune checkpoint inhibitors we will focus on the main data on the immune checkpoint inhibitors for melanoma currently available in daily practice.


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Miller AJ, Mihm MC Jr. Melanoma. N Engl J Med. 2006;

: 51-65.

AJCC Cancer Stanging Manual. 8th edition. Berlin:

Springer; 2017.

Whiteman DC, Green AC, Olsen CM. The growing burden

of invasive melanoma: projections of incidence

rates and numbers of new cases in six susceptible populations

through 2031. J Invest Dermatol. 2016; 136:

-7. doi: 10.1016/j.jid.2016.01.035.

Smittenaar CR, Petersen KA, Stewart K, Moitt N. Cancer

incidence and mortality projections in the UK until

Br J Cancer. 2016; 115: 1147-55. doi: 10.1038/


Garbe C, Eigentler TK, Keilholz U, Hauschild A, Kirkwood

JM. Systematic review of medical treatment in

melanoma: current status and future prospects. Oncologist.

; 16: 5-24. doi: 10.1634/theoncologist.


Sanches MM, Soares A, Freitas JP. Genes e melanoma.

Rev Soc Port Dermatol Venereol. 2017; 75: 231-8.

Dummer R, Hauschild A, Lindenblatt N, Pentheroudakis

G, Keilholz U. Cutaneous melanoma: ESMO Clinical

Practice Guidelines for diagnosis, treatment and follow-

-up. Ann Oncol. 2015; 26: 126-32. doi: 10.1093/annonc/


Matos-Pires E, Moura C. Immune response in melanoma:

a basis to understand the role of immunotherapy

with immune checkpoint inhibitors. Rev Soc Port Dermatol

Venereol. 2018; 76: 47-52.

Cancer Genome Atlas Network. Genomic Classification

of Cutaneous Melanoma. Cell. 2015; 161:1681-96.

doi: 10.1016/j.cell.2015.05.044.

Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC,

Weber JS, et al. Survival in BRAF V600-mutant advanced

melanoma treated with vemurafenib. N Engl J Med.

; 366:707-1. doi: 10.1056/NEJMoa1112302.

Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer

R, Millward M, et al. Dabrafenib in BRAF- mutated metastatic

melanoma: a multicentre, open-label, phase 3

randomised controlled trial. Lancet 2012; 380:358-65.

doi: 10.1016/S0140-6736(12)60868-X.

Fong L, Small EJ. Anti– cytotoxic T-lymphocyte antigen-4

antibody: the first in na emerging class of immunomodulatory

antibodies for cancer treatment. J Clin Oncol.

; 26: 5275– 83.

Keler T, Halk E, Vitale L, O'Neill T, Blanset D, Lee S, et al.

Activity and safety of CTLA-4 blockade combined with

vaccines in cynomolgus macaques. J Immunol. 2003;

: 6251–9.

Pardoll DM. The blockade of immune checkpoints in

cancer immunotherapy. Nat Rev Cancer. 2012; 12:252–

doi: 10.1038/nrc3239.

Weber JS, O'Day S, Urba W, Powderly J, Nichol G, Yellin

M, et al. Phase I/II study of ipilimumab for patients with

metastatic melanoma. J Clin Oncol. 2008; 26:5950-6.

doi: 10.1200/JCO.2008.16.1927.

Weber J, Thompson JA, Hamid O, Minor D, Amin A, Ron

I, et al. A randomized, double-blind, placebo-controlled,

phase II study comparing the tolerability and efficacy of

ipilimumab administered with or without prophylactic

budesonide in patients with unresectable stage III or IV

melanoma. Clin Cancer Res. 2009; 15: 5591-8. doi:


Wolchok JD, Neyns B, Linette G, Negrier S, Lutzky J,

Thomas L, et al. Ipilimumab monotherapy in patients

with pretreated advanced melanoma: a randomised,

double-blind, multicentre, phase 2, dose-ranging study.

Lancet Oncol. 2010; 11:155-64. doi: 10.1016/S1470-


Korn EL, Liu PY, Lee SJ, Chapman JA, Niedzwiecki D,

Suman VJ, et al. 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. 2008; 26: 527-34.

doi: 10.1200/JCO.2007.12.7837.

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.

; 363: 711-23. doi: 10.1056/NEJMoa1003466.

Robert C, Thomas L, Bondarenko I, O'Day S, Weber J,

Garbe C et al. Ipilimumab plus dacarbazine for previously

untreated metastatic melanoma. N Engl J Med.

; 364: 2517-26. doi: 10.1056/NEJMoa1104621.

Ascierto PA, Del Vecchio M, Robert C, Mackiewicz A,

Chiarion-Sileni V, Arance A, et al. Ipilimumab 10 mg/kg

versus ipilimumab 3 mg/kg in patients with unresectable

or metastatic melanoma: a randomised, double-blind,

multicentre, phase 3 trial. Lancet Oncol. 2017; 18: 611-

doi: 10.1016/S1470-2045(17)30231-0.

European Medicines Agency. Assessment report for

Yervoy (Ipilimumab). EMA 2011. [accessed 2017 Dec

Available from:

Wang C, Thudium KB, Han M, Wang XT, Huang H, Feingersh

D, et al. In vitro characterization of the anti-PD-1

antibody nivolumab, BMS-936558, and in vivo toxicology

in non-human primates. Cancer Immunol Res. 2014;

: 846–56.doi: 10.1158/2326-6066.CIR-14-0040.

Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J,

Sharfman WH, et al. 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. 2010; 28: 3167-

doi: 10.1200/JCO.2009.26.7609.

Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith

DC, McDermott DF, et al. Safety, activity, and immune

correlates of anti-PD-1 antibody in cancer. N Engl J Med.

; 366: 2443-54. doi: 10.1056/NEJMoa1200690.

Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer

R, Neyns B, et al. 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. 2015; 16: 375-84. doi: 10.1016/S1470-


Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier

L, et al. Nivolumab in previously untreated melanoma

without BRAF mutation. N Engl J Med. 2015; 372: 320-

doi: 10.1056/NEJMoa1412082.

Larkin J, Minor D, D'Angelo S, Neyns B, Smylie M, Miller

WH Jr, et al. Overall survival in patients with advanced

melanoma who received nivolumab versus investigator's

choice chemotherapy in CheckMate 037: a randomized,

controlled, open-label phase III trial. J Clin Oncol.

; 36:383-90.doi: 10.1200/JCO.2016.71.8023.

Bristol-Myers Squibb Company. Opdivo (nivolumab)

injection, for intravenous use: US prescribing information

[accessed 2017 Dec 2017] Available from:

McDermott DF, Atkins MB. PD-1 as a potential target in

cancer therapy. Cancer Med. 2013; 2: 662–73. doi:


Deeks ED. Pembrolizumab: a review in advanced melanoma.

Drugs. 2016;7 6: 375-86. doi: 10.1007/


Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford

R, et al. Safety and tumor responses with lambrolizumab

(anti-PD-1) in melanoma. N Engl J Med. 2013; 369:

-44. doi: 10.1056/NEJMoa1305133.

Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid

O, Robert C, et al. Pembrolizumab versus investigator-

-choice chemotherapy for ipilimumab-refractory melanoma

(KEYNOTE-002): a randomised, controlled, phase

trial. Lancet Oncol. 2015;16: 908–18. doi: 10.1016/


Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier

L, et al. Pembrolizumab versus ipilimumab in advanced

melanoma. N Engl J Med. 2015; 372:2521-32.

doi: 10.1016/S0140-6736(17)31601-X.

Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier

L, et al. Pembrolizumab versus ipilimumab for advanced

melanoma: final overall survival results of a multicentre,

randomised, open-label phase 3 study (KEYNOTE-006).

Lancet.2017; 390:1853-62. doi: 10.1016/S0140-


Merck Sharp and Dohme Limited. Keytruda 50 mg powder

for concentrate for solution for infusion: EU summary

of product characteristics. 2015. [accessed 2017

Dec 2017] Available from:


Das R, Verma R, Sznol M, Boddupalli CS, Gettinger SN,

Kluger H, et al. Combination therapy with anti– CTLA-4

and anti–PD-1 leads to distinct immunologic changes in

vivo. J Immunol. 2015; 194: 950–9. doi: 10.4049/jimmunol.

Bommareddy PK, Shettigar M, Kaufman HL. Integrating

oncolytic viruses in combination cancer immunotherapy.

Nat Rev Immunol. 2018 (in press) doi: 10.1038/


Charych D, Khalili S, Dixit V, Kirk P, Chang T, Langowski

J, et al. Modeling the receptor pharmacology,

pharmacokinetics, and pharmacodynamics of NKTR-

, a kinetically-controlled interleukin-2 (IL2) receptor

agonist for cancer immunotherapy. PLoS One. 2017;

:e0179431. doi: 10.1371/journal.pone.0179431.

Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi

NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in

advanced melanoma. N Engl J Med 2013; 369:122-33.

doi: 10.1016/S1470-2045(16)30409-0.

Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann

K, McDermott D, et al. Nivolumab and ipilimumab versus

ipilimumab in untreated melanoma. N Engl J Med

; 372: 2006-17. doi: 10.1056/NEJMoa1414428.

Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey

CL, Lao CD, et al. Combined nivolumab and ipilimumab

or monotherapy in untreated melanoma. N Engl J Med.

; 373: 23-34. doi: 10.1056/NEJMoa1504030.

Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P,

Grob JJ, Cowey CL, et al. Overall survival with combined

nivolumab and ipilimumab in advanced melanoma.

N Engl J Med. 2017; 377: 1345-56. doi: 10.1056/


Long GV, Atkinson V, Cebon JS, Jameson MB, Fitzharris

BM, McNeil CM, et al. Standard-dose pembrolizumab in

combination with reduced-dose ipilimumab for patients

with advanced melanoma (KEYNOTE-029): an open-label,

phase 1b trial. Lancet Oncol. 2017; 18: 1202-10.

doi: 10.1016/S1470-2045(17)30428-X.

Puzanov I, Milhem MM, Minor D, Hamid O, Li A, Chen

L, et al. Talimogene laherparepvec in combination with

ipilimumab in previously untreated, unresectable stage

iiib-iv melanoma. J Clin Oncol. 2016;34:2619-26.doi:


Chesney J, Puzanov I, Collichio F, Singh P, Milhem MM,

Glaspy J, et al. Randomized, open label phase ii study

evaluating the efficacy and safety of talimogenelaherparepvec

in combination with ipilimumab versus ipilimumab

alone in patients with advanced, unresectable

melanoma. J Clin Oncol. 2018 ;36:1658-67. doi:


Long GV, Dummer R, Ribase A, et al. Efficacy analysis of

MASTERKEY-265 phase 1b study of talimogene laherparepvec

(T-VEC) and pembrolizumab (pembro) for unresectable

stage IIIB-IV melanoma. J Clin Oncol. 2016;

: A9568.

Diab A, Hurwitz ME, Cho DC, Papadimitrakopoulou

V, Curti BD, Tykod SS, et al. NKTR-214 (CD122-biased

agonist) plus nivolumab in patients with advanced solid

tumors: Preliminary phase 1/2 results of PIVOT. Presented

at ASCO Annual Meeting 2018. June 01-05; Chicago,


Eggermont AM, Spatz A, Robert C. Cutaneous melanoma.

Lancet. 2014; 383: 816-27. doi: 10.1016/S0140-


van Akkooi AC, Nowecki ZI, Voit C, Schäfer-Hesterberg

G, Michej W, de Wilt JH, et al. Sentinel node tumor

burden according to the Rotterdam criteria is the most

important prognostic factor for survival in melanoma

patients: a multicenter study in 388 patients with positive

sentinel nodes. Ann Surg. 2008; 248: 949–55. doi:


Eggermont AM1, Chiarion-Sileni V, Grob JJ, Dummer

R, Wolchok JD, Schmidt H, et al. Prolonged survival in

stage iii melanoma with ipilimumab adjuvant therapy.

N Engl J Med. 2016; 375: 1845-55. doi: 10.1056/NEJMoa1611299.

Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance

AM, Cowey CL, et al. Adjuvant nivolumab versus ipilimumab

in resected stage III or IV melanoma. N Engl J Med.

; 377: 1824-35. doi: 10.1056/NEJMoa1709030

Larkin J, Ascierto PA, Dreno B, et al. Combined vemurafenib

and cobimetinib in BRAF-mutated melanoma. N

Engl J Med 2014; 371:1867- 76. doi: 10.1056/NEJMoa1408868.

Long GV, Stroyakovskiy D, Gogas H, et al. Dabrafenib

and trametinib versus dabrafenib and placebo for

Val600 BRAF-mutant melanoma: a multicentre, double-

-blind, phase 3 randomised controlled trial. Lancet 2015;

: 444-51. doi: 10.1016/S0140-6736(15)60898-4.

Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal

RD, SharfmanWH, et al. Survival, durable tumor remission,

and long-term safety in patients with advanced

melanoma receiving nivolumab. J Clin Oncol. 2014;

: 1020–30. doi: 10.1200/JCO.2013.53.0105.

Ott PA. Combined BRAF and MEK inhibition in

BRAF(V600E) mutant melanoma: a synergistic and potentially

safe combination partner with immunotherapy.

Ann Transl Med. 2015; 3: 313-12. doi: 10.3978/j.


Hu-Lieskovan S, Mok S, Moreno BH, Tsoi J, Faja LR,

Goedert L, et al. Improved anti-tumour anti-tumour activity

of immunotherapy with BRAF and MEK inhibitors

in BRAF (V600E) melanoma. Sci Transl Med. 2016;7:

–41. doi: 10.1126/scitranslmed.aaa4691.

Ribas A, Hodi FS, Callahan M, Konto C, Wolchock J.

Hepatotoxicity with the combination of vemurafenib and

ipilimumab. N Engl J Med. 2013; 368:1365–6. doi:


Johnson DB, Pectasides E, Feld E, Ye F, Zhao S, Johnpulle

R, et al. Sequencing treatment in BRAFV600 mutant

melanoma: Anti-PD-1 before and after BRAF inhibition.

J Immunother. 2017; 40: 31-5. doi: 10.1097/


Aya F, Fernandez-Martinez A, Gaba L, Victoria I, Tosca

M, Pineda E, et al. Sequential treatment with immunotherapy

and BRAF inhibitors in BRAF mutant advanced

melanoma. Clin Transl Oncol. 2017; 19 :119-24.


Foth M, Wouters J, de Chaumont C, Dynoodt P, Gallagher

WM. Prognostic and predictive biomarkers in melanoma:

an update. Expert Rev Mol Diagn. 2016; 16:

-37.doi: 10.1586/14737159.2016.1126511.

Jessurun CAC, Vos JAM, Limpens J, Luiten RM. Biomarkers

for response of melanoma patients to immune

checkpoint inhibitors: a systematic review. Front Oncol.

: 27: 7:233. doi: 10.3389/fonc.2017.00233.

Blank CU, Haanen JB, Ribas A, Schumacher TN. Cancer

immunology. The "cancer immunogram". Science.

; 352:658-60. doi: 10.1126/science.aaf2834.

Abate-Daga D, Ramello MC, Smalley I, Forsyth PA,

Smalley KS. The biology and therapeutic management

of melanoma brain metastases. Biochem Pharmacol.

; 153: 35-45. doi: 10.1016/j.bcp.2017.12.019.

Tan AC, Heimberger AB, Menzies AM, Pavlakis N, Khasraw

M. Immune checkpoint inhibitors for brain metastases.

Curr Oncol Rep. 2017; 19:38. doi: 10.1007/


Cohen JV, Tawbi H, Margolin KA, Amravadi R, Bosenberg

M, Brastianos PK, et al. Melanoma central nervous

system metastases: current approaches, challenges, and

opportunities. Pigment Cell Melanoma Res 2016; 29:

-42. doi: 10.1111/pcmr.12538.

Hamilton A, Sibson NR. Role of the systemic immune

system in brain metastasis. Mol Cell Neurosci. 2013;

: 42–51. doi: 10.1016/j.mcn.2012.10.004.

Berghoff AS, Preusser M. The inflammatory microenvironment

in brain metastases: potential treatment target?

Chin Clin Oncol. 2015; 4:21. doi: 10.3978/j.


Lok E, Chung AS, Swanson KD, Wong ET. Melanoma

brain metastasis globally reconfigures chemokine

and cytokine profiles in patient cerebrospinal fluid.

Melanoma Res. 2014; 24: 120-30. doi: 10.1097/


Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott

D, Puzanov I, et al. Ipilimumab in patients with melanoma

and brain metastases: an open-label, phase 2

trial. Lancet Oncol. 2012; 13: 459–65. doi: 10.1016/


Goldberg SB, Gettinger SN, Mahajan A, Chiang AC,

Herbst RS, Sznol M, et al. Pembrolizumab for patients

with melanoma or non-small-cell lung cancer and untreated

brain metastases: early analysis of a non-randomised,

open-label, phase 2 trial. Lancet Oncol. 2016;

: 976–83. doi: 10.1016/S1470-2045(16)30053-5.

Kirchberger MC, Hauschild A, Schuler G, Heinzerling L.

Combined low-dose ipilimumab and pembrolizumab

after sequential ipilimumab and pembrolizumab failure

in advanced melanoma. Eur J Cancer. 2016; 65: 182–

doi: 10.1016/j.ejca.2016.07.003.

Anderson ES, Postow MA, Wolchok JD, Young RJ, Ballangrud

Å, Chan TA, et al. Melanoma brain metastases

treated with stereotactic radiosurgery and concurrent

pembrolizumab display marked regression; efficacy and

safety of combined treatment. J Immunother Cancer.

; 5: 76. doi: 10.1186/s40425-017-0282-x.

74 - Goyal S, Silk AW, Tian S, Mehnert J, Danish S, Ranjan

S, et al. Clinical management of multiple melanoma

brain metastases: a systematic review. JAMA Oncol.

; 1: 668–76. doi: 10.1001/jamaoncol.2015.1206.

Jones PS, Cahill DP, Brastianos PK, Flaherty KT, Curry WT.

Ipilimumab and craniotomy in patients with melanoma

and brain metastases: a case series. Neurosurg Focus.

;38: E5. doi: 10.3171/2014.12.FOCUS14698.

Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting

results of cancer treatment. Cancer. 1981; 47: 207-

Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent

D, Ford R, et al. New response evaluation criteria

in solid tumors: revised RECIST guidelines (Version1.1).

Eur J Cancer. 2009; 45: 228-47. doi: 10.1016/j.


Nishino M, Ramaiya NH, Hatabu H, Hodi FS. Monitoring

immune checkpoint blockade: response evaluation and

biomarker development. Nat Rev Clin Oncol. 2017; 14:

-68. doi: 10.1038/nrclinonc.2017.88.

Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O,

Lebbé C, et al. Guidelines for the evaluation of immune

therapy activity in solid tumors: immune- related response

criteria. Clin Cancer Res. 2009; 15:7412-20. doi:


Nishino M, Giobbie-Hurder A, Manos MP, Bailey N, Buchbinder

EI, Ott PA, et al. Immune-related tumor response

dynamics in melanoma patients treated with

pembrolizumab: identifying markers for clinical outcome

and treatment decisions. Clin Cancer Res. 2017; 23:

-9. doi: 10.1158/1078-0432.CCR-17-0114.

Nair VS, Elkord E. Immune checkpoint inhibitors in cancer

therapy: a focus on T-regulatory cells. Immunol Cell

Biol. 2018; 96 :21-33. doi: 10.1111/imcb.1003.

Torphy RJ, Schulick RD, Zhu Y. Newly emerging immune

checkpoints: promises for future cancer therapy.

Int J Mol Sci. 2017; 6;18. pii: E2642. doi: 10.3390/


Knee DA, Hewes B, Brogdon JL. Rationale for anti-GITR

cancer immunotherapy. Eur J Cancer. 2016; 67:1-10.

doi: 10.1016/j.ejca.2016.06.028.

Cheong JE, Sun L. Targeting the IDO1/TDO2-KYN-AhR

pathway for cancer immunotherapy - challenges and

opportunities. Trends Pharmacol Sci. 2018; 39:307-25.

doi: 10.1016/

Cheong JE, Ekkati A, Sun L. A patent review of IDO1

inhibitors for cancer. Expert Opin Ther Pat. 2018;

:317-30. doi: 10.1080/13543776.2018.1441290.

Vanella V, Festino L, Strudel M, Simeone E, Grimaldi AM,

Ascierto PA. PD-L1 inhibitors in the pipeline: Promise and

progress. Oncoimmunology. 2017 21;7:e1365209.

doi: 10.1080/2162402X.2017.1365209.

Hamid O, Sosman JA, Lawrence DP, Sullivan RJ, Ibrahim

N, Kluger HM, et al. Clinical activity, safety, and biomarkers

of MPDL3280A, an engineered PD-L1 antibody in

patients with locally advanced or metastatic melanoma

(mM). J Clin Oncol. 2013; 31: A9010.

Ribas A, Butler M, Lutzky J, Lawrence DP, Robert C,

Miller W, et al. Phase I study combining anti-PD-L1

(MEDI4736) with BRAF (dabrafenib) and/or MEK (trametinib)

inhibitors in advanced melanoma. J Clin Oncol.

; 33:A3003.

Anvari S, Grimbergen A, Davis CM, Makedonas G. Protein

transport inhibitors downregulate the expression

of LAG -3 on regulatory T cells. J Immunol Methods.

;447:47-51. doi: 10.1016/j.jim.2017.04.006.

Grosso, JF, Kelleher CC, Harris TJ, Maris CH, Hipkiss EL,

de Marzo A, et al. LAG-3 regulates CD8+ T cell accumulation

and effector function inmurine self- and tumor-

-tolerance systems. J Clin Invest. 2007; 117: 3383–92.

doi: 10.1172/JCI31184.

Ascierto PA, Melero I, Bhatia S, Bono P, Sanborn RE,

Evan J, et al. Initial efficacy of anti-lymphocyte activation

gene-3 (anti–LAG-3; BMS-986016) in combination

with nivolumab (nivo) in pts with melanoma (MEL) previously

treated with anti–PD-1/PD-L1 therapy. Presented

at ASCO Annual Meeting 2017. June 02-06; Chicago,


Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J,

Khoury SJ, et al. The Tim-3 ligand galectin-9 negatively

regulates T helper type 1 immunity. Nat Immunol. 2005;

:1245-52. doi: 10.1038/ni1271.

Yan J, Zhang Y, Zhang JP, Liang J, Li L, Zheng L. Tim-3

expression defines regulatory T cells in human tumors.

PLoS ONE. 2013; 8: e58006. doi: 10.1371/journal.


Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo

VK, Anderson AC. Targeting Tim-3 and PD-1 pathways

to reverse T cell exhaustion and restore anti-tumour immunity.

J Exp Med. 2010; 207: 2187–94. doi: 10.1084/


Koyama S, Akbay EA, Li YY, Herter-Sprie GS, Buczkowski

KA, Richards WG, et al. Adaptive resistance to therapeutic

PD-1 blockade is associated with upregulation of

alternative immune checkpoints. Nat Commun. 2016;

; 7:1050. doi: 10.1038/ncomms10501.

Han P, Goularte OD, Rufner K, Wilkinson B, Kaye J. An

inhibitory Ig superfamily protein expressed by lymphocytes

and APCs is also an early marker of thymocyte positive

selection. J Immunol. 2004; 172:5931-9.

Murphy KM, Nelson CA, Sedý JR. Balancing

co-stimulation and inhibition with BTLA and HVEM. Nat

Rev Immunol. 2006; 6:671-81. doi: 10.1038/nri1917.

Derré L, Rivals JP, Jandus C, Pastor S, Rimoldi D, Romero

P, et al. BTLA mediates inhibition of human tumor-specific

CD8+ T cells that can be partially reversed by vaccination.

J Clin Invest. 2010; 120:157-67. doi: 10.1172/


Siu LL, Steeghs N, Meniawy T, Joerger M, Spratlin JL,

Rottey S, et al. Preliminary results of a phase I/IIa study

of BMS-986156 (glucocorticoid-induced tumor necrosis

factor receptor–related gene [GITR] agonist), alone

and in combination with nivolumab in pts with advanced

solid tumors. J Clin Oncol. 2017; 35:104.

Dummer R, Hauschild A, Lindenblatt N, Pentheroudakis

G, Keilholz U; ESMO Guidelines Committee. Cutaneous

melanoma: ESMO Clinical Practice Guidelines for diagnosis,

treatment and follow-up. Ann Oncol. 2015;

:126-32. doi: 10.1093/annonc/mdv297.

Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T,

Nishimura H, 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.

;192: 1027– 34.

Dong H, Strome SE, Salomao DR, Tamura H, Hirano F,

Flies DB, et al. Tumor-associated B7-H1 promotes T-cell

apoptosis: a potential mechanism of immune evasion.

Nat Med 2002; 8:793–800. doi: 10.1038/nm730.

Ugurel S, Röhmel J, Ascierto PA, Flaherty KT, Grob JJ,

Hauschild A, et al. Survival of patients with advanced

metastatic melanoma: the impact of novel therapies-

-update 2017. Eur J Cancer. 2017; 83: 247-57. doi:


Bertrand A, Kostine M, Barnetche T, Truchetet ME,

Schaeverbeke T. Immune related adverse events associated

with anti-CTLA-4 antibodies: systematic review

and meta-analysis. BMC Med 2015; 13: 211.

Naidoo J, Page DB, Li BT, Connell LC, Schindler K, Lacouture

ME, et al. Toxicities of the anti-PD-1 and anti-

PD-L1 immune checkpoint antibodies. Ann Oncol 2015;

: 2375–91. doi: 10.1093/annonc/mdv383.

How to Cite
Matos Pires, E., & Moura, C. (2018). Immune Checkpoint Inhibitors in Melanoma: Review and Update. Journal of the Portuguese Society of Dermatology and Venereology, 76(3), 237-252.
Original Articles