Immune Checkpoint Inhibitors in Melanoma: Review and Update
Abstract
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.
Downloads
References
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/
bjc.2016.304.
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.
-0190.
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/
mdv297.
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:
1158/1078-0432.CCR-09-1024.
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-
(09)70334-1.
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: http://www.ema.europa.eu/ema.
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-
(15)70076-8.
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:
1002/cam4.106.
Deeks ED. Pembrolizumab: a review in advanced melanoma.
Drugs. 2016;7 6: 375-86. doi: 10.1007/
s40265-016-0543-x.
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/
S1470-2045(15)00083-2.
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-
-6736(17)31601-X.
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: http://www.ema.europa.eu/
ema.
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/
s41577-018-0014-6.
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/
NEJMoa1709684.
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:
1200/JCO.2016.67.1529.
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:
1200/JCO.2017.73.7379.
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,
Illenois
Eggermont AM, Spatz A, Robert C. Cutaneous melanoma.
Lancet. 2014; 383: 816-27. doi: 10.1016/S0140-
(13)60802-8.
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:
1097/SLA.0b013e31818fefe0.
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.
issn.2305-5839.2015.10.17.
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:
1056/NEJMc1302338.
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/
CJI.0000000000000148.
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.
doi:10.1007/s12094-016-1514-0.
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/
s11912-017-0596-3.
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.
issn.2304-3865.2015.06.03.
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/
CMR.0000000000000045.
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/
S1470-2045(12)70090-6.
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.
ejca.2008.10.026.
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:
1158/1078-0432.CCR-09-1624.
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/
ijms18122642.
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/j.tips.2017.11.007.
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,
IIlenois.
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.
pone.0058006.
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/
jem.20100643.
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/
JCI40070.
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:
1016/j.ejca.2017.06.028.
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.
All articles in this journal are Open Access under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
