Current Oncology Reports

, 21:97 | Cite as

Novel Targets for the Treatment of Melanoma

  • Lara Ambrosi
  • Shaheer KhanEmail author
  • Richard D. Carvajal
  • Jessica Yang
Melanoma (RJ Sullivan, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Melanoma


Purpose of Review

In this article, we will briefly review the current treatment landscape for metastatic melanoma and provide a comprehensive update on emerging novel treatment strategies.

Recent Findings

Over the past decade, remarkable advances in immunotherapy and targeted therapy have greatly improved outcomes for patients with advanced melanoma. Although a subset of patients is able to achieve durable responses, the majority experience eventual disease progression on existing therapies. Trials evaluating novel combinatorial strategies, checkpoint inhibitors, immune agonists, T cell–based therapies, intratumoral agents, and others are ongoing.


While strides have been made in the treatment of advanced melanoma, further research is needed to identify alternative immune and molecular targets in order to overcome resistance and achieve better clinical outcomes.


Melanoma Immunotherapy Checkpoint inhibitors CTLA-4 PD-1 PD-L1 Targeted therapy MEK inhibitor BRAF inhibitor Oncolytic therapy 


Compliance with Ethical Standards

Conflict of Interest

Lara Ambrosi declares that she has no conflict of interest.

Shaheer Khan declares that he has no conflict of interest.

Richard D. Carvajal is supported by research funding (paid to his institution) by Bristol-Myers Squibb, Immunocore, Incyte Corporation, Merck, Roche/Genentech, Amgen, Novartis, Pfizer, AstraZeneca, Bellicum Pharmaceuticals, Plexxikon, Mirati Therapeutics, MacroGenics, Corvus Pharmaceuticals, Bayer, Eli Lilly, and Astellas; has received compensation from Bristol-Myers Squibb, Castle Biosciences, Compugen, Foundation Medicine, Immunocore, I-Mab Biopharma, Incyte Corporation, Merck, Roche/Genentech, PureTech Health, Sanofi Genzyme, and Sorrento Therapeutics for service as a consultant; and has received compensation from Aura Biosciences, Chimeron Bio, and Rgenix for participation on clinical/scientific advisory boards.

Jessica Yang declares that she has no conflict of interest.

Human and Animal Rights and Informed Consent

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


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

  1. 1.
    Losina E, Walensky RP, Geller A, Beddingfield FC 3rd, Wolf LL, Gilchrest BA, et al. Visual screening for malignant melanoma: a cost-effectiveness analysis. Arch Dermatol. 2007;143:21–8.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67:7–30.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Gershenwald JE, Scolyer RA, Hess KR, Sondak VK, Long GV, Ross MI, et al. Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67:472–92.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Houghton AN, Polsky D. Focus on melanoma. Cancer Cell. 2002;2:275–8.PubMedGoogle Scholar
  5. 5.
    • Schachter J, Ribas A, Long GV, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet (Lond, Engl). 2017;390:1853–62 This randomized, phase III study demonstrated improved overall survival for pembrolizumab compared to ipilimumab in the treatment of advanced melanoma regardless of dosing schedule. The 24-month overall survival rate was 55% in both the 2-week and 3-week groups and 43% in the ipilimumab group.Google Scholar
  6. 6.
    Long GV, Atkinson V, Ascierto PA, et al. Nivolumab improved survival vs dacarbazine in patients with untreated advanced melanoma. J Transl Med. 2015;13:O6–O.Google Scholar
  7. 7.
    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.PubMedGoogle Scholar
  8. 8.
    • Hodi FS, Chiarion-Sileni V, Gonzalez R, et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19:1480–92 This randomized, double-blind, phase III study demonstrated significant survival benefit with the combination of nivolumab and ipilimumab than either agent alone in patients with advanced melanoma. Three-year survival rates were 58% in the nivolumab plus ipilimumab group, 52% in the nivolumab group, and 34% in the ipilimumab group.Google Scholar
  9. 9.
    Long GV, Atkinson V, Cebon JS. Long-term follow-up of standard-dose pembrolizumab plus reduced-dose ipilimumab in 153 patients with advanced melanoma: KEYNOTE-029 1B. Presented at 2019 Society for Melanoma Research Congress. 2019.Google Scholar
  10. 10.
    Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol. 2015;33:1889–94.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Hodi FS, Kluger H, Sznol M, et al. Abstract CT001: durable, long-term survival in previously treated patients with advanced melanoma (MEL) who received nivolumab (NIVO) monotherapy in a phase I trial. Cancer Res. 2016;76:CT001.Google Scholar
  12. 12.
    Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet (Lond, Engl). 2012;380:358–65.Google Scholar
  13. 13.
    Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–16.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Larkin J, Ascierto PA, Dréno B, Atkinson V, Liszkay G, Maio M, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371:1867–76.PubMedGoogle Scholar
  15. 15.
    • Dummer R, Ascierto PA, Gogas HJ, et al. Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018;19:1315–27 This is the fourth randomized, open-label phase III study demonstrating improved response and survival with combined BRAF and MEK inhibition compared to BRAF inhibition alone. Patients achieved unprecedented survival figures (median PFS 14.9 months and median OS 33.6 months).PubMedGoogle Scholar
  16. 16.
    Larkin J, Ascierto PA, Dreno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371:1867–76.PubMedGoogle Scholar
  17. 17.
    Long GV, Flaherty KT, Stroyakovskiy D, et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Annals Oncol Off J Eur Soc Med Oncol. 2017;28:1631–9.Google Scholar
  18. 18.
    Delord JP, Robert C, Nyakas M, McArthur G, Kudchakar R, Mahipal A, et al. Phase I dose-escalation and -expansion study of the BRAF inhibitor encorafenib (LGX818) in metastatic BRAF-mutant melanoma. Clin Cancer Res. 2017;23:5339–48.PubMedGoogle Scholar
  19. 19.
    • Ascierto PA, Di Giacomo AM, Svane I, et al. 1244OKEYNOTE-022 part 3: phase II randomized study of 1L dabrafenib (D) and trametinib (T) plus pembrolizumab (Pembro) or placebo (PBO) for BRAF-mutant advanced melanoma. Ann Oncol. 2018;29 This randomized, double-blind phase II study demonstrated improved PFS and DoR with the combination of pembrolizumab and BRAF/MEK inhibition. However, this combination was associated with significantly higher serious adverse events (58% vs 27%).Google Scholar
  20. 20.
    Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015;33:2780–8.PubMedGoogle Scholar
  21. 21.
    Harrington KJ, Andtbacka RH, Collichio F, Downey G, Chen L, Szabo Z, et al. Efficacy and safety of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in patients with stage IIIB/C and IVM1a melanoma: subanalysis of the phase III OPTiM trial. Onco Targets Ther. 2016;9:7081–93.PubMedPubMedCentralGoogle Scholar
  22. 22.
    • Chesney J, Puzanov I, Collichio F, et al. Randomized, open-label phase II study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced, unresectable melanoma. J Clin Oncol. 2018;36:1658–67 This randomized, open-label phase II study was the first randomized trial to evaluate the addition of an oncolytic virus to a checkpoint inhibitor with an improved response rate (39% vs 19%) and a higher number of patients achieving responses in visceral lesions (52% vs 23%).PubMedGoogle Scholar
  23. 23.
    Long GV, Dummer R, Ribas 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;34:9568.Google Scholar
  24. 24.
    Gupta S, Weiss A, Kumar G, Wang S, Nel A. The T-cell antigen receptor utilizes Lck, Raf-1, and MEK-1 for activating mitogen-activated protein kinase. Evidence for the existence of a second protein kinase C-dependent pathway in an Lck-negative Jurkat cell mutant. J Biol Chem. 1994;269:17349–57.PubMedGoogle Scholar
  25. 25.
    Boni A, Cogdill AP, Dang P, Udayakumar D, Njauw CN, Sloss CM, et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res. 2010;70:5213–9.PubMedGoogle Scholar
  26. 26.
    Donia M, Fagone P, Nicoletti F, Andersen RS, Høgdall E, Straten PT, et al. BRAF inhibition improves tumor recognition by the immune system: potential implications for combinatorial therapies against melanoma involving adoptive T-cell transfer. Oncoimmunology. 2012;1:1476–83.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Frederick DT, Piris A, Cogdill AP, Cooper ZA, Lezcano C, Ferrone CR, et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res. 2013;19:1225–31.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Ebert PJR, Cheung J, Yang Y, McNamara E, Hong R, Moskalenko M, et al. MAP kinase inhibition promotes T cell and anti-tumor activity in combination with PD-L1 checkpoint blockade. Immunity. 2016;44:609–21.PubMedGoogle Scholar
  29. 29.
    Liu L, Mayes PA, Eastman S, Shi H, Yadavilli S, Zhang T, et al. The BRAF and MEK inhibitors dabrafenib and trametinib: effects on immune function and in combination with immunomodulatory antibodies targeting PD-1, PD-L1, and CTLA-4. Clin Cancer Res. 2015;21:1639–51.PubMedGoogle Scholar
  30. 30.
    Hu-Lieskovan S, Mok S, Homet Moreno B, et al. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma. Sci Transl Med. 2015;7:279ra41.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Loi S, Dushyanthen S, Beavis PA, Salgado R, Denkert C, Savas P, et al. RAS/MAPK activation is associated with reduced tumor-infiltrating lymphocytes in triple-negative breast cancer: therapeutic cooperation between MEK and PD-1/PD-L1 immune checkpoint inhibitors. Clin Cancer Res. 2016;22:1499–509.PubMedGoogle Scholar
  32. 32.
    Miller WH, Kim TM, Lee CB, et al. Atezolizumab (A) + cobimetinib (C) in metastatic melanoma (mel): updated safety and clinical activity. J Clin Oncol. 2017;35:3057.Google Scholar
  33. 33.
    Dummer R, Schadendorf D, Nathan P, et al. Abstract CT182: the anti-PD-1 antibody spartalizumab (PDR001) in combination with dabrafenib and trametinib in previously untreated patients with advanced BRAF V600-mutant melanoma: first efficacy, safety, and biomarker findings from the part 2 biomarker cohort of COMBi-i. Cancer Res. 2018;78:CT182.Google Scholar
  34. 34.
    Blank CU, Rozeman EA, Mallo H, et al. LBA46Phase II study comparing pembrolizumab (PEM) with intermittent/short-term dual MAPK pathway inhibition plus PEM in patients harboring the BRAFV600 mutation (IMPemBra). Ann Oncol. 2018;29.Google Scholar
  35. 35.
    Ascierto PA, Schadendorf D, Berking C, Agarwala SS, van Herpen C, Queirolo P, et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol. 2013;14:249–56.PubMedGoogle Scholar
  36. 36.
    Dummer R, Schadendorf D, Ascierto PA, Arance A, Dutriaux C, di Giacomo AM, et al. Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18:435–45.PubMedGoogle Scholar
  37. 37.
    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.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Carvajal RD, Lawrence DP, Weber JS, Gajewski TF, Gonzalez R, Lutzky J, et al. Phase II study of nilotinib in melanoma harboring KIT alterations following progression to prior KIT inhibition. Clin Cancer Res. 2015;21:2289–96.PubMedPubMedCentralGoogle Scholar
  39. 39.
    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;29:2904–9.PubMedGoogle Scholar
  40. 40.
    Hodi FS, Corless CL, Giobbie-Hurder A, Fletcher JA, Zhu M, Marino-Enriquez A, et al. Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. J Clin Oncol. 2013;31:3182–90.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Balachandran VP, Cavnar MJ, Zeng S, Bamboat ZM, Ocuin LM, Obaid H, et al. Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nat Med. 2011;17:1094–100.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Reilley MJ, Bailey A, Subbiah V, et al. Phase I clinical trial of combination imatinib and ipilimumab in patients with advanced malignancies. J Immunother Cancer. 2017;5:35.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Liu F, Yang X, Geng M, Huang M. Targeting ERK, an Achilles’ heel of the MAPK pathway, in cancer therapy. Acta Pharm Sin B. 2018;8:552–62.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Cragg MS, Jansen ES, Cook M, Harris C, Strasser A, Scott CL. Treatment of B-RAF mutant human tumor cells with a MEK inhibitor requires Bim and is enhanced by a BH3 mimetic. J Clin Invest. 2008;118:3651–9.PubMedPubMedCentralGoogle Scholar
  45. 45.
    He Y, Rivard CJ, Rozeboom L, Yu H, Ellison K, Kowalewski A, et al. Lymphocyte-activation gene-3, an important immune checkpoint in cancer. Cancer Sci. 2016;107:1193–7.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity. 2016;44:989–1004.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Baitsch L, Baumgaertner P, Devevre E, et al. Exhaustion of tumor-specific CD8(+) T cells in metastases from melanoma patients. J Clin Invest. 2011;121:2350–60.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Camisaschi C, Casati C, Rini F, et al. LAG-3 expression defines a subset of CD4(+)CD25(high)Foxp3(+) regulatory T cells that are expanded at tumor sites. J Immunol. 2010;184:6545–51.PubMedGoogle Scholar
  49. 49.
    Taube JM, Young GD, McMiller TL, Chen S, Salas JT, Pritchard TS, et al. Differential expression of immune-regulatory genes associated with PD-L1 display in melanoma: implications for PD-1 pathway blockade. Clin Cancer Res. 2015;21:3969–76.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Perez RP, Riese MJ, Lewis KD, et al. Epacadostat plus nivolumab in patients with advanced solid tumors: preliminary phase I/II results of ECHO-204. J Clin Oncol. 2017;35:3003.Google Scholar
  51. 51.
    Ascierto PA, Melero I, Bhatia S, 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. J Clin Oncol. 2017;35:9520.Google Scholar
  52. 52.
    Andrews LP, Marciscano AE, Drake CG, Vignali DAA. LAG3 (CD223) as a cancer immunotherapy target. Immunol Rev. 2017;276:80–96.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T, et al. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature. 2002;415:536–41.Google Scholar
  54. 54.
    Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher IF, Sander C, et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med. 2010;207:2175–86.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Sakuishi K, Ngiow SF, Sullivan JM, et al. TIM3(+)FOXP3(+) regulatory T cells are tissue-specific promoters of T-cell dysfunction in cancer. Oncoimmunology. 2013;2:e23849.PubMedPubMedCentralGoogle Scholar
  56. 56.
    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;6:1245–52.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Chauvin JM, Pagliano O, Fourcade J, Sun Z, Wang H, Sander C, et al. TIGIT and PD-1 impair tumor antigen-specific CD8(+) T cells in melanoma patients. J Clin Invest. 2015;125:2046–58.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Johnston RJ, Yu X, Grogan JL. The checkpoint inhibitor TIGIT limits antitumor and antiviral CD8(+) T cell responses. Oncoimmunology. 2015;4:e1036214.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Stamm H, Wellbrock J, Fiedler W. Interaction of PVR/PVRL2 with TIGIT/DNAM-1 as a novel immune checkpoint axis and therapeutic target in cancer. Mamm Genome Off J Int Mamm Genome Soc. 2018;29:694–702.Google Scholar
  60. 60.
    Liang S, Levy O, Ganguly S, et al. Discovery of COM701, a therapeutic antibody targeting the novel immune checkpoint PVRIG, for the treatment of cancer. J Clin Oncol. 2017;35:3074.Google Scholar
  61. 61.
    Lines JL, Pantazi E, Mak J, Sempere LF, Wang L, O'Connell S, et al. VISTA is an immune checkpoint molecule for human T cells. Cancer Res. 2014;74:1924–32.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Le Mercier I, Chen W, Lines JL, et al. VISTA regulates the development of protective antitumor immunity. Cancer Res. 2014;74:1933–44.PubMedGoogle Scholar
  63. 63.
    Marin-Acevedo JA, Dholaria B, Soyano AE, Knutson KL, Chumsri S, Lou Y. Next generation of immune checkpoint therapy in cancer: new developments and challenges. J Hematol Oncol. 2018;11:39.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Takeda K, Kojima Y, Uno T, et al. Combination therapy of established tumors by antibodies targeting immune activating and suppressing molecules. J Immunol. 2010;184:5493–501.PubMedGoogle Scholar
  65. 65.
    Tolcher AW, Sznol M, Hu-Lieskovan S, Papadopoulos KP, Patnaik A, Rasco DW, et al. Phase Ib study of utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in combination with pembrolizumab (MK-3475) in patients with advanced solid tumors. Clin Cancer Res. 2017;23:5349–57.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Sznol M, Hodi FS, Margolin K, et al. Phase I study of BMS-663513, a fully human anti-CD137 agonist monoclonal antibody, in patients (pts) with advanced cancer (CA). J Clin Oncol. 2008;26:3007.Google Scholar
  67. 67.
    Segal NH, Logan TF, Hodi FS, McDermott D, Melero I, Hamid O, et al. Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody. Clin Cancer Res. 2017;23:1929–36.PubMedGoogle Scholar
  68. 68.
    Post A. SITC 2016: phase I/II data combining urelumab with nivolumab suggest increased antitumor effect in patients with melanoma. 2016.Google Scholar
  69. 69.
    Jackaman C, Cornwall S, Graham PT, Nelson DJ. CD40-activated B cells contribute to mesothelioma tumor regression. Immunol Cell Biol. 2011;89:255–67.PubMedGoogle Scholar
  70. 70.
    Rakhmilevich AL, Alderson KL, Sondel PM. T-cell-independent antitumor effects of CD40 ligation. Int Rev Immunol. 2012;31:267–78.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Vonderheide RH, Glennie MJ. Agonistic CD40 antibodies and cancer therapy. Clin Cancer Res. 2013;19:1035–43.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Bajor DL, Mick R, Riese MJ, et al. Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma. Oncoimmunology. 2018;7:e1468956–e.Google Scholar
  73. 73.
    Phase Ib/II clinical trial of CD40 agonistic antibody APX005M in combination with nivolumab (nivo) in subjects with metastatic melanoma (M) or non-small cell lung cancer (NSCLC). Abstract #CT089, AACR 2019 Annual Meeting. 2019.Google Scholar
  74. 74.
    Knee DA, Hewes B, Brogdon JL. Rationale for anti-GITR cancer immunotherapy. Eur J Cancer. 2016;67:1–10.Google Scholar
  75. 75.
    Dempke WCM, Fenchel K, Uciechowski P, Dale SP. Second- and third-generation drugs for immuno-oncology treatment—the more the better? Eur J Cancer. 2017;74:55–72.PubMedGoogle Scholar
  76. 76.
    Willoughby J, Griffiths J, Tews I, Cragg MS. OX40: structure and function—what questions remain? Mol Immunol. 2017;83:13–22.PubMedGoogle Scholar
  77. 77.
    Aspeslagh S, Postel-Vinay S, Rusakiewicz S, Soria JC, Zitvogel L, Marabelle A. Rationale for anti-OX40 cancer immunotherapy. Eur J Cancer. 2016;52:50–66.PubMedGoogle Scholar
  78. 78.
    Ladanyi A, Somlai B, Gilde K, Fejos Z, Gaudi I, Timar J. T-cell activation marker expression on tumor-infiltrating lymphocytes as prognostic factor in cutaneous malignant melanoma. Clin Cancer Res. 2004;10:521–30.PubMedGoogle Scholar
  79. 79.
    Curti BD, Kovacsovics-Bankowski M, Morris N, Walker E, Chisholm L, Floyd K, et al. OX40 is a potent immune-stimulating target in late-stage cancer patients. Cancer Res. 2013;73:7189–98.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Kroemer A, Xiao X, Vu MD, Gao W, Minamimura K, Chen M, et al. OX40 controls functionally different T cell subsets and their resistance to depletion therapy. J Immunol. 2007;179:5584–91.PubMedGoogle Scholar
  81. 81.
    Buchan SL, Rogel A, Al-Shamkhani A. The immunobiology of CD27 and OX40 and their potential as targets for cancer immunotherapy. Blood. 2018;131:39–48.PubMedGoogle Scholar
  82. 82.
    Roberts DJ, Franklin NA, Kingeter LM, et al. Control of established melanoma by CD27 stimulation is associated with enhanced effector function and persistence, and reduced PD-1 expression of tumor infiltrating CD8(+) T cells. J Immunother (Hagerstown, Md: 1997). 2010;33:769–79.Google Scholar
  83. 83.
    Keller AM, Schildknecht A, Xiao Y, van den Broek M, Borst J. Expression of costimulatory ligand CD70 on steady-state dendritic cells breaks CD8+ T cell tolerance and permits effective immunity. Immunity. 2008;29:934–46.PubMedGoogle Scholar
  84. 84.
    Burris HA, Infante JR, Ansell SM, Nemunaitis JJ, Weiss GR, Villalobos VM, et al. Safety and activity of varlilumab, a novel and first-in-class agonist anti-CD27 antibody, in patients with advanced solid tumors. J Clin Oncol. 2017;35:2028–36.PubMedGoogle Scholar
  85. 85.
    Lu H. TLR agonists for cancer immunotherapy: tipping the balance between the immune stimulatory and inhibitory effects. Front Immunol. 2014;5:83.PubMedPubMedCentralGoogle Scholar
  86. 86.
    Krieg AM. Development of TLR9 agonists for cancer therapy. J Clin Invest. 2007;117:1184–94.PubMedPubMedCentralGoogle Scholar
  87. 87.
    Uemura MI, Haymaker CL, Murthy R, et al. Intratumoral (i.t.) IMO-2125 (IMO), a TLR9 agonist, in combination with ipilimumab (ipi) in PD-(L)1 refractory melanoma (RM). J Clin Oncol. 2017;35:136.Google Scholar
  88. 88.
    Diab A, Rahimian S, Haymaker CL, et al. A phase 2 study to evaluate the safety and efficacy of intratumoral (IT) injection of the TLR9 agonist IMO-2125 (IMO) in combination with ipilimumab (ipi) in PD-1 inhibitor refractory melanoma. J Clin Oncol. 2018;36:9515.Google Scholar
  89. 89.
    Thompson JF, Hersey P, Wachter E. Chemoablation of metastatic melanoma using intralesional rose bengal. Melanoma Res. 2008;18:405–11.PubMedGoogle Scholar
  90. 90.
    Thompson JF, Agarwala SS, Smithers BM, Ross MI, Scoggins CR, Coventry BJ, et al. Phase 2 study of intralesional PV-10 in refractory metastatic melanoma. Ann Surg Oncol. 2015;22:2135–42.PubMedGoogle Scholar
  91. 91.
    Immunotherapy Bridge 2018 and Melanoma Bridge 2018: meeting abstracts. J Transl Med 2019;17:1-18.Google Scholar
  92. 92.
    Atkins MB, Robertson MJ, Gordon M, Lotze MT, DeCoste M, DuBois J, et al. Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies. Clin Cancer Res. 1997;3:409–17.PubMedGoogle Scholar
  93. 93.
    Daud AI, DeConti RC, Andrews S, Urbas P, Riker AI, Sondak VK, et al. Phase I trial of interleukin-12 plasmid electroporation in patients with metastatic melanoma. J Clin Oncol. 2008;26:5896–903.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Daud A, Algazi AP, Ashworth MT, et al. Systemic antitumor effect and clinical response in a phase 2 trial of intratumoral electroporation of plasmid interleukin-12 in patients with advanced melanoma. J Clin Oncol. 2014;32:9025.Google Scholar
  95. 95.
    Algazi AP, Tsai KK, Rosenblum M, et al. Immune monitoring outcomes of patients with stage III/IV melanoma treated with a combination of pembrolizumab and intratumoral plasmid interleukin 12 (pIL-12). J Clin Oncol. 2017;35:78.Google Scholar
  96. 96.
    Corrales L, Woo S-R, Gajewski TF. Extremely potent immunotherapeutic activity of a STING agonist in the B16 melanoma model in vivo. J Immunother Cancer. 2013;1:O15.PubMedCentralGoogle Scholar
  97. 97.
    Balkwill FR, Capasso M, Hagemann T. The tumor microenvironment at a glance. J Cell Sci. 2012;125:5591–6.PubMedGoogle Scholar
  98. 98.
    Mellor AL, Keskin DB, Johnson T, Chandler P, Munn DH. Cells expressing indoleamine 2,3-dioxygenase inhibit T cell responses. J Immunol. 2002;168:3771–6.PubMedGoogle Scholar
  99. 99.
    Holmgaard RB, Zamarin D, Li Y, Gasmi B, Munn DH, Allison JP, et al. Tumor-expressed IDO recruits and activates MDSCs in a Treg-dependent manner. Cell Rep. 2015;13:412–24.PubMedPubMedCentralGoogle Scholar
  100. 100.
    Chevolet I, Speeckaert R, Schreuer M, et al. Characterization of the in vivo immune network of IDO, tryptophan metabolism, PD-L1, and CTLA-4 in circulating immune cells in melanoma. Oncoimmunology. 2015;4:e982382.PubMedPubMedCentralGoogle Scholar
  101. 101.
    Beatty GL, O’Dwyer PJ, Clark J, et al. First-in-human phase I study of the oral inhibitor of indoleamine 2,3-dioxygenase-1 epacadostat (INCB024360) in patients with advanced solid malignancies. Clin Cancer Res. 2017;23:3269–76.PubMedPubMedCentralGoogle Scholar
  102. 102.
    Gibney G, Hamid O, Lutzky J, et al. 511 Updated results from a phase 1/2 study of epacadostat (INCB024360) in combination with ipilimumab in patients with metastatic melanoma. Eur J Cancer. 2015;51:S106–S7.Google Scholar
  103. 103.
    Hamid O, Gajewski T, Frankel A. Epacadostat plus pembrolizumab in patients with advanced melanoma: phase 1 and 2 efficacy and safety results from ECHO-202/KEYNOTE-037. In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract 1214O.Google Scholar
  104. 104.
    Long GV, Dummer R, Hamid O, et al. Epacadostat (E) plus pembrolizumab (P) versus pembrolizumab alone in patients (pts) with unresectable or metastatic melanoma: results of the phase 3 ECHO-301/KEYNOTE-252 study. 2018;36:108.Google Scholar
  105. 105.
    Zakharia Y, Rixe O, Ward JH, et al. Phase 2 trial of the IDO pathway inhibitor indoximod plus checkpoint inhibition for the treatment of patients with advanced melanoma. J Clin Oncol. 2018;36:9512.Google Scholar
  106. 106.
    Allard B, Longhi MS, Robson SC, Stagg J. The ectonucleotidases CD39 and CD73: novel checkpoint inhibitor targets. Immunol Rev. 2017;276:121–44.PubMedPubMedCentralGoogle Scholar
  107. 107.
    Antonioli L, Pacher P, Vizi ES, Haskó G. CD39 and CD73 in immunity and inflammation. Trends Mol Med. 2013;19:355–67.PubMedPubMedCentralGoogle Scholar
  108. 108.
    Sadej R, Spychala J, Skladanowski AC. Expression of ecto-5′-nucleotidase (eN, CD73) in cell lines from various stages of human melanoma. Melanoma Res. 2006;16:213–22.PubMedGoogle Scholar
  109. 109.
    Monteiro I, Vigano S, Faouzi M, et al. CD73 expression and clinical significance in human metastatic melanoma. Oncotarget. 2018;9:26659–69.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Terp MG, Olesen KA, Arnspang EC, et al. Anti-human CD73 monoclonal antibody inhibits metastasis formation in human breast cancer by inducing clustering and internalization of CD73 expressed on the surface of cancer cells. J Immunol. 2013;191:4165–73.PubMedGoogle Scholar
  111. 111.
    Sun X, Han L, Seth P, Bian S, Li L, Csizmadia E, et al. Disordered purinergic signaling and abnormal cellular metabolism are associated with development of liver cancer in Cd39/ENTPD1 null mice. Hepatology. 2013;57:205–16.PubMedPubMedCentralGoogle Scholar
  112. 112.
    Siu LL, Burris H, Le DT, et al. Abstract CT180: preliminary phase 1 profile of BMS-986179, an anti-CD73 antibody, in combination with nivolumab in patients with advanced solid tumors. Cancer Res. 2018;78:CT180.Google Scholar
  113. 113.
    Allard D, Turcotte M, Stagg J. Targeting A2 adenosine receptors in cancer. Immunol Cell Biol. 2017;95:333–9.PubMedGoogle Scholar
  114. 114.
    Leone RD, Emens LA. Targeting adenosine for cancer immunotherapy. J Immunother Cancer. 2018;6:57.PubMedPubMedCentralGoogle Scholar
  115. 115.
    Fong L, Forde PM, Powderly JD, et al. Safety and clinical activity of adenosine A2a receptor (A2aR) antagonist, CPI-444, in anti-PD1/PDL1 treatment-refractory renal cell (RCC) and non-small cell lung cancer (NSCLC) patients. J Clin Oncol. 2017;35:3004.Google Scholar
  116. 116.
    Neubert NJ, Schmittnaegel M, Bordry N, et al. T cell-induced CSF1 promotes melanoma resistance to PD1 blockade. Sci Transl Med. 2018;10.PubMedPubMedCentralGoogle Scholar
  117. 117.
    Calvo A, Joensuu H, Sebastian M, et al. Phase Ib/II study of lacnotuzumab (MCS110) combined with spartalizumab (PDR001) in patients (pts) with advanced tumors. J Clin Oncol. 2018;36:3014.Google Scholar
  118. 118.
    Schoumacher M, Burbridge M. Key roles of AXL and MER receptor tyrosine kinases in resistance to multiple anticancer therapies. Curr Oncol Rep. 2017;19:19.PubMedPubMedCentralGoogle Scholar
  119. 119.
    Corno C, Gatti L, Lanzi C, Zaffaroni N, Colombo D, Perego P. Role of the receptor tyrosine kinase Axl and its targeting in cancer cells. Curr Med Chem. 2016;23:1496–512.PubMedGoogle Scholar
  120. 120.
    Matsui J, Funahashi Y, Uenaka T, Watanabe T, Tsuruoka A, Asada M. Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin Cancer Res. 2008;14:5459–65.PubMedGoogle Scholar
  121. 121.
    Matsui J, Yamamoto Y, Funahashi Y, Tsuruoka A, Watanabe T, Wakabayashi T, et al. E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition. Int J Cancer. 2008;122:664–71.PubMedGoogle Scholar
  122. 122.
    Boss DS, Glen H, Beijnen JH, Keesen M, Morrison R, Tait B, et al. A phase I study of E7080, a multitargeted tyrosine kinase inhibitor, in patients with advanced solid tumours. Br J Cancer. 2012;106:1598–604.PubMedPubMedCentralGoogle Scholar
  123. 123.
    Hong DS, Kurzrock R, Wheler JJ, Naing A, Falchook GS, Fu S, et al. Phase I dose-escalation study of the multikinase inhibitor lenvatinib in patients with advanced solid tumors and in an expanded cohort of patients with melanoma. Clin Cancer Res. 2015;21:4801–10.PubMedPubMedCentralGoogle Scholar
  124. 124.
    Hutson TE, Lesovoy V, Al-Shukri S, et al. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncol. 2013;14:1287–94.PubMedGoogle Scholar
  125. 125.
    Fruehauf J, Lutzky J, McDermott D, Brown CK, Meric JB, Rosbrook B, et al. Multicenter, phase II study of axitinib, a selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, in patients with metastatic melanoma. Clin Cancer Res. 2011;17:7462–9.PubMedGoogle Scholar
  126. 126.
    Algazi AP, Cha E, Ortiz-Urda SM, et al. The combination of axitinib followed by paclitaxel/carboplatin yields extended survival in advanced BRAF wild-type melanoma: results of a clinical/correlative prospective phase II clinical trial. Br J Cancer. 2015;112:1326–31.PubMedPubMedCentralGoogle Scholar
  127. 127.
    Guo J, Sheng X, Si L, et al. A phase Ib study of JS001, a humanized IgG4 mAb against programmed death-1 (PD-1) combination with axitinib in patients with metastatic mucosal melanoma. J Clin Oncol. 2018;36:9528.Google Scholar
  128. 128.
    Minucci S, Pelicci PG. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer. 2006;6:38–51.PubMedGoogle Scholar
  129. 129.
    Zhu P, Martin E, Mengwasser J, Schlag P, Janssen KP, Gottlicher M. Induction of HDAC2 expression upon loss of APC in colorectal tumorigenesis. Cancer Cell. 2004;5:455–63.PubMedGoogle Scholar
  130. 130.
    Kwon SH, Ahn SH, Kim YK, Bae GU, Yoon JW, Hong S, et al. Apicidin, a histone deacetylase inhibitor, induces apoptosis and Fas/Fas ligand expression in human acute promyelocytic leukemia cells. J Biol Chem. 2002;277:2073–80.PubMedGoogle Scholar
  131. 131.
    Sullivan RJ, Moschos SJ, Johnson ML. Efficacy and safety of entinostat (ENT) and pembrolizumab (PEMBRO) in patients with melanoma previously treated with anti-PD1 therapy. Abstract #CT072, AACR Annual Meeting 2019; 2019.Google Scholar
  132. 132.
    Hagner PR, Man HW, Fontanillo C, Wang M, Couto S, Breider M, et al. CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL. Blood. 2015;126:779–89.PubMedPubMedCentralGoogle Scholar
  133. 133.
    Grossmann V, Schnittger S, Kohlmann A, Eder C, Roller A, Dicker F, et al. A novel hierarchical prognostic model of AML solely based on molecular mutations. Blood. 2012;120:2963–72.PubMedGoogle Scholar
  134. 134.
    Rasco DW, Papadopoulos KP, Pourdehnad M, Gandhi AK, Hagner PR, Li Y, et al. A first-in-human study of novel cereblon modulator avadomide (CC-122) in advanced malignancies. Clin Cancer Res. 2019;25:90–8.PubMedGoogle Scholar
  135. 135.
    Bose N, Ottoson N, Harrison B, et al. Effect of Imprime PGG on innate immune-activating pharmacodynamic changes in a phase I clinical study in healthy human volunteers. J Clin Oncol. 2017;35:33.Google Scholar
  136. 136.
    Zent CS, Call TG, Bowen DA, Conte MJ, LaPlant B, Witzig TE, et al. Early treatment of high risk chronic lymphocytic leukemia with alemtuzumab, rituximab and poly-(1-6)-beta-glucotriosyl-(1-3)- beta-glucopyranose beta-glucan is well tolerated and achieves high complete remission rates. Leuk Lymphoma. 2015;56:2373–8.PubMedPubMedCentralGoogle Scholar
  137. 137.
    Huhn RD, Lowe J, Grady MM, Taitt CC, Braun AH. A phase 3 open-label, randomized, multicenter study of Imprime PGG in combination with cetuximab in patients with KRAS wild type metastatic colorectal cancer. J Clin Oncol. 2015;33:TPS3635–TPS.Google Scholar
  138. 138.
    Uhlik MT, Harrison B, Gorden K, et al. Abstract LB-129: Imprime PGG, a soluble yeast β-glucan PAMP, in combination with pembrolizumab induces infiltration and activation of both innate and adaptive immune cells within tumor sites in melanoma and triple-negative breast cancer (TNBC) patients. Cancer Res. 2018;78:LB–129–LB.Google Scholar
  139. 139.
    Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000;6(Suppl 1):S11–4.PubMedGoogle Scholar
  140. 140.
    Diab A, Tannir N, Cho D, et al. Pivot-02: preliminary safety, efficacy and biomarker results from dose escalation of the phase 1/2 study of CD-122-biased agonist NKTR-214 plus nivolumab in patients with locally advanced/metastatic melanoma, renal cell carcinoma and non-small cell lung cancer. J Immunother Cancer. 2017;5:O20.Google Scholar
  141. 141.
    Davar D, Wang H, Chauvin JM, et al. Phase Ib/II study of pembrolizumab and pegylated-interferon Alfa-2b in advanced melanoma. J Clin Oncol. 2018;JCO1800632.Google Scholar
  142. 142.
    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;17:4550–7.PubMedPubMedCentralGoogle Scholar
  143. 143.
    Rosenberg SA, Packard BS, Aebersold PM, Solomon D, Topalian SL, Toy ST, et al. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med. 1988;319:1676–80.PubMedGoogle Scholar
  144. 144.
    Rosenberg SA, Yannelli JR, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, et al. Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2. J Natl Cancer Inst. 1994;86:1159–66.PubMedGoogle Scholar
  145. 145.
    Deniger DC, Kwong ML, Pasetto A, et al. A pilot trial of the combination of vemurafenib with adoptive cell therapy in patients with metastatic melanoma. Clin Cancer Res. 2017;23:351–62.PubMedGoogle Scholar
  146. 146.
    Mullinax JE, Hall M, Prabhakaran S, et al. Combination of ipilimumab and adoptive cell therapy with tumor-infiltrating lymphocytes for patients with metastatic melanoma. Front Oncol. 2018;8:44.PubMedPubMedCentralGoogle Scholar
  147. 147.
    Bossi G, Buisson S, Oates J, Jakobsen BK, Hassan NJ. ImmTAC-redirected tumour cell killing induces and potentiates antigen cross-presentation by dendritic cells. Cancer Immunol Immunother. 2014;63:437–48.PubMedGoogle Scholar
  148. 148.
    Middleton MR, Steven NM, Evans TJ, et al. Safety, pharmacokinetics and efficacy of IMCgp100, a first-in-class soluble TCR-antiCD3 bispecific t cell redirector with solid tumour activity: results from the FIH study in melanoma. J Clin Oncol. 2016;34:3016.Google Scholar
  149. 149.
    Sato T, Nathan PD, Hernandez-Aya LF, et al. Intra-patient escalation dosing strategy with IMCgp100 results in mitigation of T-cell based toxicity and preliminary efficacy in advanced uveal melanoma. J Clin Oncol. 2017;35:9531.Google Scholar
  150. 150.
    Lu YC, Parker LL, Lu T, Zheng Z, Toomey MA, White DE, et al. Treatment of patients with metastatic cancer using a major histocompatibility complex class II-restricted T-cell receptor targeting the cancer germline antigen MAGE-A3. J Clin Oncol. 2017;35:3322–9.PubMedPubMedCentralGoogle Scholar
  151. 151.
    Ott PA, Hu Z, Keskin DB, Shukla SA, Sun J, Bozym DJ, et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature. 2017;547:217–21.PubMedPubMedCentralGoogle Scholar
  152. 152.
    Saxena M, Bhardwaj N. Re-emergence of dendritic cell vaccines for cancer treatment. Trends in Cancer. 2018;4:119–37.PubMedPubMedCentralGoogle Scholar
  153. 153.
    Schreibelt G, Bol KF, Westdorp H, Wimmers F, Aarntzen EH, Duiveman-de Boer T, et al. Effective clinical responses in metastatic melanoma patients after vaccination with primary myeloid dendritic cells. Clin Cancer Res. 2016;22:2155–66.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Lara Ambrosi
    • 1
  • Shaheer Khan
    • 2
    Email author
  • Richard D. Carvajal
    • 2
  • Jessica Yang
    • 2
  1. 1.Stony Brook SOMStony BrookUSA
  2. 2.Division of Hematology/OncologyColumbia University Medical CenterNew YorkUSA

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