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Rational combination of cancer immunotherapy in melanoma

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Abstract

The recent advances in cancer immunotherapy with unprecedented success in therapy of advanced melanoma represent a turning point in the landscape of melanoma treatment. Given the complexity of activation of immunological system and the physiologic multifactorial homeostatic mechanisms controlling immune responses, combinatorial strategies are eagerly needed in melanoma therapy. Nevertheless, rational selection of immunotherapy combinations should be more biomarker-guided, including not only the cancer immunogram, PD-L1 expression, interferon gene expression signature, mutational burden, and tumor infiltration by CD8+ T cells but also intratumoral T cell exhaustion and microbiota composition. In this review, we summarize the rationale to develop combination treatment strategies in melanoma and discuss biological background that could help to design new combinations in order to improve patients’ outcome.

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References

  1. Luke JJ, Flaherty KT, Ribas A, Long GV (2017) Targeted agents and immunotherapies: optimizing outcomes in melanoma. Nat Rev Clin Oncol 14:463–482

    CAS  PubMed  Google Scholar 

  2. Mandalà, M., Tondini, C., Merelli, B and Daniela Massi. Rationale for new checkpoint inhibitor combinations in melanoma. Am J Clin Dermatol 2017; 18: 597–611

  3. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JWC, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954

    CAS  PubMed  Google Scholar 

  4. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH Jr, Kaempgen E, Martín-Algarra S, Karaszewska B, Mauch C, Chiarion-Sileni V, Martin AM, Swann S, Haney P, Mirakhur B, Guckert ME, Goodman V, Chapman PB (2012) Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380:358–365

    CAS  PubMed  Google Scholar 

  5. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O’Day SJ, Sosman JA, Kirkwood JM, Eggermont AMM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364:2507–2516

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ, Chiarion-Sileni V, Lebbe C, Mandalà M, Millward M, Arance A, Bondarenko I, Haanen JBAG, Hansson J, Utikal J, Ferraresi V, Kovalenko N, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, DeMarini DJ, Irani JG, Swann S, Legos JJ, Jin F, Mookerjee B, Flaherty K (2015) Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet 386:444–451

    CAS  PubMed  Google Scholar 

  7. Ascierto PA, McArthur GA, Dréno B, Atkinson V, Liszkay G, Di Giacomo AM et al (2016) Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 17:1248–1260

    CAS  PubMed  Google Scholar 

  8. Trunzer K, Pavlick AC, Schuchter L et al (2013) Pharmacodynamic effects and mechanisms of resistance to vemurafenib in patients with metastatic melanoma. J Clin Oncol 31:1767–1774

    CAS  PubMed  Google Scholar 

  9. Villanueva J, Vultur A, Lee JT, Somasundaram R, Fukunaga-Kalabis M, Cipolla AK, Wubbenhorst B, Xu X, Gimotty PA, Kee D, Santiago-Walker AE, Letrero R, D’Andrea K, Pushparajan A, Hayden JE, Brown KD, Laquerre S, McArthur GA, Sosman JA, Nathanson KL, Herlyn M (2010) Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell 18:683–695

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Lito P, Rosen N, Solit DB (2013) Tumor adaptation and resistance to RAF inhibitors. Nat Med 19:1401–1409

    CAS  PubMed  Google Scholar 

  11. Long GV, Grob JJ, Nathan P, Ribas A, Robert C, Schadendorf D, Lane SR, Mak C, Legenne P, Flaherty KT, Davies MA (2016) Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: a pooled analysis of individual patient data from randomised trials. Lancet Oncol 17(12):1743–1754

    CAS  PubMed  Google Scholar 

  12. Schadendorf D, Long GV, Stroiakovski D, Karaszewska B, Hauschild A, Levchenko E, Chiarion-Sileni V, Schachter J, Garbe C, Dutriaux C, Gogas H, Mandalà M, Haanen JBAG, Lebbé C, Mackiewicz A, Rutkowski P, Grob JJ, Nathan P, Ribas A, Davies MA, Zhang Y, Kaper M, Mookerjee B, Legos JJ, Flaherty KT, Robert C (2017) Three-year pooled analysis of factors associated with clinical outcomes across dabrafenib and trametinib combination therapy phase 3 randomised trials. Eur J Cancer 82:45–55

    CAS  PubMed  Google Scholar 

  13. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L et al (2015) Pembrolizumab vs ipilimumab in advanced melanoma. N Engl J Med 372:2521–2532

    CAS  PubMed  Google Scholar 

  14. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O et al (2015) Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 17:1889–1894

    Google Scholar 

  16. Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H et al (2016) Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med 375:1845–1855

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL et al (2017) Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 377:1824–1835

    CAS  PubMed  Google Scholar 

  18. Eggermont AMM, Blank CU, Mandala M (2018) Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med 378:1789–1801

    CAS  PubMed  Google Scholar 

  19. Caroline Robert, Antoni Ribas, Omid Hamid, et al. Durable complete response after discontinuation of pembrolizumab in patients with metastatic melanoma J Clin Oncol https://doi.org/10.1200/JCO.2017.75.6270, 2018

  20. Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao CD, Wagstaff J, Schadendorf D, Ferrucci PF, Smylie M, Dummer R, Hill A, Hogg D, Haanen J, Carlino MS, Bechter O, Maio M, Marquez-Rodas I, Guidoboni M, McArthur G, Lebbé C, Ascierto PA, Long GV, Cebon J, Sosman J, Postow MA, Callahan MK, Walker D, Rollin L, Bhore R, Hodi FS, Larkin J (2017) Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 377:1345–1356

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Lebbé C, Meyer N, Mortier L, Marquez-Rodas I, Robert C, Rutkowski P (2018) Initial results from a phase IIIb/IV study evaluating two dosing regimens of nivolumab (NIVO) in combination with ipilimumab (IPI) in patients with advanced melanoma (CheckMate 511) LBA47 abstract. Ann Oncol (suppl_8)

  22. O’Donnell JS, Long GV, Scolyer RA, Teng MW, Smyth MJ (2017) Resistance to PD1/PDL1 checkpoint inhibition. Cancer Treat Rev 52:71–81

    PubMed  Google Scholar 

  23. Chowdhury PS, Chamoto K, Honjo T (2018) Combination therapy strategies for improving PD-1 blockade efficacy: a new era in cancer immunotherapy. J Intern Med 283(2):110–120

    CAS  PubMed  Google Scholar 

  24. Thommen DS, Schreiner J, Muller P, Herzig P, Roller A, Belousov A, Umana P, Pisa P, Klein C, Bacac M, Fischer OS, Moersig W, Savic Prince S, Levitsky V, Karanikas V, Lardinois D, Zippelius A (2015) (2015) progression of lung cancer is associated with increased dysfunction of T cells defined by coexpression of multiple inhibitory receptors. Cancer Immunol Res 3:1344–1355

    CAS  PubMed  Google Scholar 

  25. Zappasodi R, Merghoub T, Wolchok JD (2018) Emerging concepts for immune checkpoint blockade-based combination therapies. Cancer Cell 33:581–598

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Patel SA, Minn AJ (2018) Combination cancer therapy with immune checkpoint blockade: mechanisms and strategies. Immunity 48(3):417–433

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Sakuishi K, Apetoh L, Sullivan J.M., Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med 2010; 207: 2187–2194

  28. Ascierto P, Melero I, Bhatia S et al (2017) 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 35(suppl):9520–9520

    Google Scholar 

  29. Koyama S, Akbay EA, Li YY et al (2016) Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun 7:10501

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Liu J, Yuan Y, Chen W, Putra J, Suriawinata AA, Schenk AD, Miller HE, Guleria I, Barth RJ, Huang YH, Wang L (2015) Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses. Proc Natl Acad Sci U S A 112:6682–6687

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Wang L, Rubinstein R, Lines JL, Wasiuk A, Ahonen C, Guo Y, Lu LF, Gondek D, Wang Y, Fava RA, Fiser A, Almo S, Noelle RJ (2011) VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses. J Exp Med 208:577–592

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Wolchok JD, Saenger Y (2008) The mechanism of anti-CTLA-4 activity and the negative regulation of T-cell activation. Oncologist 13(suppl):2–9

    CAS  PubMed  Google Scholar 

  33. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, Linsley PS, Thompson CB, Riley JL (2005) CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 25:9543–9553

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Woo SR, Turnis ME, Goldberg MV, Bankoti J, Selby M, Nirschl CJ, Bettini ML, Gravano DM, Vogel P, Liu CL, Tangsombatvisit S, Grosso JF, Netto G, Smeltzer MP, Chaux A, Utz PJ, Workman CJ, Pardoll DM, Korman AJ, Drake CG, Vignali DAA (2012) Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res 72:917–927

    CAS  PubMed  Google Scholar 

  35. Nguyen LT, Ohashi PS (2015) Clinical blockade of PD1 and LAG3 potential mechanisms of action. Nat Rev Immunol 15:45–56

    CAS  PubMed  Google Scholar 

  36. Sanmamed MF, Pastor F, Rodriguez A, Perez-Gracia JL, Rodriguez-Ruiz ME, Jure-Kunkel M, Melero I (2015) Agonists of co-stimulation in cancer immunotherapy directed against CD137, OX40, GITR, CD27, CD28, and ICOS. Semin Oncol 42:640–655

    CAS  PubMed  Google Scholar 

  37. Bulliard Y, Jolicoeur R, Zhang J, Dranoff G, Wilson NS, Brogdon JL (2014) OX40 engagement depletes intratumoral Tregs via activating FcgammaRs, leading to antitumor efficacy. Immunol Cell Biol 92:475–480

    CAS  PubMed  Google Scholar 

  38. Guo Z, Wang X, Cheng D, Xia Z, Luan M, Zhang S (2014) PD-1 blockade and OX40 triggering synergistically protects against tumor growth in a murine model of ovarian cancer. PLoS One 9:e89350

    PubMed  PubMed Central  Google Scholar 

  39. Infante JR, Hansen AR, Pishvaian MJ et al (2016) A phase Ib dose escalation study of the OX40 agonist MOXR0916 and the PD-L1 inhibitor atezolizumab in patients with advanced solid tumors. J Clin Oncol 34:101

    Google Scholar 

  40. El-Khoueiry AB, Hamid O, Thompson JA et al (2017) The relationship of pharmacodynamics (PD) and pharmacokinetics (PK) to clinical outcomes in a phase I study of OX40 agonistic monoclonal antibody (mAb) PF- 04518600 (PF 8600). J Clin Oncol 35:3027

    Google Scholar 

  41. Bauer TM, Chae YK, Patel S et al (2015) A phase I study of MEDI6383, an OX40 agonist, in adult patients with select advanced solid tumors. J Clin Oncol 33:TPS3093

    Google Scholar 

  42. Siu LL, Steeghs N, Meniawy T, 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 patients with advanced solid tumors. 2017 ASCO Annual Meeting. Abstract 104

  43. Sanchez-Paulete AR, Cueto FJ, Martinez-Lopez M, Labiano S, Morales-Kastresana A, Rodriguez-Ruiz ME, Jure-Kunkel M, Azpilikueta A, Aznar MA, Quetglas JI, Sancho D, Melero I (2016) Cancer immunotherapy with immunomodulatory anti-CD137 and anti-PD-1 monoclonal antibodies requires BATF3-dependent dendritic cells. Cancer Discov 6:71–79

    CAS  PubMed  Google Scholar 

  44. Segal NH, Logan TF, Hodi FS, McDermott D, Melero I, Hamid O, Schmidt H, Robert C, Chiarion-Sileni V, Ascierto PA, Maio M, Urba WJ, Gangadhar TC, Suryawanshi S, Neely J, Jure-Kunkel M, Krishnan S, Kohrt H, Sznol M, Levy R (2017) Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody. Clin Cancer Res 23:1929–1936

    CAS  PubMed  Google Scholar 

  45. Tolcher AW, Sznol M, Hu-Lieskovan S, Papadopoulos KP, Patnaik A, Rasco DW, di Gravio D, Huang B, Gambhire D, Chen Y, Thall AD, Pathan N, Schmidt EV, Chow LQM (2017) 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 23:5349–5357

    CAS  PubMed  Google Scholar 

  46. Prendergast GC, Malachowski WP, DuHadaway JB, Muller AJ (2017) Discovery of IDO1 inhibitors: from bench to bedside. Cancer Res 77:6795–6811

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Beatty GL, O’Dwyer PJ, Clark J, Shi JG, Bowman KJ, Scherle PA, Newton RC, Schaub R, Maleski J, Leopold L, Gajewski TF (2017) 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 23:3269–3276

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Ribas A, Dummer R, Puzanov I, VanderWalde A, Andtbacka RHI, Michielin O, Olszanski AJ, Malvehy J, Cebon J, Fernandez E, Kirkwood JM, Gajewski TF, Chen L, Gorski KS, Anderson AA, Diede SJ, Lassman ME, Gansert J, Hodi FS, Long GV (2017) Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell 170:1109–1119

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Andtbacka RH et al (2015) Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol 33:2780–2788

    CAS  PubMed  Google Scholar 

  50. Chesney J, Puzanov I, Collichio F, Singh P, Milhem MM, John Glaspy J (2018) 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 36:1658–1667

    CAS  PubMed  Google Scholar 

  51. Sahin U, Derhovanessian E, Miller M, Kloke BP, Simon P, Löwer M, Bukur V, Tadmor AD, Luxemburger U, Schrörs B, Omokoko T, Vormehr M, Albrecht C, Paruzynski A, Kuhn AN, Buck J, Heesch S, Schreeb KH, Müller F, Ortseifer I, Vogler I, Godehardt E, Attig S, Rae R, Breitkreuz A, Tolliver C, Suchan M, Martic G, Hohberger A, Sorn P, Diekmann J, Ciesla J, Waksmann O, Brück AK, Witt M, Zillgen M, Rothermel A, Kasemann B, Langer D, Bolte S, Diken M, Kreiter S, Nemecek R, Gebhardt C, Grabbe S, Höller C, Utikal J, Huber C, Loquai C, Türeci Ö (2017) Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547:222–226

    CAS  PubMed  Google Scholar 

  52. M. Milhem, R. Gonzales, T. Medina, et al Intratumoral toll-like receptor 9 (TLR9) agonist, CMP-001, in combination with pembrolizumab can reverse resistance to PD-1 inhibition in a phase Ib trial in subjects with advanced melanoma. Presented at: AACR Annual Meeting 2018; April 14–18, 2018; Chicago, Illinois. Abstract CT0101

  53. Leidner R, Kang H, Haddad R et al (2016) Preliminary efficacy from a phase 1/2 study of the natural killer cell–targeted antibody, lirilumab in combination with nivolumab in squamous cell carcinoma of the head and neck. J Immunother Cancer 4:91

    PubMed Central  Google Scholar 

  54. Cekic C, Day YJ, Sag D, Linden J (2014) Myeloid expression of adenosine A2A receptor suppresses T and NK cell responses in the solid tumor microenvironment. Cancer Res 74:7250–7259

    CAS  PubMed  PubMed Central  Google Scholar 

  55. O’Donnell JS, Massi D, Teng MWL, Mandala M (2017) PI3K-AKT-mTOR inhibition in cancer immunotherapy, redux. Semin Cancer Biol 48:91–103. https://doi.org/10.1016/j.semcancer.2017.04.015

    Article  CAS  PubMed  Google Scholar 

  56. Charych DH, Hoch U, Langowski JL, Lee SR, Addepalli MK, Kirk PB, Sheng D, Liu X, Sims PW, VanderVeen LA, Ali CF, Chang TK, Konakova M, Pena RL, Kanhere RS, Kirksey YM, Ji C, Wang Y, Huang J, Sweeney TD, Kantak SS, Doberstein SK (2016) NKTR-214, an engineered cytokine with biased IL2 receptor binding, increased tumor exposure, and marked efficacy in mouse tumor models. Clin Cancer Res 22:680–690

    CAS  PubMed  Google Scholar 

  57. Diab A, Hurwitz ME, Cho DC, Papadimitrakopoulou V, Curti BD, Scott S et al (2016) Tykodi NKTR-214 (CD122-biased agonist) plus nivolumab in patients with advanced solid tumors: preliminary phase 1/2 results of PIVOT. ASCO meeting abstract 3006. J Clin Oncol (suppl)

  58. Koller KM, Mackley HB, Liu J, Wagner H, Talamo G, Schell TD, Pameijer C, Neves RI, Anderson B, Kokolus KM, Mallon CA, Drabick JJ (2017) Improved survival and complete response rates in patients with advanced melanoma treated with concurrent ipilimumab and radiotherapy versus ipilimumab alone. Cancer Biol Ther 18:36–42

    CAS  PubMed  Google Scholar 

  59. Liniker E, Menzies AM, Kong BY, Cooper A, Ramanujam S, Lo S, Kefford RF, Fogarty GB, Guminski A, Wang TW, Carlino MS, Hong A, Long GV (2016) Activity and safety of radiotherapy with anti-PD-1 drug therapy in patients with metastatic melanoma. Oncoimmunology 5:e1214788

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, Benci JL, Xu B, Dada H, Odorizzi PM, Herati RS, Mansfield KD, Patsch D, Amaravadi RK, Schuchter LM, Ishwaran H, Mick R, Pryma DA, Xu X, Feldman MD, Gangadhar TC, Hahn SM, Wherry EJ, Vonderheide RH, Minn AJ (2015) Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520:373–377

    CAS  PubMed  Google Scholar 

  61. Hiniker SM, Reddy SA, Maecker HT, Subrahmanyam PB, Rosenberg-Hasson Y, Swetter SM, Saha S, Shura L, Knox SJ (2016) A prospective clinical trial combining radiation therapy with systemic immunotherapy in metastatic melanoma. Int J Radiat Oncol Biol Phys 96:578–588

    PubMed  PubMed Central  Google Scholar 

  62. Ghoneim HE, Fan Y, Moustaki A, Abdelsamed HA, Dash P, Dogra P, Carter R, Awad W, Neale G, Thomas PG, Youngblood B et al (2017) De novo epigenetic programs inhibit PD-1 blockade-mediated T cell rejuvenation. Cell 170:142–157

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Baylin SB, Jones PA (2011) A decade of exploring the cancer epigenome biological and translational implications. Nat Rev Cancer 11:726–734

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Shen H, Laird PW (2013) Interplay between the cancer genome and epigenome. Cell 153:38–55

    CAS  PubMed  PubMed Central  Google Scholar 

  65. James SR, Link PA, Karpf AR (2006) Epigenetic regulation of X-linked cancer/germline antigen genes by DNMT1 and DNMT3b. Oncogene 25:6975–6985

    CAS  PubMed  Google Scholar 

  66. Zhu Y, Knolhoff B, Meyer MA et al (2014) CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res 74:5057–5069

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Frederick DT, Piris A, Cogdill AP, Cooper ZA, Lezcano C, Ferrone CR, Mitra D, Boni A, Newton LP, Liu C, Peng W, Sullivan RJ, Lawrence DP, Hodi FS, Overwijk WW, Lizee G, Murphy GF, Hwu P, Flaherty KT, Fisher DE, Wargo JA (2013) BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res 19:1225–1231

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Hugo W, Shi H, Sun L, Piva M, Song C, Kong X et al (2015) Nongenomic and immune evolution of melanoma acquiring MAPKi resistance. Cell 162(6):1271e85

    Google Scholar 

  69. Spranger S, Bao R, Gajewski TF (2015) Melanoma-intrinsic betacatenin signalling prevents anti-tumour immunity. Nature 523(7559):231e5

    Google Scholar 

  70. Massi D, Romano E, Rulli E, Merelli B, Nassini R, De Logu F, Bieche I, Baroni G, Cattaneo L, Xue G, Mandalà M (2017) Baseline ß-catenin, PD-L1 expression and tumor-infiltrating lymphocytes predict response and poor prognosis in BRAFi-treated melanoma patients. Eur J Cancer 78:70–81

    CAS  PubMed  Google Scholar 

  71. Massi D, Brusa D, Merelli B, Falcone C, Xue G, Carobbio A, Nassini R, Baroni G, Tamborini E, Cattaneo L, Audrito V, Deaglio S, Mandalà M (2015) The status of PD-L1 and tumor-infiltrating immune cells predict resistance and poor prognosis in BRAFi-treated melanoma patients harboring mutant BRAFV600. Ann Oncol 26:1980–1987

    CAS  PubMed  Google Scholar 

  72. Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, du J, Davis A, Mongare MM, Gould J, Frederick DT, Cooper ZA, Chapman PB, Solit DB, Ribas A, Lo RS, Flaherty KT, Ogino S, Wargo JA, Golub TR (2012) Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487:500–504

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Smith MP, Sanchez-Laorden B, O’Brien K, Brunton H, Ferguson J, Young H, Dhomen N, Flaherty KT, Frederick DT, Cooper ZA, Wargo JA, Marais R, Wellbrock C (2014) The immune microenvironment confers resistance to MAPK pathway inhibitors through macrophage-derived TNFα. Cancer Discov 4:1214–1229

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J (2013) Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med 368:1365–1366

    CAS  PubMed  Google Scholar 

  75. Ribas AF, Hodi S, Lawrence DP, et al (2016) Pembrolizumab (pembro) in combination with dabrafenib (D) and trametinib (T) for BRAF-mutant advanced melanoma: phase 1 KEYNOTE-022 study. J Clin Oncol 34, 2016 (suppl; abstr 3014) ASCO Abstract 3014

  76. Ascierto P, Ferrucci PF, Stephens R, Del Vecchio M, Atkinson V, Schmidt H et al (2018) KEYNOTE-022 part 3: phase 2 randomized study of 1L dabrafenib (D) and trametinib (T) plus pembrolizumab (Pembro) or placebo (PBO) for BRAF-mutant advanced melanoma. Abstract 12440 ESMO meeting 2018. Ann Oncol 29(suppl 8)

  77. Sullivan R, Hamid O, Patel M et al (2016) Melanoma and immunotherapy bridge 2015. Naples, Italy. 1–5 December 2015. J Transl Med 14:65

    PubMed Central  Google Scholar 

  78. Verver D, van Klaveren D, van Akkooi ACJ, Rutkowski P, Powell BW, Robert C et al (2018) Risk stratification of sentinel node-positive melanoma patients defines surgical management and adjuvant therapy treatment considerations. Eur J Cancer 96:25–33

    PubMed  Google Scholar 

  79. Hauschild A, Dummer R, Schadendorf D, Santinami M, Atkinson V, Mandalà M et al (2018) Sustained relapse-free survival benefit with adjuvant dabrafenib plus trametinib in patients with resected BRAF V600-mutant stage III melanoma. J Clin Oncol. https://doi.org/10.1001/jamaoncol.2018.4514

  80. Faries MB, Thompson JF, Cochran AJ, Andtbacka RH, Mozzillo N, Zager JS, Jahkola T, Bowles TL, Testori A, Beitsch PD, Hoekstra HJ, Moncrieff M, Ingvar C, Wouters MWJM, Sabel MS, Levine EA, Agnese D, Henderson M, Dummer R, Rossi CR, Neves RI, Trocha SD, Wright F, Byrd DR, Matter M, Hsueh E, MacKenzie-Ross A, Johnson DB, Terheyden P, Berger AC, Huston TL, Wayne JD, Smithers BM, Neuman HB, Schneebaum S, Gershenwald JE, Ariyan CE, Desai DC, Jacobs L, McMasters KM, Gesierich A, Hersey P, Bines SD, Kane JM, Barth RJ, McKinnon G, Farma JM, Schultz E, Vidal-Sicart S, Hoefer RA, Lewis JM, Scheri R, Kelley MC, Nieweg OE, Noyes RD, Hoon DSB, Wang HJ, Elashoff DA, Elashoff RM (2017) Completion dissection or observation for sentinel-node metastasis in melanoma. N Engl J Med 376:2211–2222

    PubMed  PubMed Central  Google Scholar 

  81. Leiter U, Stadler R, Mauch C, Hohenberger W, Brockmeyer N, Berking C, Sunderkötter C, Kaatz M, Schulte KW, Lehmann P, Vogt T, Ulrich J, Herbst R, Gehring W, Simon JC, Keim U, Martus P, Garbe C (2016) Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial. Lancet Oncol 17:757–767

    PubMed  Google Scholar 

  82. Blank CU, Haanen JB, Ribas A, Schumacher TN (2016) CANCER IMMUNOLOGY. The “cancer immunogram”. Science 352(6286):658–660

    CAS  PubMed  Google Scholar 

  83. Zitvogel L, Ma Y, Raoult D, Kroemer G, Gajewski TF (2018) The microbiome in cancer immunotherapy: diagnostic tools and therapeutic strategies. Science 359:1366–1370

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Unit of Medical Oncology, Department of Oncology and Haematology, Papa Giovanni XXIII Cancer Center Hospital, Piazza OMS 1, 24100, Bergamo, Italy

    Mario Mandalà

  2. Maria Sklodowska-Curie Institute, Oncology Center, Warsaw, Poland

    Piotr Rutkowski

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  1. Mario Mandalà
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  2. Piotr Rutkowski
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Dr. Mandalà planned the workflow of the manuscript. Dr. Mandala and Prof. Rutkowski wrote the manuscript and approved the final version.

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Correspondence to Mario Mandalà.

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Conflict of interest

Dr. Mandala received honoraria for invited speeches, consulting, and advisory board from Novartis, Roche, BMS, MSD, Pierre Fabre, and Incyte.

Dr. Mandala received research funding from Roche, Novartis.

Prof Rutkowski received grants/research supports: BMS, Novartis and honoraria or consultation fees: Novartis, MSD, BMS, GSK, Roche, Amgen, Bayer, Blueprint Medicines, Pierre Fabre.

Participation in a company sponsored speaker’s bureau: Pfizer, MSD, Novartis, Roche.

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Mandalà, M., Rutkowski, P. Rational combination of cancer immunotherapy in melanoma. Virchows Arch 474, 433–447 (2019). https://doi.org/10.1007/s00428-018-2506-y

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