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Recent success and limitations of immune checkpoint inhibitors for cancer: a lesson from melanoma

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Abstract

Several researches have been carried over the last few decades to understand of how cancer evades the immune system and thus to identify therapies that could directly act on patient’s immune system in the way of restore or induce a response to cancer. As a consequence, “cancer immunotherapy” is conquering predominantly the modern scenario of the fight against cancer. The recent clinical success of immune checkpoint inhibitors (ICIs) has created an entire new class of anti-cancer drugs and restored interest in the field of immuno-oncology, leading to regulatory approvals of several agents for the treatment of a variety of malignancies. The first to be approved in 2011 was the anti-CTLA-4 antibody ipilimumab for the treatment of unresectable or metastatic melanoma. Subsequently, the anti-PD-1s, nivolumab and pembrolizumab, received regulatory approvals for the treatment of melanoma and several other cancers. More recently, three anti-PD-L1 antibodies have received approval: atezolizumab and durvalumab for locally advanced or metastatic urothelial carcinoma and metastatic non-small cell lung cancer (NSCLC) and avelumab for the treatment of locally advanced or metastatic urothelial carcinoma and metastatic Merkel cell carcinoma. This review, starting from the results of melanoma trials, highlights in turn different ICIs and data for different indications in several malignancies are included under each drug class.

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References

  1. Drake CG, Jaffee E, Pardoll DM (2006) Mechanisms of immune evasion by tumors. Adv Immunol 90:51–81. https://doi.org/10.1016/S0065-2776(06)90002-9

    Article  CAS  PubMed  Google Scholar 

  2. Couzin-Frankel J (2013) Breakthrough of the year 2013. Cancer immunotherapy. Science 342(6165):1432–1433. https://doi.org/10.1126/science.342.6165.1432

    Article  CAS  PubMed  Google Scholar 

  3. Buchbinder EI, Desai A (2016) CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol 39(1):98–106. https://doi.org/10.1097/COC.0000000000000239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Smith JL Jr, Stehlin JS Jr (1965) Spontaneous regression of primary malignant melanomas with regional metastases. Cancer 18(11):1399–1415

    Article  PubMed  Google Scholar 

  5. Chan DV, Gibson HM, Aufiero BM, Wilson AJ, Hafner MS, Mi QS, Wong HK (2014) Differential CTLA-4 expression in human CD4+ versus CD8+ T cells is associated with increased NFAT1 and inhibition of CD4+ proliferation. Genes Immun 15(1):25–32. https://doi.org/10.1038/gene.2013.57

    Article  CAS  PubMed  Google Scholar 

  6. Leung HT, Bradshaw J, Cleaveland JS, Linsley PS (1995) Cytotoxic T lymphocyte-associated molecule-4, a high-avidity receptor for CD80 and CD86, contains an intracellular localization motif in its cytoplasmic tail. J Biol Chem 270(42):25107–25114

    Article  CAS  PubMed  Google Scholar 

  7. Rudd CE, Taylor A, Schneider H (2009) CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol Rev 229(1):12–26. https://doi.org/10.1111/j.1600-065X.2009.00770.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Qureshi OS, Zheng Y, Nakamura K, Attridge K, Manzotti C, Schmidt EM, Baker J, Jeffery LE, Kaur S, Briggs Z, Hou TZ, Futter CE, Anderson G, Walker LS, Sansom DM (2011) Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 332(6029):600–603. https://doi.org/10.1126/science.1202947

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, Nomura T, Sakaguchi S (2008) CTLA-4 control over Foxp3+ regulatory T cell function. Science 322(5899):271–275. https://doi.org/10.1126/science.1160062

    Article  CAS  PubMed  Google Scholar 

  10. Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, Thompson CB, Griesser H, Mak TW (1995) Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270(5238):985–988

    Article  CAS  PubMed  Google Scholar 

  11. Gough SC, Walker LS, Sansom DM (2005) CTLA4 gene polymorphism and autoimmunity. Immunol Rev 204:102–115. https://doi.org/10.1111/j.0105-2896.2005.00249.x

    Article  CAS  PubMed  Google Scholar 

  12. Nakamoto N, Cho H, Shaked A, Olthoff K, Valiga ME, Kaminski M, Gostick E, Price DA, Freeman GJ, Wherry EJ, Chang KM (2009) Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade. PLoS Pathog 5(2):e1000313. https://doi.org/10.1371/journal.ppat.1000313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Curran MA, Montalvo W, Yagita H, Allison JP (2010) PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A 107(9):4275–4280. https://doi.org/10.1073/pnas.0915174107

    Article  PubMed  PubMed Central  Google Scholar 

  14. Nishimura H, Nose M, Hiai H, Minato N, Honjo T (1999) Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11(2):141–151

    Article  CAS  PubMed  Google Scholar 

  15. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T (2000) Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192(7):1027–1034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R, Greenfield EA, Bourque K, Boussiotis VA, Carter LL, Carreno BM, Malenkovich N, Nishimura H, Okazaki T, Honjo T, Sharpe AH, Freeman GJ (2001) PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2(3):261–268. https://doi.org/10.1038/85330

    Article  CAS  PubMed  Google Scholar 

  17. Goldberg MV, Maris CH, Hipkiss EL, Flies AS, Zhen L, Tuder RM, Grosso JF, Harris TJ, Getnet D, Whartenby KA, Brockstedt DG, Dubensky TW Jr, Chen L, Pardoll DM, Drake CG (2007) Role of PD-1 and its ligand, B7-H1, in early fate decisions of CD8 T cells. Blood 110(1):186–192. https://doi.org/10.1182/blood-2006-12-062422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK, Sharpe AH (2009) PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 206(13):3015–3029. https://doi.org/10.1084/jem.20090847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T, Gajewski TF (2004) PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res 64(3):1140–1145

    Article  CAS  PubMed  Google Scholar 

  20. Iwai Y, Terawaki S, Ikegawa M, Okazaki T, Honjo T (2003) PD-1 inhibits antiviral immunity at the effector phase in the liver. J Exp Med 198(1):39–50. https://doi.org/10.1084/jem.20022235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R (2006) Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439(7077):682–687. https://doi.org/10.1038/nature04444

    Article  CAS  PubMed  Google Scholar 

  22. Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE, Rosenberg SA (2009) Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 114(8):1537–1544. https://doi.org/10.1182/blood-2008-12-195792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Peggs KS, Quezada SA, Chambers CA, Korman AJ, Allison JP (2009) Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J Exp Med 206(8):1717–1725. https://doi.org/10.1084/jem.20082492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wei SC, Levine JH, Cogdill AP, Zhao Y, Anang NAS, Andrews MC, Sharma P, Wang J, Wargo JA, Pe’er D, Allison JP (2017) Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell 170(6):1120–1133 e1117. https://doi.org/10.1016/j.cell.2017.07.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723. https://doi.org/10.1056/NEJMoa1003466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Phan GQ, Yang JC, Sherry RM, Hwu P, Topalian SL, Schwartzentruber DJ, Restifo NP, Haworth LR, Seipp CA, Freezer LJ, Morton KE, Mavroukakis SA, Duray PH, Steinberg SM, Allison JP, Davis TA, Rosenberg SA (2003) Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A 100(14):8372–8377. https://doi.org/10.1073/pnas.1533209100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O, Patt D, Chen TT, Berman DM, Wolchok JD (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 33(17):1889–1894. https://doi.org/10.1200/JCO.2014.56.2736

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ascierto PA, Del Vecchio M, Robert C, Mackiewicz A, Chiarion-Sileni V, Arance A, Lebbe C, Bastholt L, Hamid O, Rutkowski P, McNeil C, Garbe C, Loquai C, Dreno B, Thomas L, Grob JJ, Liszkay G, Nyakas M, Gutzmer R, Pikiel J, Grange F, Hoeller C, Ferraresi V, Smylie M, Schadendorf D, Mortier L, Svane IM, Hennicken D, Qureshi A, Maio M (2017) 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 18(5):611–622. https://doi.org/10.1016/S1470-2045(17)30231-0

    Article  CAS  PubMed  Google Scholar 

  29. Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364(26):2517–2526. https://doi.org/10.1056/NEJMoa1104621

    Article  CAS  PubMed  Google Scholar 

  30. Maio M, Grob JJ, Aamdal S, Bondarenko I, Robert C, Thomas L, Garbe C, Chiarion-Sileni V, Testori A, Chen TT, Tschaika M, Wolchok JD (2015) Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol 33(10):1191–1196. https://doi.org/10.1200/JCO.2014.56.6018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Topalian SL, Drake CG, Pardoll DM (2015) Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27(4):450–461. https://doi.org/10.1016/j.ccell.2015.03.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O’Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A (2015) Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol 16(8):908–918. https://doi.org/10.1016/S1470-2045(15)00083-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hamid O, Puzanov I, Dummer R, Schachter J, Daud A, Schadendorf D, Blank C, Cranmer LD, Robert C, Pavlick AC, Gonzalez R, Hodi FS, Ascierto PA, Salama A, Margolin KA, Gangadhar TC, Wei Z, Ebbinghaus SW, Ibrahim N, Ribas A (2016) Final overall survival for KEYNOTE-002: pembrolizumab (pembro) versus investigator-choice chemotherapy (chemo) for ipilimumab (ipi)-refractory melanoma. Ann Oncol 27(suppl_6):1107O-1107O. https://doi.org/10.1093/annonc/mdw379.02

    Article  Google Scholar 

  34. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A, investigators K (2015) Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 372(26):2521–2532. https://doi.org/10.1056/NEJMoa1503093

    Article  CAS  PubMed  Google Scholar 

  35. Long GV, Schachter J, Ribas A, Arance AM, Grob J-J, Mortier L, Daud A, Carlino MS, McNeil CM, Lotem M, Larkin JMG, Lorigan P, Neyns B, Blank CU, Petrella TM, Hamid O, Anderson J, Krepler C, Ibrahim N, Robert C (2018) 4-year survival and outcomes after cessation of pembrolizumab (pembro) after 2-years in patients (pts) with ipilimumab (ipi)-naive advanced melanoma in KEYNOTE-006. 36(15_suppl):9503–9503. https://doi.org/10.1200/JCO.2018.36.15_suppl.9503

  36. Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB (2016) Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387(10027):1540–1550. https://doi.org/10.1016/S0140-6736(15)01281-7

    Article  CAS  PubMed  Google Scholar 

  37. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O’Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR, Investigators K (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375(19):1823–1833. https://doi.org/10.1056/NEJMoa1606774

    Article  CAS  PubMed  Google Scholar 

  38. Chen R, Zinzani PL, Fanale MA, Armand P, Johnson NA, Brice P, Radford J, Ribrag V, Molin D, Vassilakopoulos TP, Tomita A, von Tresckow B, Shipp MA, Zhang Y, Ricart AD, Balakumaran A, Moskowitz CH, Keynote (2017) Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin Oncol 35(19):2125–2132. https://doi.org/10.1200/JCO.2016.72.1316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Chow LQM, Haddad R, Gupta S, Mahipal A, Mehra R, Tahara M, Berger R, Eder JP, Burtness B, Lee SH, Keam B, Kang H, Muro K, Weiss J, Geva R, Lin CC, Chung HC, Meister A, Dolled-Filhart M, Pathiraja K, Cheng JD, Seiwert TY (2016) Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion cohort. J Clin Oncol 34(32):3838–3845. https://doi.org/10.1200/JCO.2016.68.1478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF, Investigators K (2017) Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 376(11):1015–1026. https://doi.org/10.1056/NEJMoa1613683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Fuchs CS, Doi T, Jang RW, Muro K, Satoh T, Machado M, Sun W, Jalal SI, Shah MA, Metges JP, Garrido M, Golan T, Mandala M, Wainberg ZA, Catenacci DV, Ohtsu A, Shitara K, Geva R, Bleeker J, Ko AH, Ku G, Philip P, Enzinger PC, Bang YJ, Levitan D, Wang J, Rosales M, Dalal RP, Yoon HH (2018) Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol 4(5):e180013. https://doi.org/10.1001/jamaoncol.2018.0013

    Article  PubMed  PubMed Central  Google Scholar 

  42. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26):2443–2454. https://doi.org/10.1056/NEJMoa1200690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Robert C, Ascierto PA, Maio M, Hernberg M, Schmidt H, Waxman I, Garbe C, Lebbé C, Hauschild A (2013) A phase III, randomized, double-blind study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus dacarbazine in patients (pts) with previously untreated, unresectable, or metastatic melanoma (MEL). 31(15_suppl):TPS9106-TPS9106. https://doi.org/10.1200/jco.2013.31.15_suppl.tps9106

  44. Long GV, Atkinson V, Ascierto PA, Robert C, Hassel JC, Rutkowski P, Savage KJ, Taylor F, Coon C, Gilloteau I, Dastani HB, Waxman IM, Abernethy AP (2016) Effect of nivolumab on health-related quality of life in patients with treatment-naive advanced melanoma: results from the phase III CheckMate 066 study. Ann Oncol 27(10):1940–1946. https://doi.org/10.1093/annonc/mdw265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Weber JS, D’Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J (2015) 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 16(4):375–384. https://doi.org/10.1016/S1470-2045(15)70076-8

    Article  CAS  PubMed  Google Scholar 

  46. Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, Dalle S, Schenker M, Chiarion-Sileni V, Marquez-Rodas I, Grob JJ, Butler MO, Middleton MR, Maio M, Atkinson V, Queirolo P, Gonzalez R, Kudchadkar RR, Smylie M, Meyer N, Mortier L, Atkins MB, Long GV, Bhatia S, Lebbe C, Rutkowski P, Yokota K, Yamazaki N, Kim TM, de Pril V, Sabater J, Qureshi A, Larkin J, Ascierto PA, CheckMate C (2017) Adjuvant Nivolumab versus Ipilimumab in resected stage III or IV melanoma. N Engl J Med 377(19):1824–1835. https://doi.org/10.1056/NEJMoa1709030

    Article  CAS  PubMed  Google Scholar 

  47. Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Aren Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR (2015) Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373(2):123–135. https://doi.org/10.1056/NEJMoa1504627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhaufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crino L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR (2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373(17):1627–1639. https://doi.org/10.1056/NEJMoa1507643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P, CheckMate I (2015) Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373(19):1803–1813. https://doi.org/10.1056/NEJMoa1510665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ferris R, Gillison ML (2017) Nivolumab for squamous-cell cancer of head and neck. N Engl J Med 376(6):596–596. https://doi.org/10.1056/NEJMc1615565

    Article  PubMed  Google Scholar 

  51. Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, Plimack ER, Vaena D, Grimm MO, Bracarda S, Arranz JA, Pal S, Ohyama C, Saci A, Qu X, Lambert A, Krishnan S, Azrilevich A, Galsky MD (2017) Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol 18(3):312–322. https://doi.org/10.1016/S1470-2045(17)30065-7

    Article  CAS  PubMed  Google Scholar 

  52. El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim TY, Choo SP, Trojan J, Welling THR, Meyer T, Kang YK, Yeo W, Chopra A, Anderson J, Dela Cruz C, Lang L, Neely J, Tang H, Dastani HB, Melero I (2017) Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 389(10088):2492–2502. https://doi.org/10.1016/S0140-6736(17)31046-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, Desai J, Hill A, Axelson M, Moss RA, Goldberg MV, Cao ZA, Ledeine JM, Maglinte GA, Kopetz S, Andre T (2017) Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 18(9):1182–1191. https://doi.org/10.1016/S1470-2045(17)30422-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, Schuster SJ, Millenson MM, Cattry D, Freeman GJ, Rodig SJ, Chapuy B, Ligon AH, Zhu L, Grosso JF, Kim SY, Timmerman JM, Shipp MA, Armand P (2015) PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 372(4):311–319. https://doi.org/10.1056/NEJMoa1411087

    Article  CAS  PubMed  Google Scholar 

  55. Younes A, Santoro A, Shipp M, Zinzani PL, Timmerman JM, Ansell S, Armand P, Fanale M, Ratanatharathorn V, Kuruvilla J, Cohen JB, Collins G, Savage KJ, Trneny M, Kato K, Farsaci B, Parker SM, Rodig S, Roemer MG, Ligon AH, Engert A (2016) Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol 17(9):1283–1294. https://doi.org/10.1016/S1470-2045(16)30167-X

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Yokoi T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeno J, Wadsworth C, Melillo G, Jiang H, Huang Y, Dennis PA, Ozguroglu M, Investigators P (2017) Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 377(20):1919–1929. https://doi.org/10.1056/NEJMoa1709937

    Article  CAS  PubMed  Google Scholar 

  57. Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, Cortinovis DL, Leach J, Polikoff J, Barrios C, Kabbinavar F, Frontera OA, De Marinis F, Turna H, Lee JS, Ballinger M, Kowanetz M, He P, Chen DS, Sandler A, Gandara DR, Group OAKS (2017) Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 389(10066):255–265. https://doi.org/10.1016/S0140-6736(16)32517-X

    Article  PubMed  Google Scholar 

  58. Powles T, Duran I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Flechon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE III, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A (2018) Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet 391(10122):748–757. https://doi.org/10.1016/S0140-6736(17)33297-X

    Article  CAS  PubMed  Google Scholar 

  59. Kaufman HL, Russell J, Hamid O, Bhatia S, Terheyden P, D’Angelo SP, Shih KC, Lebbe C, Linette GP, Milella M, Brownell I, Lewis KD, Lorch JH, Chin K, Mahnke L, von Heydebreck A, Cuillerot JM, Nghiem P (2016) Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol 17(10):1374–1385. https://doi.org/10.1016/S1470-2045(16)30364-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Selby MJ, Engelhardt JJ, Johnston RJ, Lu LS, Han M, Thudium K, Yao D, Quigley M, Valle J, Wang C, Chen B, Cardarelli PM, Blanset D, Korman AJ (2016) Preclinical development of ipilimumab and nivolumab combination immunotherapy: mouse tumor models, in vitro functional studies, and cynomolgus macaque toxicology. PLoS One 11(9):e0161779. https://doi.org/10.1371/journal.pone.0161779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M (2013) Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 369(2):122–133. https://doi.org/10.1056/NEJMoa1302369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Callahan MK, Kluger H, Postow MA, Segal NH, Lesokhin A, Atkins MB, Kirkwood JM, Krishnan S, Bhore R, Horak C, Wolchok JD, Sznol M (2018) Nivolumab plus ipilimumab in patients with advanced melanoma: updated survival, response, and safety data in a phase i dose-Escalation study. 36 (4):391–398. doi:https://doi.org/10.1200/jco.2017.72.2850

  63. Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS (2015) Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 372(21):2006–2017. https://doi.org/10.1056/NEJMoa1414428

    Article  PubMed  PubMed Central  Google Scholar 

  64. Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor DR, Salama AK, Taylor MH, Ott PA, Horak C, Gagnier P, Jiang J, Wolchok JD, Postow MA (2016) Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol 17(11):1558–1568. https://doi.org/10.1016/S1470-2045(16)30366-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD (2015) Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373(1):23–34. https://doi.org/10.1056/NEJMoa1504030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 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, Lebbe 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(14):1345–1356. https://doi.org/10.1056/NEJMoa1709684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Tawbi HA, Forsyth PA, Algazi A, Hamid O, Hodi FS, Moschos SJ, Khushalani NI, Lewis K, Lao CD, Postow MA, Atkins MB, Ernstoff MS, Reardon DA, Puzanov I, Kudchadkar RR, Thomas RP, Tarhini A, Pavlick AC, Jiang J, Avila A, Demelo S, Margolin K (2018) Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N Engl J Med 379(8):722–730. https://doi.org/10.1056/NEJMoa1805453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Motzer RJ, Tannir NM, McDermott DF, Aren Frontera O, Melichar B, Choueiri TK, Plimack ER, Barthelemy P, Porta C, George S, Powles T, Donskov F, Neiman V, Kollmannsberger CK, Salman P, Gurney H, Hawkins R, Ravaud A, Grimm MO, Bracarda S, Barrios CH, Tomita Y, Castellano D, Rini BI, Chen AC, Mekan S, McHenry MB, Wind-Rotolo M, Doan J, Sharma P, Hammers HJ, Escudier B, CheckMate I (2018) Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 378(14):1277–1290. https://doi.org/10.1056/NEJMoa1712126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Hellmann MD, Rizvi NA, Goldman JW, Gettinger SN, Borghaei H, Brahmer JR, Ready NE, Gerber DE, Chow LQ, Juergens RA, Shepherd FA, Laurie SA, Geese WJ, Agrawal S, Young TC, Li X, Antonia SJ (2017) Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol 18(1):31–41. https://doi.org/10.1016/S1470-2045(16)30624-6

    Article  CAS  PubMed  Google Scholar 

  70. Antonia SJ, Lopez-Martin JA, Bendell J, Ott PA, Taylor M, Eder JP, Jager D, Pietanza MC, Le DT, de Braud F, Morse MA, Ascierto PA, Horn L, Amin A, Pillai RN, Evans J, Chau I, Bono P, Atmaca A, Sharma P, Harbison CT, Lin CS, Christensen O, Calvo E (2016) Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol 17(7):883–895. https://doi.org/10.1016/S1470-2045(16)30098-5

    Article  CAS  PubMed  Google Scholar 

  71. Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, Minenza E, Linardou H, Burgers S, Salman P, Borghaei H, Ramalingam SS, Brahmer J, Reck M, O’Byrne KJ, Geese WJ, Green G, Chang H, Szustakowski J, Bhagavatheeswaran P, Healey D, Fu Y, Nathan F, Paz-Ares L (2018) Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med 378(22):2093–2104. https://doi.org/10.1056/NEJMoa1801946

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Long GV, Atkinson V, Cebon JS, Jameson MB, Fitzharris BM, McNeil CM, Hill AG, Ribas A, Atkins MB, Thompson JA, Hwu WJ, Hodi FS, Menzies AM, Guminski AD, Kefford R, Kong BY, Tamjid B, Srivastava A, Lomax AJ, Islam M, Shu X, Ebbinghaus S, Ibrahim N, Carlino MS (2017) Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial. Lancet Oncol 18(9):1202–1210. https://doi.org/10.1016/S1470-2045(17)30428-X

    Article  CAS  PubMed  Google Scholar 

  73. Olson D, Luke JJ, Hallmeyer S, Bajaj M, Carll T, Krausz T, Zha Y, Karrison T, Brockstein B, Sondak VK, Eroglu Z, Gajewski T, Khushalani NI (2018) Phase II trial of pembrolizumab (pembro) plus 1 mg/kg ipilimumab (ipi) immediately following progression on anti-PD-1 Ab in melanoma (mel). 36(15_suppl):9514–9514. https://doi.org/10.1200/JCO.2018.36.15_suppl.9514

  74. Antonia S, Goldberg SB, Balmanoukian A, Chaft JE, Sanborn RE, Gupta A, Narwal R, Steele K, Gu Y, Karakunnel JJ, Rizvi NA (2016) Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol 17(3):299–308. https://doi.org/10.1016/S1470-2045(15)00544-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Zaretsky JM, Garcia-Diaz A, Shin DS, Escuin-Ordinas H, Hugo W, Hu-Lieskovan S, Torrejon DY, Abril-Rodriguez G, Sandoval S, Barthly L, Saco J, Homet Moreno B, Mezzadra R, Chmielowski B, Ruchalski K, Shintaku IP, Sanchez PJ, Puig-Saus C, Cherry G, Seja E, Kong X, Pang J, Berent-Maoz B, Comin-Anduix B, Graeber TG, Tumeh PC, Schumacher TN, Lo RS, Ribas A (2016) Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med 375(9):819–829. https://doi.org/10.1056/NEJMoa1604958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Gao J, Ward JF, Pettaway CA, Shi LZ, Subudhi SK, Vence LM, Zhao H, Chen J, Chen H, Efstathiou E, Troncoso P, Allison JP, Logothetis CJ, Wistuba II, Sepulveda MA, Sun J, Wargo J, Blando J, Sharma P (2017) VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. Nat Med 23(5):551–555. https://doi.org/10.1038/nm.4308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Koyama S, Akbay EA, Li YY, Herter-Sprie GS, Buczkowski KA, Richards WG, Gandhi L, Redig AJ, Rodig SJ, Asahina H, Jones RE, Kulkarni MM, Kuraguchi M, Palakurthi S, Fecci PE, Johnson BE, Janne PA, Engelman JA, Gangadharan SP, Costa DB, Freeman GJ, Bueno R, Hodi FS, Dranoff G, Wong KK, Hammerman PS (2016) Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun 7:10501. https://doi.org/10.1038/ncomms10501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Arlauckas SP, Garris CS, Kohler RH, Kitaoka M, Cuccarese MF, Yang KS, Miller MA, Carlson JC, Freeman GJ, Anthony RM, Weissleder R, Pittet MJ (2017) In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy. Sci Transl Med 9(389):eaal3604. https://doi.org/10.1126/scitranslmed.aal3604

    Article  PubMed  PubMed Central  Google Scholar 

  79. Lines JL, Sempere LF, Broughton T, Wang L, Noelle R (2014) VISTA is a novel broad-spectrum negative checkpoint regulator for cancer immunotherapy. Cancer Immunol Res 2(6):510–517. https://doi.org/10.1158/2326-6066.CIR-14-0072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Blake SJ, Dougall WC, Miles JJ, Teng MW, Smyth MJ (2016) Molecular pathways: targeting CD96 and TIGIT for cancer immunotherapy. Clin Cancer Res 22(21):5183–5188. https://doi.org/10.1158/1078-0432.CCR-16-0933

    Article  CAS  PubMed  Google Scholar 

  81. Chew GM, Fujita T, Webb GM, Burwitz BJ, Wu HL, Reed JS, Hammond KB, Clayton KL, Ishii N, Abdel-Mohsen M, Liegler T, Mitchell BI, Hecht FM, Ostrowski M, Shikuma CM, Hansen SG, Maurer M, Korman AJ, Deeks SG, Sacha JB, Ndhlovu LC (2016) TIGIT marks exhausted T cells, correlates with disease progression, and serves as a target for immune restoration in HIV and SIV infection. PLoS Pathog 12(1):e1005349. https://doi.org/10.1371/journal.ppat.1005349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Ascierto PA, Melero I, Bhatia S, Bono P, Sanborn RE, Lipson EJ, Callahan MK, Gajewski T, Gomez-Roca CA, Hodi FS, Curigliano G, Nyakas M, Preusser M, Koguchi Y, Maurer M, Clynes R, Mitra P, Suryawanshi S, Muñoz-Couselo E (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. 35 (15_suppl):9520–9520. doi:https://doi.org/10.1200/JCO.2017.35.15_suppl.9520

  83. Moon YW, Hajjar J, Hwu P, Naing A (2015) Targeting the indoleamine 2,3-dioxygenase pathway in cancer. J Immunother Cancer 3:51. https://doi.org/10.1186/s40425-015-0094-9

    Article  PubMed  PubMed Central  Google Scholar 

  84. Liu X, Shin N, Koblish HK, Yang G, Wang Q, Wang K, Leffet L, Hansbury MJ, Thomas B, Rupar M, Waeltz P, Bowman KJ, Polam P, Sparks RB, Yue EW, Li Y, Wynn R, Fridman JS, Burn TC, Combs AP, Newton RC, Scherle PA (2010) Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity. Blood 115(17):3520–3530. https://doi.org/10.1182/blood-2009-09-246124

    Article  CAS  PubMed  Google Scholar 

  85. Hamid O, Gajewski TF, Frankel AE, Bauer TM, Olszanski AJ, Luke JJ, Balmanoukian AS, Schmidt EV, Sharkey B, Maleski J, Jones MJ, Gangadhar TC (2017) 1214OEpacadostat plus pembrolizumab in patients with advanced melanoma: phase 1 and 2 efficacy and safety results from ECHO-202/KEYNOTE-037. Ann Oncol 28(suppl_5):mdx377.001-mdx377.001. https://doi.org/10.1093/annonc/mdx377.001

    Article  Google Scholar 

  86. Mitchell TC, Hamid O, Smith DC, Bauer TM, Wasser JS, Olszanski AJ, Luke JJ, Balmanoukian AS, Schmidt EV, Zhao Y, Gong X, Maleski J, Leopold L, Gajewski TF (2018) Epacadostat plus Pembrolizumab in patients with advanced solid tumors: phase I results from a multicenter, open-label phase I/II trial (ECHO-202/KEYNOTE-037). J Clin Oncol:JCO2018789602. https://doi.org/10.1200/JCO.2018.78.9602

  87. Long GV, Dummer R, Hamid O, Gajewski T, Caglevic C, Dalle S, Arance A, Carlino MS, Grob J-J, Kim TM, Demidov LV, Robert C, Larkin JMG, Anderson J, Maleski JE, Jones MM, Diede SJ, Mitchell TC (2018) 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. 36 (15_suppl):108–108. doi:https://doi.org/10.1200/JCO.2018.36.15_suppl.108

  88. (2017) 32nd Annual Meeting and Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2017): Late-Breaking Abstracts %. J Immunol Ther Cancer 5(3):89. https://doi.org/10.1186/s40425-017-0297-3

  89. Diab A, Tannir NM, Bernatchez C, Haymaker CL, Bentebibel SE, Curti BD, Wong MKK, Gergel I, Tagliaferri MA, Zalevsky J, Hoch U, Aung S, Imperiale M, Cho DC, Tykodi SS, Puzanov I, Kluger HM, Hurwitz ME, Hwu P, Sznol M (2017) A phase 1/2 study of a novel IL-2 cytokine, NKTR-214, and nivolumab in patients with select locally advanced or metastatic solid tumors. 35(15_suppl):e14040-e14040. https://doi.org/10.1200/JCO.2017.35.15_suppl.e14040

  90. Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A (2017) Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168(4):707–723. https://doi.org/10.1016/j.cell.2017.01.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF (2014) Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8(+) T cells directly within the tumor microenvironment. J Immunother Cancer 2:3. https://doi.org/10.1186/2051-1426-2-3

    Article  PubMed  PubMed Central  Google Scholar 

  92. Antonios JP, Soto H, Everson RG, Moughon D, Orpilla JR, Shin NP, Sedighim S, Treger J, Odesa S, Tucker A, Yong WH, Li G, Cloughesy TF, Liau LM, Prins RM (2017) Immunosuppressive tumor-infiltrating myeloid cells mediate adaptive immune resistance via a PD-1/PD-L1 mechanism in glioblastoma. Neuro-Oncology 19(6):796–807. https://doi.org/10.1093/neuonc/now287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Quezada SA, Peggs KS, Curran MA, Allison JP (2006) CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J Clin Invest 116(7):1935–1945. https://doi.org/10.1172/JCI27745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Sorensen MR, Holst PJ, Steffensen MA, Christensen JP, Thomsen AR (2010) Adenoviral vaccination combined with CD40 stimulation and CTLA-4 blockage can lead to complete tumor regression in a murine melanoma model. Vaccine 28(41):6757–6764. https://doi.org/10.1016/j.vaccine.2010.07.066

    Article  CAS  PubMed  Google Scholar 

  95. Chesney J, Puzanov I, Collichio F, Singh P, Milhem MM, Glaspy J, Hamid O, Ross M, Friedlander P, Garbe C, Logan TF, Hauschild A, Lebbe C, Chen L, Kim JJ, Gansert J, Andtbacka RHI, Kaufman HL (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(17):1658–1667. https://doi.org/10.1200/JCO.2017.73.7379

    Article  CAS  PubMed  Google Scholar 

  96. 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(6):1109–1119 e1110. https://doi.org/10.1016/j.cell.2017.08.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Vetizou M, Pitt JM, Daillere R, Lepage P, Waldschmitt N, Flament C, Rusakiewicz S, Routy B, Roberti MP, Duong CP, Poirier-Colame V, Roux A, Becharef S, Formenti S, Golden E, Cording S, Eberl G, Schlitzer A, Ginhoux F, Mani S, Yamazaki T, Jacquelot N, Enot DP, Berard M, Nigou J, Opolon P, Eggermont A, Woerther PL, Chachaty E, Chaput N, Robert C, Mateus C, Kroemer G, Raoult D, Boneca IG, Carbonnel F, Chamaillard M, Zitvogel L (2015) Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350(6264):1079–1084. https://doi.org/10.1126/science.aad1329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillere R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, Fidelle M, Flament C, Poirier-Colame V, Opolon P, Klein C, Iribarren K, Mondragon L, Jacquelot N, Qu B, Ferrere G, Clemenson C, Mezquita L, Masip JR, Naltet C, Brosseau S, Kaderbhai C, Richard C, Rizvi H, Levenez F, Galleron N, Quinquis B, Pons N, Ryffel B, Minard-Colin V, Gonin P, Soria JC, Deutsch E, Loriot Y, Ghiringhelli F, Zalcman G, Goldwasser F, Escudier B, Hellmann MD, Eggermont A, Raoult D, Albiges L, Kroemer G, Zitvogel L (2018) Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359(6371):91–97. https://doi.org/10.1126/science.aan3706

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Clinical Medicine and Surgery, Oncology Unit, Università degli Studi di Napoli Federico II, Via Sergio Pansini 5, 80131, Naples, Italy

    Margaret Ottaviano & Sabino De Placido

  2. Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori – IRCCS - “Fondazione G. Pascale”, Via Mariano Semmola, 80131, Naples, Italy

    Paolo Antonio Ascierto

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Ottaviano Margaret wrote the manuscript; she acted as corresponding author;

De Placido Sabino provided to data interpretation and reference checking;

Ascierto Paolo Antonio provided to conceptualization of work and its realization; he also checked the references.

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Correspondence to Margaret Ottaviano.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this review formal consent is not required.

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Ottaviano Margaret and De Placido Sabino have not potential conflicts of interest.

Ascierto Paolo Antonio has a consultant/advisory role for Bristol-Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Amgen, Array, Merck Serono, Pierre-Fabre, Incyte, NewLink Genetics, Genmab, Medimmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, and Ultimovacs. He also received research funds from Bristol-Myers Squibb, Roche-Genentech, and Array.

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Ottaviano, M., De Placido, S. & Ascierto, P.A. Recent success and limitations of immune checkpoint inhibitors for cancer: a lesson from melanoma. Virchows Arch 474, 421–432 (2019). https://doi.org/10.1007/s00428-019-02538-4

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