Tumor Biology

, Volume 36, Issue 3, pp 1411–1422 | Cite as

Immunotherapy for lung cancer: for whom the bell tolls?

  • Pedro Madureira
  • Ramon Andrade de Mello
  • Alessandro de Vasconcelos
  • Yan Zhang


Lung cancer is the leading cause of cancer-related death and accounts for approximately 30 % of all cancer deaths. Despite the recent developments in personalized therapy, the prognosis in lung cancer is still very poor. Immunotherapy is now emerging as a new hope for patients with lung cancer. It is well known that standard chemotherapeutic regimens have devastating effects for the patient’s immune system. Therefore, the aim of immunotherapy is to specifically enhance the immune response against the tumour. Recently, many trials addressed the role of such therapies for metastatic non-small cell lung cancer (NSCLC) treatment: ipilimumab, tremelimumab, nivolumab and pembrolizumab are immunotherapeutic agents of high relevance in this field. Anti-tumour vaccines, as well as dendritic cell-based therapies, have emerged as potent inducers of immune response against the tumour. Herein, we will review some of the most promising cancer immunotherapies, highlighting their advantages and try to understand, in an immunological perspective, the missteps associated with the current treatments for cancer.


Lung cancer Immunotherapy CTLA-4 Ipilimumab Nivolumab Pembrolizumab Dendritic cells PD-1 Anti-PD-L1 


  1. 1.
    Centers for Disease C, Prevention. Annual smoking-attributable mortality, years of potential life lost, and productivity losses–United States, 1997–2001. MMWR Morb Mortal Wkly Rep. 2005;54(25):625–8.Google Scholar
  2. 2.
    Cokkinides V, Bandi P, McMahon C, Jemal A, Glynn T, Ward E. Tobacco control in the United States—recent progress and opportunities. CA Cancer J Clin. 2009;59(6):352–65.PubMedGoogle Scholar
  3. 3.
    Jemal A, Thomas A, Murray T, Thun M. Cancer statistics, 2002. CA Cancer J Clin. 2002;52(1):23–47.PubMedGoogle Scholar
  4. 4.
    Myers ML. The FCTC’s evidence-based policies remain a key to ending the tobacco epidemic. Tob Control. 2013;22 Suppl 1:i45–6.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Mulshine JL. Screening for lung cancer: in pursuit of pre-metastatic disease. Nat Rev Cancer. 2003;3(1):65–73.PubMedGoogle Scholar
  6. 6.
    de Mello RA, Marques DS, Medeiros R, Araujo AM. Epidermal growth factor receptor and K-Ras in non-small cell lung cancer-molecular pathways involved and targeted therapies. World J Clin Oncol. 2011;2(11):367–76.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Felip E, Stahel R, Pavlidis N. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of non-small-cell lung cancer (NSCLC). Ann Oncol. 2005;16(1):i28–9.PubMedGoogle Scholar
  8. 8.
    Herbst R, Heymach J, Lippman S. Lung cancer. N Engl J Med. 2008;359(13):1367–80.PubMedGoogle Scholar
  9. 9.
    Drilon A, Rekhtman N, Ladanyi M, Paik P. Squamous-cell carcinomas of the lung: emerging biology, controversies, and the promise of targeted therapy. Lancet Oncol. 2012;13(10):e418–26.PubMedGoogle Scholar
  10. 10.
    Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007;7(3):169–81.PubMedGoogle Scholar
  11. 11.
    de Mello RA, Pires FS, Marques DS, Oliveira J, Rodrigues A, Soares M, et al. EGFR exon mutation distribution and outcome in non-small-cell lung cancer: a Portuguese retrospective study. Tumour Biol. 2012. doi: 10.1007/s13277-012-0465-5.Google Scholar
  12. 12.
    Dienstmann R, Martinez P, Felip E. Personalizing therapy with targeted agents in non-small cell lung cancer. Oncotarget. 2011;2(3):165–77.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Jemal A, Bray F, Center M, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.PubMedGoogle Scholar
  14. 14.
    Sculier J, Chansky K, Crowley J, Van Meerbeeck J, Goldstraw P. The impact of additional prognostic factors on survival and their relationship with the anatomical extent of disease expressed by the 6th Edition of the TNM Classification of Malignant Tumors and the proposals for the 7th Edition. J Thorac Oncol. 2008;3(5):457–66.PubMedGoogle Scholar
  15. 15.
    Nicholson RI, Gee JM, Harper ME. EGFR and cancer prognosis. Eur J Cancer. 2001;37 Suppl 4:S9–15.PubMedGoogle Scholar
  16. 16.
    Hirsch FR, Varella-Garcia M, Bunn Jr PA, Di Maria MV, Veve R, Bremmes RM, et al. Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol Off J Am Soc Clin Oncol. 2003;21(20):3798–807.Google Scholar
  17. 17.
    Ohsaki Y, Tanno S, Fujita Y, Toyoshima E, Fujiuchi S, Nishigaki Y, et al. Epidermal growth factor receptor expression correlates with poor prognosis in non-small cell lung cancer patients with p53 overexpression. Oncol Rep. 2000;7(3):603–7.PubMedGoogle Scholar
  18. 18.
    de Mello RA, Madureira P, Carvalho LS, Araujo A, O’Brien M, Popat S. EGFR and KRAS mutations, and ALK fusions: current developments and personalized therapies for patients with advanced non-small-cell lung cancer. Pharmacogenomics. 2013;14(14):1765–77.PubMedGoogle Scholar
  19. 19.
    de Mello RA. Genetic polymorphisms and non-small-cell lung cancer: future paradigms. Einstein (São Paulo). 2014;12(4):524–6.Google Scholar
  20. 20.
    Krause D, Van Etten R. Tyrosine kinases as targets for cancer therapy. N Engl J Med. 2005;353(2):172–87.PubMedGoogle Scholar
  21. 21.
    Shepherd F, Rodrigues Pereira J, Ciuleanu T, Tan E, Hirsh V, Thongprasert S, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353(2):123–32.PubMedGoogle Scholar
  22. 22.
    Lynch T, Bell D, Sordella R, Gurubhagavatula S, Okimoto R, Brannigan B, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129–39.PubMedGoogle Scholar
  23. 23.
    Cappuzzo F, Hirsch F, Rossi E, Bartolini S, Ceresoli G, Bemis L, et al. Epidermal growth factor receptor gene and protein and gefi tinib sensitivity in non-small-cell lung cancer. J Nat Cancer Inst. 2005;97(9):643–55.PubMedGoogle Scholar
  24. 24.
    Brundage M, Davies D, Mackillop W. Prognostic factors in non-small cell lung cancer. Chest. 2002;122(3):1037–57.PubMedGoogle Scholar
  25. 25.
    Flajnik MF, Kasahara M. Origin and evolution of the adaptive immune system: genetic events and selective pressures. Nat Rev Genet. 2010;11(1):47–59.PubMedGoogle Scholar
  26. 26.
    Lanzavecchia A, Sallusto F. Antigen decoding by T lymphocytes: from synapses to fate determination. Nat Immunol. 2001;2(6):487–92.PubMedGoogle Scholar
  27. 27.
    Li QJ, Dinner AR, Qi S, Irvine DJ, Huppa JB, Davis MM, et al. CD4 enhances T cell sensitivity to antigen by coordinating Lck accumulation at the immunological synapse. Nat Immunol. 2004;5(8):791–9.PubMedGoogle Scholar
  28. 28.
    Schwartz JC, Zhang X, Nathenson SG, Almo SC. Structural mechanisms of costimulation. Nat Immunol. 2002;3(5):427–34.PubMedGoogle Scholar
  29. 29.
    Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol. 2012;30:531–64.PubMedGoogle Scholar
  30. 30.
    Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010;140(6):805–20.PubMedGoogle Scholar
  31. 31.
    Schenten D, Medzhitov R. The control of adaptive immune responses by the innate immune system. Adv Immunol. 2011;109:87–124.PubMedGoogle Scholar
  32. 32.
    Pradere JP, Dapito DH, Schwabe RF. The Yin and Yang of Toll-like receptors in cancer. Oncogene. 2014;33(27):3485–95.Google Scholar
  33. 33.
    Tang D, Kang R, Coyne CB, Zeh HJ, Lotze MT. PAMPs and DAMPs: signal 0s that spur autophagy and immunity. Immunol Rev. 2012;249(1):158–75.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Moseley P. Stress proteins and the immune response. Immunopharmacology. 2000;48(3):299–302.PubMedGoogle Scholar
  35. 35.
    Dhodapkar MV, Steinman RM, Krasovsky J, Munz C, Bhardwaj N. Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells. J Exp Med. 2001;193(2):233–8.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Garbi N, Hammerling GJ, Probst HC, van den Broek M. Tonic T cell signalling and T cell tolerance as opposite effects of self-recognition on dendritic cells. Curr Opin Immunol. 2010;22(5):601–8.PubMedGoogle Scholar
  37. 37.
    Mueller DL. Mechanisms maintaining peripheral tolerance. Nat Immunol. 2010;11(1):21–7.PubMedGoogle Scholar
  38. 38.
    Burnet M. Cancer; a biological approach. I. The processes of control. Br Med J. 1957;1(5022):779–86.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Burnet M. Cancer: a biological approach. III. Viruses associated with neoplastic conditions. IV. Practical applications. Br Med J. 1957;1(5023):841–7.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Dighe AS, Richards E, Old LJ, Schreiber RD. Enhanced in vivo growth and resistance to rejection of tumor cells expressing dominant negative IFN gamma receptors. Immunity. 1994;1(6):447–56.PubMedGoogle Scholar
  41. 41.
    Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, et al. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature. 2001;410(6832):1107–11.PubMedGoogle Scholar
  42. 42.
    Smyth MJ, Thia KY, Street SE, MacGregor D, Godfrey DI, Trapani JA. Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. J Exp Med. 2000;192(5):755–60.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Nishikawa H, Kato T, Tanida K, Hiasa A, Tawara I, Ikeda H, et al. CD4+ CD25+ T cells responding to serologically defined autoantigens suppress antitumor immune responses. Proc Natl Acad Sci U S A. 2003;100(19):10902–6.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Nishikawa H, Kato T, Tawara I, Saito K, Ikeda H, Kuribayashi K, et al. Definition of target antigens for naturally occurring CD4(+) CD25(+) regulatory T cells. J Exp Med. 2005;201(5):681–6.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Nishikawa H, Kato T, Tawara I, Takemitsu T, Saito K, Wang L, et al. Accelerated chemically induced tumor development mediated by CD4+CD25+ regulatory T cells in wild-type hosts. Proc Natl Acad Sci U S A. 2005;102(26):9253–7.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol. 2004;22:329–60.PubMedGoogle Scholar
  47. 47.
    Clark CE, Beatty GL, Vonderheide RH. Immunosurveillance of pancreatic adenocarcinoma: insights from genetically engineered mouse models of cancer. Cancer Lett. 2009;279(1):1–7.PubMedGoogle Scholar
  48. 48.
    Fuchs EJ, Matzinger P. Is cancer dangerous to the immune system? Semin Immunol. 1996;8(5):271–80.PubMedGoogle Scholar
  49. 49.
    Li Z, Pang Y, Gara SK, Achyut BR, Heger C, Goldsmith PK, et al. Gr-1+CD11b+cells are responsible for tumor promoting effect of TGF-beta in breast cancer progression. Int J Cancer J Int Cancer. 2012;131(11):2584–95.Google Scholar
  50. 50.
    Yang L. TGFbeta, a potent regulator of tumor microenvironment and host immune response, implication for therapy. Curr Mol Med. 2010;10(4):374–80.PubMedGoogle Scholar
  51. 51.
    Holmgaard RB, Zamarin D, Munn DH, Wolchok JD, Allison JP. Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J Exp Med. 2013;210(7):1389–402.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Motz GT, Santoro SP, Wang LP, Garrabrant T, Lastra RR, Hagemann IS, et al. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat Med. 2014;20(6):607–15.Google Scholar
  53. 53.
    Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Han EC, Lee J, Ryu SW, Choi C. Tumor-conditioned Gr-1(+)CD11b(+) myeloid cells induce angiogenesis through the synergistic action of CCL2 and CXCL16 in vitro. Biochem Biophys Res Commun. 2014;443(4):1218–25.PubMedGoogle Scholar
  55. 55.
    Chang S, Lin X, Higashikubo R, Toth K, Gelman AE, Kreisel D, et al. Unique pulmonary antigen presentation may call for an alternative approach toward lung cancer immunotherapy. Oncoimmunology. 2013;2(3):e23563.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Declerck S, Vansteenkiste J. Immunotherapy for lung cancer: ongoing clinical trials. Future Oncol. 2014;10(1):91–105.PubMedGoogle Scholar
  57. 57.
    McCarthy F, Roshani R, Steele J, Hagemann T. Current clinical immunotherapy targets in advanced nonsmall cell lung cancer (NSCLC). J Leukoc Biol. 2013;94(6):1201–6.PubMedGoogle Scholar
  58. 58.
    Winter H, van den Engel NK, Rusan M, Schupp N, Poehlein CH, Hu HM, et al. Active-specific immunotherapy for non-small cell lung cancer. J Thorac Dis. 2011;3(2):105–14.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Woo EY, Chu CS, Goletz TJ, Schlienger K, Yeh H, Coukos G, et al. Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res. 2001;61(12):4766–72.PubMedGoogle Scholar
  60. 60.
    Arnold JN, Magiera L, Kraman M, Fearon DT. Tumoral immune suppression by macrophages expressing fibroblast activation protein-alpha and heme oxygenase-1. Cancer Immunol Res. 2014;2(2):121–6.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Bonde AK, Tischler V, Kumar S, Soltermann A, Schwendener RA. Intratumoral macrophages contribute to epithelial-mesenchymal transition in solid tumors. BMC Cancer. 2012;12:35.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Joshi S, Singh AR, Zulcic M, Bao L, Messer K, Ideker T, et al. Rac2 controls tumor growth, metastasis and m1-m2 macrophage differentiation in vivo. PLoS One. 2014;9(4):e95893.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Liu CY, Xu JY, Shi XY, Huang W, Ruan TY, Xie P, et al. M2-polarized tumor-associated macrophages promoted epithelial-mesenchymal transition in pancreatic cancer cells, partially through TLR4/IL-10 signaling pathway. Lab Investig J Tech Methods Pathol. 2013;93(7):844–54.Google Scholar
  64. 64.
    Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14(10):1014–22.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu Rev Immunol. 2013;31:51–72.PubMedGoogle Scholar
  66. 66.
    Vacchelli E, Senovilla L, Eggermont A, Fridman WH, Galon J, Zitvogel L, et al. Trial watch: chemotherapy with immunogenic cell death inducers. Oncoimmunology. 2013;2(3):e23510.PubMedPubMedCentralGoogle Scholar
  67. 67.
    Eggermont AM, Kroemer G, Zitvogel L. Immunotherapy and the concept of a clinical cure. Eur J Cancer. 2013;49(14):2965–7.PubMedGoogle Scholar
  68. 68.
    Rijavec E, Genova C, Alama A, Barletta G, Sini C, Pronzato P, et al. Role of immunotherapy in the treatment of advanced non-small-cell lung cancer. Future Oncol. 2014;10(1):79–90.PubMedGoogle Scholar
  69. 69.
    Correale P, Tindara Miano S, Remondo C, Migali C, Saveria Rotundo M, Macri P, et al. Second-line treatment of non small cell lung cancer by biweekly gemcitabine and docetaxel +/− granulocyte-macrophage colony stimulating factor and low dose aldesleukine. Cancer Biol Ther. 2009;8(6):497–502.PubMedGoogle Scholar
  70. 70.
    Ridolfi L, Bertetto O, Santo A, Naglieri E, Lopez M, Recchia F, et al. Chemotherapy with or without low-dose interleukin-2 in advanced non-small cell lung cancer: results from a phase III randomized multicentric trial. Int J Oncol. 2011;39(4):1011–7.PubMedGoogle Scholar
  71. 71.
    Amin A, White Jr RL. High-dose interleukin-2: is it still indicated for melanoma and RCC in an era of targeted therapies? Oncology. 2013;27(7):680–91.PubMedGoogle Scholar
  72. 72.
    Chambers CA, Kuhns MS, Egen JG, Allison JP. CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol. 2001;19:565–94.PubMedGoogle Scholar
  73. 73.
    Krummel MF, Allison JP. CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells. J Exp Med. 1996;183(6):2533–40.PubMedGoogle Scholar
  74. 74.
    Schneider H, Downey J, Smith A, Zinselmeyer BH, Rush C, Brewer JM, et al. Reversal of the TCR stop signal by CTLA-4. Science. 2006;313(5795):1972–5.PubMedGoogle Scholar
  75. 75.
    Egen JG, Allison JP. Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity. 2002;16(1):23–35.PubMedGoogle Scholar
  76. 76.
    Linsley PS, Greene JL, Brady W, Bajorath J, Ledbetter JA, Peach R. Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity. 1994;1(9):793–801.PubMedGoogle Scholar
  77. 77.
    Riley JL, Mao M, Kobayashi S, Biery M, Burchard J, Cavet G, et al. Modulation of TCR-induced transcriptional profiles by ligation of CD28, ICOS, and CTLA-4 receptors. Proc Natl Acad Sci U S A. 2002;99(18):11790–5.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Schneider H, Mandelbrot DA, Greenwald RJ, Ng F, Lechler R, Sharpe AH, et al. Cutting edge: CTLA-4 (CD152) differentially regulates mitogen-activated protein kinases (extracellular signal-regulated kinase and c-Jun N-terminal kinase) in CD4+ T cells from receptor/ligand-deficient mice. J Immunol. 2002;169(7):3475–9.PubMedGoogle Scholar
  79. 79.
    Rudd CE, Taylor A, Schneider H. CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol Rev. 2009;229(1):12–26.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Qureshi OS, Zheng Y, Nakamura K, Attridge K, Manzotti C, Schmidt EM, et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science. 2011;332(6029):600–3.PubMedPubMedCentralGoogle Scholar
  81. 81.
    Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995;3(5):541–7.PubMedGoogle Scholar
  82. 82.
    Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271(5256):1734–6.PubMedGoogle Scholar
  83. 83.
    van Elsas A, Hurwitz AA, Allison JP. Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J Exp Med. 1999;190(3):355–66.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Hodi FS, Mihm MC, Soiffer RJ, Haluska FG, Butler M, Seiden MV, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U S A. 2003;100(8):4712–7.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Beck KE, Blansfield JA, Tran KQ, Feldman AL, Hughes MS, Royal RE, et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol Off J Am Soc Clin Oncol. 2006;24(15):2283–9.Google Scholar
  86. 86.
    Phan GQ, Yang JC, Sherry RM, Hwu P, Topalian SL, Schwartzentruber DJ, et al. 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. 2003;100(14):8372–7.PubMedPubMedCentralGoogle Scholar
  87. 87.
    Ribas A, Camacho LH, Lopez-Berestein G, Pavlov D, Bulanhagui CA, Millham R, et al. Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(35):8968–77.Google Scholar
  88. 88.
    Ribas A. Clinical development of the anti-CTLA-4 antibody tremelimumab. Semin Oncol. 2010;37(5):450–4.PubMedGoogle Scholar
  89. 89.
    Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30(17):2046–54.Google Scholar
  90. 90.
    Reck M, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Ann Oncol. 2013;24(1):75–83.PubMedGoogle Scholar
  91. 91.
    Hannani D, Vetizou M, Enot D, Rusakiewicz S, Chaput N, Klatzmann D, et al. Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25. Cell Res. 2015;25(2):208–24.PubMedPubMedCentralGoogle Scholar
  92. 92.
    Shrikant P, Khoruts A, Mescher MF. CTLA-4 blockade reverses CD8+ T cell tolerance to tumor by a CD4+ T cell- and IL-2-dependent mechanism. Immunity. 1999;11(4):483–93.PubMedGoogle Scholar
  93. 93.
    Maker AV, Phan GQ, Attia P, Yang JC, Sherry RM, Topalian SL, et al. Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study. Ann Surg Oncol. 2005;12(12):1005–16.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999;5(12):1365–9.PubMedGoogle Scholar
  95. 95.
    Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027–34.PubMedPubMedCentralGoogle Scholar
  96. 96.
    Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261–8.PubMedGoogle Scholar
  97. 97.
    Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. 2009;206(13):3015–29.PubMedPubMedCentralGoogle Scholar
  98. 98.
    Keir ME, Liang SC, Guleria I, Latchman YE, Qipo A, Albacker LA, et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med. 2006;203(4):883–95.PubMedPubMedCentralGoogle Scholar
  99. 99.
    Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793–800.PubMedGoogle Scholar
  100. 100.
    Creelan BC, Antonia SJ. Immunotherapy in lung cancer: “b7-bombers” and other new developments. Semin Respir Crit Care Med. 2013;34(6):810–21.PubMedGoogle Scholar
  101. 101.
    Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28(19):3167–75.Google Scholar
  102. 102.
    Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54.PubMedPubMedCentralGoogle Scholar
  103. 103.
    de Mello RA, Pousa I, Pereira D. Nivolumab for advanced squamous cell lung cancer: what are the next steps? Lancet Oncol. 2015. doi: 10.1016/S1470-2045(15)70074-4.
  104. 104.
    Fanoni D, Tavecchio S, Recalcati S, Balice Y, Venegoni L, Fiorani R, et al. New monoclonal antibodies against B-cell antigens: possible new strategies for diagnosis of primary cutaneous B-cell lymphomas. Immunol Lett. 2011;134(2):157–60.PubMedGoogle Scholar
  105. 105.
    Terme M, Ullrich E, Aymeric L, Meinhardt K, Desbois M, Delahaye N, et al. IL-18 induces PD-1-dependent immunosuppression in cancer. Cancer Res. 2011;71(16):5393–9.PubMedGoogle Scholar
  106. 106.
    Velu V, Titanji K, Zhu B, Husain S, Pladevega A, Lai L, et al. Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature. 2009;458(7235):206–10.PubMedGoogle Scholar
  107. 107.
    Langer CJ. Emerging Immunotherapies in the treatment of non-small cell lung cancer (NSCLC): the role of immune checkpoint inhibitors. Am J Clin Oncol. 2014.Google Scholar
  108. 108.
    Hosoi A, Matsushita H, Shimizu K, Fujii S, Ueha S, Abe J, et al. Adoptive cytotoxic T lymphocyte therapy triggers a counter-regulatory immunosuppressive mechanism via recruitment of myeloid-derived suppressor cells. Int J Cancer J Int Cancer. 2014;134(8):1810–22.Google Scholar
  109. 109.
    Larmonier N, Fraszczak J, Lakomy D, Bonnotte B, Katsanis E. Killer dendritic cells and their potential for cancer immunotherapy. Cancer Immunol Immunother CII. 2010;59(1):1–11.PubMedGoogle Scholar
  110. 110.
    Wimmers F, Schreibelt G, Skold AE, Figdor CG, De Vries IJ. Paradigm shift in dendritic cell-based immunotherapy: from generated monocyte-derived DCs to naturally circulating DC subsets. Front Immunol. 2014;5:165.PubMedPubMedCentralGoogle Scholar
  111. 111.
    Hsu FJ, Benike C, Fagnoni F, Liles TM, Czerwinski D, Taidi B, et al. Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat Med. 1996;2(1):52–8.PubMedGoogle Scholar
  112. 112.
    Skachkova OV, Khranovska NM, Gorbach OI, Svergun NM, Sydor RI, Nikulina VV. Immunological markers of anti-tumor dendritic cells vaccine efficiency in patients with non-small cell lung cancer. Exp Oncol. 2013;35(2):109–13.PubMedGoogle Scholar
  113. 113.
    Vansteenkiste J, Zielinski M, Linder A, Dahabreh J, Gonzalez EE, Malinowski W, et al. Adjuvant MAGE-A3 immunotherapy in resected non-small-cell lung cancer: phase II randomized study results. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(19):2396–403.Google Scholar
  114. 114.
    Butts C, Murray N, Maksymiuk A, Goss G, Marshall E, Soulières D, et al. Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(27):6674–81.Google Scholar
  115. 115.
    Butts C, Maksymiuk A, Goss G, Soulières D, Marshall E, Cormier Y, et al. Updated survival analysis in patients with stage IIIB or IV non-small-cell lung cancer receiving BLP25 liposome vaccine (L-BLP25): phase IIB randomized, multicenter, open-label trial. J Cancer Res Clin Oncol. 2011;137(9):1337–42.PubMedGoogle Scholar
  116. 116.
    Ramlau R, Quoix E, Rolski J, Pless M, Lena H, Lévy E, et al. A phase II study of Tg4010 (Mva-Muc1-Il2) in association with chemotherapy in patients with stage III/IV non-small cell lung cancer. J Thorac Oncol. 2008;3(7):735–44.PubMedGoogle Scholar
  117. 117.
    Quoix E, Ramlau R, Westeel V, Papai Z, Madroszyk A, Riviere A, et al. Therapeutic vaccination with TG4010 and first-line chemotherapy in advanced non-small-cell lung cancer: a controlled phase 2B trial. Lancet Oncol. 2011;12(12):1125–33.PubMedGoogle Scholar
  118. 118.
    Vinageras EN, de la Torre A, Rodríguez MO, Ferrer MC, Bravo I, del Pino MM, et al. Phase II randomized controlled trial of an epidermal growth factor vaccine in advanced non-small-cell lung cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26(9):1452–8.Google Scholar
  119. 119.
    Grant SC, Kris MG, Houghton AN, Chapman PB. Long survival of patients with small cell lung cancer after adjuvant treatment with the anti-idiotypic antibody BEC2 plus Bacillus Calmette-Guerin. Clin Cancer Res. 1999;5(6):1319–23.PubMedGoogle Scholar
  120. 120.
    Alfonso S, Valdés-Zayas A, Santiesteban ER, Flores YI, Areces F, Hernández M, et al. A randomized, multicenter, placebo-controlled clinical trial of racotumomab-alum vaccine as switch maintenance therapy in advanced non-small cell lung cancer patients. Clin Cancer Res. 2014;20(14):3660–71.PubMedGoogle Scholar
  121. 121.
    Nemunaitis J, Jahan T, Ross H, Sterman D, Richards D, Fox B, et al. Phase 1/2 trial of autologous tumor mixed with an allogeneic GVAX® vaccine in advanced-stage non-small-cell lung cancer. Cancer Gene Ther. 2006;13(6):555–62.PubMedGoogle Scholar
  122. 122.
    Nemunaitis J, Dillman RO, Schwarzenberger PO, Senzer N, Cunningham C, Cutler J, et al. Phase II study of belagenpumatucel-L, a transforming growth factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non-small-cell lung cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2006;24(29):4721–30.Google Scholar
  123. 123.
    Domingues D, Turner A, Silva MD, Marques DS, Mellidez JC, Wannesson L, et al. Immunotherapy and lung cancer: current developments and novel targeted therapies. Immunotherapy. 2014;6(11):1221–35.PubMedGoogle Scholar
  124. 124.
    Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.PubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Pedro Madureira
    • 1
    • 2
    • 3
  • Ramon Andrade de Mello
    • 4
    • 5
  • Alessandro de Vasconcelos
    • 6
    • 7
  • Yan Zhang
    • 8
  1. 1.Instituto de Investigação e Inovação em SaúdeUniversidade do PortoPortoPortugal
  2. 2.IBMC–Instituto de Biologia Molecular e CelularUniversidade do PortoPortoPortugal
  3. 3.ICBAS–Instituto de Ciências Biomédicas Abel SalazarUniversidade do PortoPortoPortugal
  4. 4.Department of Biomedical Sciences and MedicineUniversity of AlgarveFaroPortugal
  5. 5.Research Center, Department of Medical OncologyPortuguese Oncology InstitutePortoPortugal
  6. 6.Service of Medical Oncology, Núcleo de Terapia OncológicaHospital Jorge ValenteSalvadorBrazil
  7. 7.Clinical Research UnitInstituto de Oncologia da BahiaLauro de Freitas, SalvadorBrazil
  8. 8.The Respiratory DepartmentNingbo No. 7 HospitalNingboPeople’s Republic of China

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