Skip to main content

Immune Therapy

  • Chapter
  • First Online:

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 893))

Abstract

Lung cancer has long been considered an unsuitable target for immunotherapy due to its proposed immunoresistant properties. However, recent evidence has shown that anti-tumor immune responses can occur in lung cancer patients, paving the way for lung cancer as a novel target for immunotherapy. In order to take full advantage of the potential of immunotherapy, research is focusing on the presence and function of various immunological cell types in the tumor microenvironment. Immune cells which facilitate or inhibit antitumor responses have been identified and their prognostic value in lung cancer has been established. Knowledge regarding these pro- and anti-tumor immune cells and their mechanisms of action has facilitated the identification of numerous potential immunotherapeutic strategies and opportunities for intervention. A plethora of immunotherapeutic approaches is currently being developed and studied in lung cancer patients and phase 3 clinical trials are ongoing. Many different immunotherapies have shown promising clinical effects in patients with limited and advanced stage lung cancer, however, future years will have to tell whether immunotherapy will earn its place in the standard treatment of lung cancer.

This is a preview of subscription content, log in via an institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Couzin-Frankel J (2013) Breakthrough of the year 2013. Cancer immunotherapy. Science 342(6165):1432–1433

    Article  CAS  PubMed  Google Scholar 

  2. Kantoff PW et al (2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363(5):411–422

    Article  CAS  PubMed  Google Scholar 

  3. Hodi FS et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Holzel M, Bovier A, Tuting T (2013) Plasticity of tumour and immune cells: a source of heterogeneity and a cause for therapy resistance? Nat Rev Cancer 13(5):365–376

    Article  PubMed  CAS  Google Scholar 

  5. Tartour E, Zitvogel L (2013) Lung cancer: potential targets for immunotherapy. Lancet Respir Med 1:551–563

    Article  CAS  PubMed  Google Scholar 

  6. Heuvers ME et al (2012) Patient-tailored modulation of the immune system may revolutionize future lung cancer treatment. BMC Cancer 12:580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Becknell B, Caligiuri MA (2008) Natural killer cells in innate immunity and cancer. J Immunother 31(8):685–692

    Article  PubMed  Google Scholar 

  8. Caligiuri MA (2008) Human natural killer cells. Blood 112(3):461–469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Al-Shibli K et al (2009) The prognostic value of intraepithelial and stromal innate immune system cells in non-small cell lung carcinoma. Histopathology 55(3):301–312

    Article  PubMed  Google Scholar 

  10. Rijavec M et al (2011) Natural killer T cells in pulmonary disorders. Respir Med 105(Suppl 1):S20–S25

    Article  PubMed  Google Scholar 

  11. Shimizu T et al (2009) Activation of Valpha24NKT cells in malignant pleural effusion in patients with lung cancer. Oncol Rep 22(3):581–586

    Article  CAS  PubMed  Google Scholar 

  12. Molling JW et al (2005) Peripheral blood IFN-gamma-secreting Valpha24+ Vbeta11+ NKT cell numbers are decreased in cancer patients independent of tumor type or tumor load. Int J Cancer 116(1):87–93

    Article  CAS  PubMed  Google Scholar 

  13. Tahir SM et al (2001) Loss of IFN-gamma production by invariant NK T cells in advanced cancer. J Immunol 167(7):4046–4050

    Article  CAS  PubMed  Google Scholar 

  14. O’Callaghan DS et al (2010) The role of inflammation in the pathogenesis of non-small cell lung cancer. J Thorac Oncol 5(12):2024–2036

    Article  PubMed  Google Scholar 

  15. Dundar E et al (2008) The significance and relationship between mast cells and tumour angiogenesis in non-small cell lung carcinoma. J Int Med Res 36(1):88–95

    Article  CAS  PubMed  Google Scholar 

  16. Stoyanov E et al (2012) Mast cells and histamine enhance the proliferation of non-small cell lung cancer cells. Lung Cancer 75(1):38–44

    Article  PubMed  Google Scholar 

  17. Khazaie K et al (2011) The significant role of mast cells in cancer. Cancer Metastasis Rev 30(1):45–60

    Article  CAS  PubMed  Google Scholar 

  18. Niczyporuk M et al (2012) A lack of correlation between mast cells, angiogenesis, and outcome in non-small cell lung cancer. Exp Lung Res 38(6):281–285

    Article  CAS  PubMed  Google Scholar 

  19. Heijmans J et al (2012) Role of mast cells in colorectal cancer development, the jury is still out. Biochim Biophys Acta 1822(1):9–13

    Article  CAS  PubMed  Google Scholar 

  20. Nechushtan H (2010) The complexity of the complicity of mast cells in cancer. Int J Biochem Cell Biol 42(5):551–554

    Article  CAS  PubMed  Google Scholar 

  21. Sarraf KM et al (2009) Neutrophil/lymphocyte ratio and its association with survival after complete resection in non-small cell lung cancer. J Thorac Cardiovasc Surg 137(2):425–428

    Article  PubMed  Google Scholar 

  22. Teramukai S et al (2009) Pretreatment neutrophil count as an independent prognostic factor in advanced non-small-cell lung cancer: an analysis of Japan Multinational Trial Organisation LC00-03. Eur J Cancer 45(11):1950–1958

    Article  PubMed  Google Scholar 

  23. Tomita M et al (2011) Preoperative neutrophil to lymphocyte ratio as a prognostic predictor after curative resection for non-small cell lung cancer. Anticancer Res 31(9):2995–2998

    PubMed  Google Scholar 

  24. Mantovani A (2009) The yin-yang of tumor-associated neutrophils. Cancer Cell 16(3):173–174

    Article  CAS  PubMed  Google Scholar 

  25. Colotta F et al (2009) Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 30(7):1073–1081

    Article  CAS  PubMed  Google Scholar 

  26. Fridlender ZG et al (2009) Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell 16(3):183–194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Soehnlein O (2009) An elegant defense: how neutrophils shape the immune response. Trends Immunol 30(11):511–512

    Article  CAS  PubMed  Google Scholar 

  28. Puga I et al (2012) B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen. Nat Immunol 13(2):170–180

    Article  CAS  Google Scholar 

  29. Yang D et al (2009) Alarmins link neutrophils and dendritic cells. Trends Immunol 30(11):531–537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ilie M et al (2011) Predictive clinical outcome of the intratumoral CD66b-positive neutrophil- to-CD8-positive T-cell ratio in patients with resectable nonsmall cell lung cancer. Cancer 118(6):1726–37

    Google Scholar 

  31. Gottlin EB et al (2011) The association of intratumoral germinal centers with early-stage non-small cell lung cancer. J Thorac Oncol 6(10):1687–1690

    Article  PubMed  Google Scholar 

  32. Pelletier MP et al (2001) Prognostic markers in resectable non-small cell lung cancer: a multivariate analysis. Can J Surg 44(3):180–188

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Kazarian M, Laird-Offringa IA (2011) Small-cell lung cancer-associated autoantibodies: potential applications to cancer diagnosis, early detection, and therapy. Mol Cancer 10:33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mihn DC, Kim TY (2009) Various autoantibodies are found in small-cell lung cancer. Lung Cancer 64(2):250

    Article  PubMed  Google Scholar 

  35. Nagashio R et al (2008) Detection of tumor-specific autoantibodies in sera of patients with lung cancer. Lung Cancer 62(3):364–373

    Article  PubMed  Google Scholar 

  36. Amornsiripanitch N et al (2010) Complement factor H autoantibodies are associated with early stage NSCLC. Clin Cancer Res 16(12):3226–3231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Andersen MH et al (2006) Cytotoxic T cells. J Invest Dermatol 126(1):32–41

    Article  CAS  PubMed  Google Scholar 

  38. Hiraoka K et al (2006) Concurrent infiltration by CD8+ T cells and CD4+ T cells is a favourable prognostic factor in non-small-cell lung carcinoma. Br J Cancer 94(2):275–280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. McCoy MJ et al (2012) Peripheral CD8(+) T cell proliferation is prognostic for patients with advanced thoracic malignancies. Cancer Immunol Immunother 62(3):529–39

    Google Scholar 

  40. Mori M et al (2000) Infiltration of CD8+ T cells in non-small cell lung cancer is associated with dedifferentiation of cancer cells, but not with prognosis. Tohoku J Exp Med 191(2):113–118

    Article  CAS  PubMed  Google Scholar 

  41. Suzuki K et al (2011) 2011. Prognostic immune markers in non-small cell lung cancer. Clin Cancer Res 17(16):5247–56

    Google Scholar 

  42. Trojan A et al (2004) Immune activation status of CD8+ T cells infiltrating non-small cell lung cancer. Lung Cancer 44(2):143–147

    Article  PubMed  Google Scholar 

  43. Wakabayashi O et al (2003) CD4+ T cells in cancer stroma, not CD8+ T cells in cancer cell nests, are associated with favorable prognosis in human non-small cell lung cancers. Cancer Sci 94(11):1003–1009

    Article  CAS  PubMed  Google Scholar 

  44. Wherry EJ (2011) T cell exhaustion. Nat Immunol 12(6):492–499

    Article  CAS  PubMed  Google Scholar 

  45. Kayser G et al (2012) Stromal CD4/CD25 positive T-cells are a strong and independent prognostic factor in non-small cell lung cancer patients, especially with adenocarcinomas. Lung Cancer 76(3):445–51

    Google Scholar 

  46. Ruffini E et al (2009) Clinical significance of tumor-infiltrating lymphocytes in lung neoplasms. Ann Thorac Surg 87(2):365–371, discussion 371-2

    Article  PubMed  Google Scholar 

  47. Ni XY et al (2012) TGF-beta of lung cancer microenvironment upregulates B7H1 and GITRL expression in dendritic cells and is associated with regulatory T cell generation. Oncol Rep 28(2):615–621

    CAS  PubMed  Google Scholar 

  48. Hawrylowicz CM, O’Garra A (2005) Potential role of interleukin-10-secreting regulatory T cells in allergy and asthma. Nat Rev Immunol 5(4):271–283

    Article  CAS  PubMed  Google Scholar 

  49. Thornton AM, Shevach EM (1998) CD4 + CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 188(2):287–296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Fu HY et al (2013) FOXP3 and TLR4 protein expression are correlated in non-small cell lung cancer: implications for tumor progression and escape. Acta Histochem 115(2):151–157

    Article  CAS  PubMed  Google Scholar 

  51. Woo EY et al (2001) Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res 61(12):4766–4772

    CAS  PubMed  Google Scholar 

  52. Erfani N et al (2012) Increase of regulatory T cells in metastatic stage and CTLA-4 over expression in lymphocytes of patients with non-small cell lung cancer (NSCLC). Lung Cancer 77(2):306–311

    Article  PubMed  Google Scholar 

  53. Okita R et al (2005) CD4+ CD25+ regulatory T cells in the peripheral blood of patients with breast cancer and non-small cell lung cancer. Oncol Rep 14(5):1269–1273

    CAS  PubMed  Google Scholar 

  54. Dimitrakopoulos FI et al (2011) Association of FOXP3 expression with non-small cell lung cancer. Anticancer Res 31(5):1677–1683

    CAS  PubMed  Google Scholar 

  55. Zaynagetdinov R et al (2012) Epithelial nuclear factor-kappaB signaling promotes lung carcinogenesis via recruitment of regulatory T lymphocytes. Oncogene 31(26):3164–3176

    Article  CAS  PubMed  Google Scholar 

  56. Tao H et al (2012) Prognostic potential of FOXP3 expression in non-small cell lung cancer cells combined with tumor-infiltrating regulatory T cells. Lung Cancer 75(1):95–101

    Article  PubMed  Google Scholar 

  57. Li H et al (2011) Increased prevalence of regulatory T cells in the lung cancer microenvironment: a role of thymic stromal lymphopoietin. Cancer Immunol Immunother 60(11):1587–1596

    Article  CAS  PubMed  Google Scholar 

  58. Sharma S et al (2005) Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+ CD25+ T regulatory cell activities in lung cancer. Cancer Res 65(12):5211–5220

    Article  CAS  PubMed  Google Scholar 

  59. Zou W (2006) Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 6(4):295–307

    Article  CAS  PubMed  Google Scholar 

  60. Iwakura Y et al (2011) Functional specialization of interleukin-17 family members. Immunity 34(2):149–162

    Article  CAS  PubMed  Google Scholar 

  61. Zou W, Restifo NP (2010) T(H)17 cells in tumour immunity and immunotherapy. Nat Rev Immunol 10(4):248–256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ye ZJ et al (2010) Generation and differentiation of IL-17-producing CD4+ T cells in malignant pleural effusion. J Immunol 185(10):6348–6354

    Article  CAS  PubMed  Google Scholar 

  63. Li Y et al (2011) Effects of IL-17A on the occurrence of lung adenocarcinoma. Cancer Biol Ther 12(7):610–616

    Article  CAS  PubMed  Google Scholar 

  64. Chen X et al (2010) Increased IL-17-producing cells correlate with poor survival and lymphangiogenesis in NSCLC patients. Lung Cancer 69(3):348–354

    Article  PubMed  Google Scholar 

  65. Wilke CM et al (2011) Th17 cells in cancer: help or hindrance? Carcinogenesis 32(5):643–649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Gallina G et al (2006) Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells. J Clin Invest 116(10):2777–2790

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Watanabe S et al (2008) Tumor-induced CD11b+ Gr-1+ myeloid cells suppress T cell sensitization in tumor-draining lymph nodes. J Immunol 181(5):3291–3300

    Article  CAS  PubMed  Google Scholar 

  68. Lu T et al (2011) Tumor-infiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice. J Clin Invest 121(10):4015–4029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Serafini P et al (2008) Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells. Cancer Res 68(13):5439–5449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Hoechst B et al (2009) Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology 50(3):799–807

    Article  CAS  PubMed  Google Scholar 

  71. Li H et al (2009) Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-beta 1. J Immunol 182(1):240–249

    Article  CAS  PubMed  Google Scholar 

  72. Nausch N et al (2008) Mononuclear myeloid-derived “suppressor” cells express RAE-1 and activate natural killer cells. Blood 112(10):4080–4089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Cheng P et al (2008) Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J Exp Med 205(10):2235–2249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hoechst B et al (2008) A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology 135(1):234–243

    Article  CAS  PubMed  Google Scholar 

  75. Pan PY et al (2010) Immune stimulatory receptor CD40 is required for T-cell suppression and T regulatory cell activation mediated by myeloid-derived suppressor cells in cancer. Cancer Res 70(1):99–108

    Article  CAS  PubMed  Google Scholar 

  76. Finke J et al (2011) MDSC as a mechanism of tumor escape from sunitinib mediated anti-angiogenic therapy. Int Immunopharmacol 11(7):856–861

    Article  CAS  PubMed  Google Scholar 

  77. Ostrand-Rosenberg S (2010) Myeloid-derived suppressor cells: more mechanisms for inhibiting antitumor immunity. Cancer Immunol Immunother 59(10):1593–1600

    Article  PubMed  PubMed Central  Google Scholar 

  78. Bronte V, Zanovello P (2005) Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol 5(8):641–654

    Article  CAS  PubMed  Google Scholar 

  79. Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9(3):162–174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Rodriguez PC, Ochoa AC (2008) Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives. Immunol Rev 222:180–191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Youn JI, Gabrilovich DI (2010) The biology of myeloid-derived suppressor cells: the blessing and the curse of morphological and functional heterogeneity. Eur J Immunol 40(11):2969–2975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Ostrand-Rosenberg S et al (2012) Cross-talk between myeloid-derived suppressor cells (MDSC), macrophages, and dendritic cells enhances tumor-induced immune suppression. Semin Cancer Biol 22(4):275–81

    Google Scholar 

  83. Liu CY et al (2010) Population alterations of L-arginase- and inducible nitric oxide synthase-expressed CD11b+/CD14/CD15+/CD33+ myeloid-derived suppressor cells and CD8+ T lymphocytes in patients with advanced-stage non-small cell lung cancer. J Cancer Res Clin Oncol 136(1):35–45

    Article  CAS  PubMed  Google Scholar 

  84. Bremnes RM et al (2011) The role of tumor-infiltrating immune cells and chronic inflammation at the tumor site on cancer development, progression, and prognosis: emphasis on non-small cell lung cancer. J Thorac Oncol 6(4):824–833

    Article  PubMed  Google Scholar 

  85. Schmid MC, Varner JA (2010) Myeloid cells in the tumor microenvironment: modulation of tumor angiogenesis and tumor inflammation. J Oncol 2010:201026

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Lewis C, Murdoch C (2005) Macrophage responses to hypoxia: implications for tumor progression and anti-cancer therapies. Am J Pathol 167(3):627–635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Dai F et al (2010) The number and microlocalization of tumor-associated immune cells are associated with patient’s survival time in non-small cell lung cancer. BMC Cancer 10:220

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Kawai O et al (2008) Predominant infiltration of macrophages and CD8(+) T Cells in cancer nests is a significant predictor of survival in stage IV nonsmall cell lung cancer. Cancer 113(6):1387–1395

    Article  CAS  PubMed  Google Scholar 

  89. Ma J et al (2010) The M1 form of tumor-associated macrophages in non-small cell lung cancer is positively associated with survival time. BMC Cancer 10:112

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Ohri CM et al (2009) Macrophages within NSCLC tumour islets are predominantly of a cytotoxic M1 phenotype associated with extended survival. Eur Respir J 33(1):118–126

    Article  CAS  PubMed  Google Scholar 

  91. Welsh TJ et al (2005) Macrophage and mast-cell invasion of tumor cell islets confers a marked survival advantage in non-small-cell lung cancer. J Clin Oncol 23(35):8959–8967

    Article  PubMed  Google Scholar 

  92. Sautes-Fridman C et al (2011) Tumor microenvironment is multifaceted. Cancer Metastasis Rev 30(1):13–25

    Article  PubMed  Google Scholar 

  93. Becker Y (1993) Dendritic cell activity against primary tumors: an overview. In Vivo 7(3):187–191

    CAS  PubMed  Google Scholar 

  94. Mitra R, Singh S, Khar A (2003) Antitumour immune responses. Expert Rev Mol Med 5(3):1–19

    Article  PubMed  Google Scholar 

  95. Kusmartsev S, Gabrilovich DI (2006) Effect of tumor-derived cytokines and growth factors on differentiation and immune suppressive features of myeloid cells in cancer. Cancer Metastasis Rev 25(3):323–331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Pinzon-Charry A, Maxwell T, Lopez JA (2005) Dendritic cell dysfunction in cancer: a mechanism for immunosuppression. Immunol Cell Biol 83(5):451–461

    Article  CAS  PubMed  Google Scholar 

  97. Shurin MR et al (2006) Intratumoral cytokines/chemokines/growth factors and tumor infiltrating dendritic cells: friends or enemies? Cancer Metastasis Rev 25(3):333–356

    Article  CAS  PubMed  Google Scholar 

  98. Almand B et al (2000) Clinical significance of defective dendritic cell differentiation in cancer. Clin Cancer Res 6(5):1755–1766

    CAS  PubMed  Google Scholar 

  99. Bergeron A et al (2006) Characterisation of dendritic cell subsets in lung cancer micro-environments. Eur Respir J 28(6):1170–1177

    Article  CAS  PubMed  Google Scholar 

  100. Gabrilovich D (2004) Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat Rev Immunol 4(12):941–952

    Article  CAS  PubMed  Google Scholar 

  101. Gabrilovich DI et al (1996) Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 2(10):1096–1103

    Article  CAS  PubMed  Google Scholar 

  102. Laxmanan S et al (2005) Vascular endothelial growth factor impairs the functional ability of dendritic cells through Id pathways. Biochem Biophys Res Commun 334(1):193–198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Menetrier-Caux C et al (1998) Inhibition of the differentiation of dendritic cells from CD34(+) progenitors by tumor cells: role of interleukin-6 and macrophage colony-stimulating factor. Blood 92(12):4778–4791

    CAS  PubMed  Google Scholar 

  104. Steinman RM (1991) The dendritic cell system and its role in immunogenicity. Annu Rev Immunol 9:271–296

    Article  CAS  PubMed  Google Scholar 

  105. Dumitriu IE et al (2009) Human dendritic cells produce TGF-beta 1 under the influence of lung carcinoma cells and prime the differentiation of CD4 + CD25 + Foxp3+ regulatory T cells. J Immunol 182(5):2795–2807

    Article  CAS  PubMed  Google Scholar 

  106. Mu CY et al (2011) High expression of PD-L1 in lung cancer may contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating dendritic cells maturation. Med Oncol 28(3):682–688

    Article  CAS  PubMed  Google Scholar 

  107. Schneider T et al (2011) Non-small cell lung cancer induces an immunosuppressive phenotype of dendritic cells in tumor microenvironment by upregulating B7-H3. J Thorac Oncol 6(7):1162–1168

    Article  PubMed  Google Scholar 

  108. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70

    Article  CAS  PubMed  Google Scholar 

  109. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674

    Article  CAS  PubMed  Google Scholar 

  110. Dieu-Nosjean MC et al (2008) Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol 26(27):4410–4417

    Article  CAS  PubMed  Google Scholar 

  111. Al-Shibli KI et al (2008) Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. Clin Cancer Res 14(16):5220–5227

    Article  CAS  PubMed  Google Scholar 

  112. Ito N et al (2005) Prognostic significance of T helper 1 and 2 and T cytotoxic 1 and 2 cells in patients with non-small cell lung cancer. Anticancer Res 25(3B):2027–2031

    CAS  PubMed  Google Scholar 

  113. Petersen RP et al (2006) Tumor infiltrating Foxp3+ regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients. Cancer 107(12):2866–2872

    Article  PubMed  Google Scholar 

  114. Shimizu K et al (2010) Tumor-infiltrating Foxp3+ regulatory T cells are correlated with cyclooxygenase-2 expression and are associated with recurrence in resected non-small cell lung cancer. J Thorac Oncol 5(5):585–590

    Article  PubMed  Google Scholar 

  115. Fridman WH et al (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12(4):298–306

    Article  CAS  PubMed  Google Scholar 

  116. Bindea G et al (2013) Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 39(4):782–795

    Article  CAS  PubMed  Google Scholar 

  117. Ruffell B, Affara NI, Coussens LM (2012) Differential macrophage programming in the tumor microenvironment. Trends Immunol 33(3):119–126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Escribese MM, Casas M, Corbi AL (2012) Influence of low oxygen tensions on macrophage polarization. Immunobiology 217(12):1233–1240

    Article  CAS  PubMed  Google Scholar 

  119. Lewis CE, Hughes R (2007) Inflammation and breast cancer. Microenvironmental factors regulating macrophage function in breast tumours: hypoxia and angiopoietin-2. Breast Cancer Res 9(3):209

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. White JR et al (2004) Genetic amplification of the transcriptional response to hypoxia as a novel means of identifying regulators of angiogenesis. Genomics 83(1):1–8

    Article  CAS  PubMed  Google Scholar 

  121. Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331(6024):1565–1570

    Article  CAS  PubMed  Google Scholar 

  122. Ruckdeschel JC et al (1972) Postoperative empyema improves survival in lung cancer. Documentation and analysis of a natural experiment. N Engl J Med 287(20):1013–1017

    Article  CAS  PubMed  Google Scholar 

  123. McKneally MF, Maver C, Kausel HW (1976) Regional immunotherapy of lung cancer with intrapleural B.C.G. Lancet 1(7956):377–379

    Article  CAS  PubMed  Google Scholar 

  124. Giaccone G et al (2005) Phase III study of adjuvant vaccination with Bec2/bacille Calmette-Guerin in responding patients with limited-disease small-cell lung cancer (European Organisation for Research and Treatment of Cancer 08971-08971B; Silva Study). J Clin Oncol 23(28):6854–6864

    Article  CAS  PubMed  Google Scholar 

  125. Malmstrom PU et al (1999) 5-year follow-up of a randomized prospective study comparing mitomycin C and bacillus Calmette-Guerin in patients with superficial bladder carcinoma. Swedish-Norwegian Bladder Cancer Study Group. J Urol 161(4):1124–1127

    Article  CAS  PubMed  Google Scholar 

  126. O’Brien ME et al (2000) A randomized phase II study of SRL172 (Mycobacterium vaccae) combined with chemotherapy in patients with advanced inoperable non-small-cell lung cancer and mesothelioma. Br J Cancer 83(7):853–857

    Article  PubMed  PubMed Central  Google Scholar 

  127. O’Brien ME et al (2004) SRL172 (killed Mycobacterium vaccae) in addition to standard chemotherapy improves quality of life without affecting survival, in patients with advanced non-small-cell lung cancer: phase III results. Ann Oncol 15(6):906–914

    Article  PubMed  Google Scholar 

  128. Grange JM et al (2008) The use of mycobacterial adjuvant-based agents for immunotherapy of cancer. Vaccine 26(39):4984–4990

    Article  CAS  PubMed  Google Scholar 

  129. Droemann D et al (2005) Human lung cancer cells express functionally active Toll-like receptor 9. Respir Res 6:1

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Manegold C et al (2012) A phase III randomized study of gemcitabine and cisplatin with or without PF-3512676 (TLR9 agonist) as first-line treatment of advanced non-small-cell lung cancer. Ann Oncol 23(1):72–77

    Article  CAS  PubMed  Google Scholar 

  131. Hirsh V et al (2011) Randomized phase III trial of paclitaxel/carboplatin with or without PF-3512676 (Toll-like receptor 9 agonist) as first-line treatment for advanced non-small-cell lung cancer. J Clin Oncol 29(19):2667–2674

    Article  CAS  PubMed  Google Scholar 

  132. Perret R et al (2013) Adjuvants that improve the ratio of antigen-specific effector to regulatory T cells enhance tumor immunity. Cancer Res 73(22):6597–6608

    Article  CAS  PubMed  Google Scholar 

  133. Ettinger DS, Harwood K (1988) Phase II study of recombinant beta interferon in patients with advanced non-small-cell lung carcinoma. Med Pediatr Oncol 16(1):30–32

    Article  CAS  PubMed  Google Scholar 

  134. Olesen BK et al (1987) Recombinant interferon A (IFL-rA) therapy of small cell and squamous cell carcinoma of the lung. A phase II study. Eur J Cancer Clin Oncol 23(7):987–989

    Article  CAS  PubMed  Google Scholar 

  135. Jansen RL et al (1992) Interleukin-2 and interferon-alpha in the treatment of patients with advanced non-small-cell lung cancer. J Immunother (1991) 12(1):70–73

    Article  CAS  Google Scholar 

  136. Jett JR et al (1994) Phase III trial of recombinant interferon gamma in complete responders with small-cell lung cancer. J Clin Oncol 12(11):2321–2326

    Article  CAS  PubMed  Google Scholar 

  137. Mattson K et al (1991) Recombinant interferon gamma treatment in non-small cell lung cancer. Antitumour effect and cardiotoxicity. Acta Oncol 30(5):607–610

    Article  CAS  PubMed  Google Scholar 

  138. van Zandwijk N et al (1997) Role of recombinant interferon-gamma maintenance in responding patients with small cell lung cancer. A randomised phase III study of the EORTC Lung Cancer Cooperative Group. Eur J Cancer 33(11):1759–1766

    Article  PubMed  Google Scholar 

  139. Schiller JH, Morgan-Ihrig C, Levitt ML (1995) Concomitant administration of interleukin-2 plus tumor necrosis factor in advanced non-small cell lung cancer. Am J Clin Oncol 18(1):47–51

    Article  CAS  PubMed  Google Scholar 

  140. Timmer-Bonte JN et al (2005) Prevention of chemotherapy-induced febrile neutropenia by prophylactic antibiotics plus or minus granulocyte colony-stimulating factor in small-cell lung cancer: a Dutch Randomized Phase III Study. J Clin Oncol 23(31):7974–7984

    Article  CAS  PubMed  Google Scholar 

  141. Timmer-Bonte JN et al (2008) Prophylactic G-CSF and antibiotics enable a significant dose-escalation of triplet-chemotherapy in non-small cell lung cancer. Lung Cancer 60(2):222–230

    Article  CAS  PubMed  Google Scholar 

  142. Spadaro M et al (2008) Lactoferrin, a major defense protein of innate immunity, is a novel maturation factor for human dendritic cells. FASEB J 22(8):2747–2757

    Article  CAS  PubMed  Google Scholar 

  143. Parikh PM et al (2011) Randomized, double-blind, placebo-controlled phase II study of single-agent oral talactoferrin in patients with locally advanced or metastatic non-small-cell lung cancer that progressed after chemotherapy. J Clin Oncol 29(31):4129–4136

    Article  CAS  PubMed  Google Scholar 

  144. Ramalingam S et al (2013) Talactoferrin alfa versus placebo in patients with refractory advanced non-small-cell lung cancer (FORTIS-M trial). Ann Oncol 24(11):2875–2880

    Article  CAS  PubMed  Google Scholar 

  145. Pirker R (2013) EGFR-directed monoclonal antibodies in non-small cell lung cancer. Target Oncol 8(1):47–53

    Article  PubMed  Google Scholar 

  146. Mazieres J et al (2013) Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives. J Clin Oncol 31(16):1997–2003

    Article  CAS  PubMed  Google Scholar 

  147. Arnould L et al (2006) Trastuzumab-based treatment of HER2-positive breast cancer: an antibody-dependent cellular cytotoxicity mechanism? Br J Cancer 94(2):259–267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Hassan R, Ho M (2008) Mesothelin targeted cancer immunotherapy. Eur J Cancer 44(1):46–53

    Article  CAS  PubMed  Google Scholar 

  149. Hassan R et al (2010) Phase I clinical trial of the chimeric anti-mesothelin monoclonal antibody MORAb-009 in patients with mesothelin-expressing cancers. Clin Cancer Res 16(24):6132–6138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Cui J et al (2013) The efficacy of bevacizumab compared with other targeted drugs for patients with advanced NSCLC: a meta-analysis from 30 randomized controlled clinical trials. PLoS One 8(4), e62038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Mansfield AS et al (2013) The immunomodulatory effects of bevacizumab on systemic immunity in patients with metastatic melanoma. Oncoimmunology 2(5), e24436

    Article  PubMed  PubMed Central  Google Scholar 

  152. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Aerts JG, Hegmans JP (2013) Tumor-specific cytotoxic T cells are crucial for efficacy of immunomodulatory antibodies in patients with lung cancer. Cancer Res 73(8):2381–2388

    Article  CAS  PubMed  Google Scholar 

  154. Robert C et al (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364(26):2517–2526

    Article  CAS  PubMed  Google Scholar 

  155. Lynch TJ et al (2012) 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 30(17):2046–2054

    Article  CAS  PubMed  Google Scholar 

  156. Calabro L et al (2013) Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol 14(11):1104–1111

    Article  CAS  PubMed  Google Scholar 

  157. Zhang Y et al (2010) Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer. Cell Mol Immunol 7(5):389–395

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Topalian SL et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26):2443–2454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Brahmer JR et al (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366(26):2455–2465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Lievense LA, Hegmans JP, Aerts JG (2014) Biomarkers for immune checkpoint inhibitors. Lancet Oncol 15(1), e1

    Article  PubMed  Google Scholar 

  161. van der Bruggen P et al (1991) A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 254(5038):1643–1647

    Article  PubMed  Google Scholar 

  162. Jang SJ et al (2001) Activation of melanoma antigen tumor antigens occurs early in lung carcinogenesis. Cancer Res 61(21):7959–7963

    CAS  PubMed  Google Scholar 

  163. Thomas A, Hassan R (2012) Immunotherapies for non-small-cell lung cancer and mesothelioma. Lancet Oncol 13(7):e301–e310

    Article  CAS  PubMed  Google Scholar 

  164. Bolli M et al (2002) Tissue microarray evaluation of Melanoma antigen E (MAGE) tumor-associated antigen expression: potential indications for specific immunotherapy and prognostic relevance in squamous cell lung carcinoma. Ann Surg 236(6):785–793, discussion 793

    Article  PubMed  PubMed Central  Google Scholar 

  165. Gure AO et al (2005) Cancer-testis genes are coordinately expressed and are markers of poor outcome in non-small cell lung cancer. Clin Cancer Res 11(22):8055–8062

    Article  CAS  PubMed  Google Scholar 

  166. Vansteenkiste J et al (2013) Adjuvant MAGE-A3 immunotherapy in resected non-small-cell lung cancer: Phase II Randomized Study Results. J Clin Oncol 31(19):2396–2403

    Article  CAS  PubMed  Google Scholar 

  167. Garcia B et al (2008) Effective inhibition of the epidermal growth factor/epidermal growth factor receptor binding by anti-epidermal growth factor antibodies is related to better survival in advanced non-small-cell lung cancer patients treated with the epidermal growth factor cancer vaccine. Clin Cancer Res 14(3):840–846

    Article  CAS  PubMed  Google Scholar 

  168. Rodriguez PC et al (2011) Safety, immunogenicity and preliminary efficacy of multiple-site vaccination with an Epidermal Growth Factor (EGF) based cancer vaccine in advanced non small cell lung cancer (NSCLC) patients. J Immune Based Ther Vaccines 9:7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Krug LM et al (2010) WT1 peptide vaccinations induce CD4 and CD8 T cell immune responses in patients with mesothelioma and non-small cell lung cancer. Cancer Immunol Immunother 59(10):1467–1479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Kim NW et al (1994) Specific association of human telomerase activity with immortal cells and cancer. Science 266(5193):2011–2015

    Article  CAS  PubMed  Google Scholar 

  171. Fernandez-Garcia I, Ortiz-de-Solorzano C, Montuenga LM (2008) Telomeres and telomerase in lung cancer. J Thorac Oncol 3(10):1085–1088

    Article  PubMed  Google Scholar 

  172. Kyte JA (2009) Cancer vaccination with telomerase peptide GV1001. Expert Opin Investig Drugs 18(5):687–694

    Article  CAS  PubMed  Google Scholar 

  173. Brunsvig PF et al (2011) Telomerase peptide vaccination in NSCLC: a phase II trial in stage III patients vaccinated after chemoradiotherapy and an 8-year update on a phase I/II trial. Clin Cancer Res 17(21):6847–6857

    Article  CAS  PubMed  Google Scholar 

  174. Henriksen-Lacey M et al (2011) Liposomal vaccine delivery systems. Expert Opin Drug Deliv 8(4):505–519

    Article  CAS  PubMed  Google Scholar 

  175. Sangha R, Butts C (2007) L-BLP25: a peptide vaccine strategy in non small cell lung cancer. Clin Cancer Res 13(15 Pt 2):s4652–s4654

    Article  PubMed  CAS  Google Scholar 

  176. Decoster L, Wauters I, Vansteenkiste JF (2012) Vaccination therapy for non-small-cell lung cancer: review of agents in phase III development. Ann Oncol 23(6):1387–1393

    Article  CAS  PubMed  Google Scholar 

  177. Butts C et al (2005) Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung cancer. J Clin Oncol 23(27):6674–6681

    Article  CAS  PubMed  Google Scholar 

  178. Kroemer G, Zitvogel L, Galluzzi L (2013) Victories and deceptions in tumor immunology: Stimuvax. Oncoimmunology 2(1), e23687

    Article  PubMed  PubMed Central  Google Scholar 

  179. Ramlau R et al (2008) 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 3(7):735–744

    Article  PubMed  Google Scholar 

  180. Quoix E et al (2011) Therapeutic vaccination with TG4010 and first-line chemotherapy in advanced non-small-cell lung cancer: a controlled phase 2B trial. Lancet Oncol 12(12):1125–1133

    Article  CAS  PubMed  Google Scholar 

  181. Thomas AM et al (2004) Mesothelin-specific CD8(+) T cell responses provide evidence of in vivo cross-priming by antigen-presenting cells in vaccinated pancreatic cancer patients. J Exp Med 200(3):297–306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Le DT et al (2012) A live-attenuated Listeria vaccine (ANZ-100) and a live-attenuated Listeria vaccine expressing mesothelin (CRS-207) for advanced cancers: phase I studies of safety and immune induction. Clin Cancer Res 18(3):858–868

    Article  CAS  PubMed  Google Scholar 

  183. Kochenderfer JN, Gress RE (2007) A comparison and critical analysis of preclinical anticancer vaccination strategies. Exp Biol Med (Maywood) 232(9):1130–1141

    Article  CAS  Google Scholar 

  184. Nemunaitis J et al (2004) Granulocyte-macrophage colony-stimulating factor gene-modified autologous tumor vaccines in non-small-cell lung cancer. J Natl Cancer Inst 96(4):326–331

    Article  CAS  PubMed  Google Scholar 

  185. Nemunaitis J et al (2006) Phase 1/2 trial of autologous tumor mixed with an allogeneic GVAX vaccine in advanced-stage non-small-cell lung cancer. Cancer Gene Ther 13(6):555–562

    Article  CAS  PubMed  Google Scholar 

  186. Ikushima H, Miyazono K (2010) TGFbeta signalling: a complex web in cancer progression. Nat Rev Cancer 10(6):415–424

    Article  CAS  PubMed  Google Scholar 

  187. Kong F et al (1999) Plasma transforming growth factor-beta1 level before radiotherapy correlates with long term outcome of patients with lung carcinoma. Cancer 86(9):1712–1719

    Article  CAS  PubMed  Google Scholar 

  188. Nemunaitis J et al (2006) 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 24(29):4721–4730

    Article  CAS  PubMed  Google Scholar 

  189. Ballen K, Stewart FM (1997) Adoptive immunotherapy. Curr Opin Oncol 9(6):579–583

    Article  CAS  PubMed  Google Scholar 

  190. Restifo NP, Dudley ME, Rosenberg SA (2012) Adoptive immunotherapy for cancer: harnessing the T cell response. Nat Rev Immunol 12(4):269–281

    Article  CAS  PubMed  Google Scholar 

  191. Zheng YW et al (2013) Current adoptive immunotherapy in non-small cell lung cancer and potential influence of therapy outcome. Cancer Invest 31(3):197–205

    Article  CAS  PubMed  Google Scholar 

  192. Perroud MW Jr et al (2011) Mature autologous dendritic cell vaccines in advanced non-small cell lung cancer: a phase I pilot study. J Exp Clin Cancer Res 30:65

    Article  PubMed  PubMed Central  Google Scholar 

  193. Wang K et al (2009) An autologous therapeutic dendritic cell vaccine transfected with total lung carcinoma RNA stimulates cytotoxic T lymphocyte responses against non-small cell lung cancer. Immunol Invest 38(7):665–680

    Article  CAS  PubMed  Google Scholar 

  194. Zhou Q et al (2008) A dendritic cell-based tumour vaccine for lung cancer: full-length XAGE-1b protein-pulsed dendritic cells induce specific cytotoxic T lymphocytes in vitro. Clin Exp Immunol 153(3):392–400

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Hegmans JP et al (2010) Consolidative dendritic cell-based immunotherapy elicits cytotoxicity against malignant mesothelioma. Am J Respir Crit Care Med 181(12):1383–1390

    Article  CAS  PubMed  Google Scholar 

  196. Kimura H, Yamaguchi Y (1995) Adjuvant immunotherapy with interleukin 2 and lymphokine-activated killer cells after noncurative resection of primary lung cancer. Lung Cancer 13(1):31–44

    Article  CAS  PubMed  Google Scholar 

  197. Kimura H, Yamaguchi Y (1997) A phase III randomized study of interleukin-2 lymphokine-activated killer cell immunotherapy combined with chemotherapy or radiotherapy after curative or noncurative resection of primary lung carcinoma. Cancer 80(1):42–49

    Article  CAS  PubMed  Google Scholar 

  198. Hontscha C et al (2011) Clinical trials on CIK cells: first report of the international registry on CIK cells (IRCC). J Cancer Res Clin Oncol 137(2):305–310

    Article  CAS  PubMed  Google Scholar 

  199. Hui KM (2012) CIK cells–current status, clinical perspectives and future prospects–the good news. Expert Opin Biol Ther 12(6):659–661

    Article  PubMed  Google Scholar 

  200. Li R et al (2012) Autologous cytokine-induced killer cell immunotherapy in lung cancer: a phase II clinical study. Cancer Immunol Immunother 61(11):2125–2133

    Article  CAS  PubMed  Google Scholar 

  201. Iwai K et al (2012) Extended survival observed in adoptive activated T lymphocyte immunotherapy for advanced lung cancer: results of a multicenter historical cohort study. Cancer Immunol Immunother 61(10):1781–1790

    Article  PubMed  PubMed Central  Google Scholar 

  202. Nakajima J et al (2010) A phase I study of adoptive immunotherapy for recurrent non-small-cell lung cancer patients with autologous gammadelta T cells. Eur J Cardiothorac Surg 37(5):1191–1197

    Article  PubMed  Google Scholar 

  203. Sakamoto M et al (2011) Adoptive immunotherapy for advanced non-small cell lung cancer using zoledronate-expanded gammadeltaTcells: a phase I clinical study. J Immunother 34(2):202–211

    Article  CAS  PubMed  Google Scholar 

  204. Iliopoulou EG et al (2010) A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer. Cancer Immunol Immunother 59(12):1781–1789

    Article  PubMed  Google Scholar 

  205. Dhodapkar MV, Richter J (2011) Harnessing natural killer T (NKT) cells in human myeloma: progress and challenges. Clin Immunol 140(2):160–166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Motohashi S, Nakayama T (2009) Natural killer T cell-mediated immunotherapy for malignant diseases. Front Biosci (Schol Ed) 1:108–116

    Article  Google Scholar 

  207. Wolchok JD et al (2009) Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 15(23):7412–7420

    Article  CAS  PubMed  Google Scholar 

  208. Cornelissen R et al (2012) New roads open up for implementing immunotherapy in mesothelioma. Clin Dev Immunol 2012:927240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Hegmans JP, Aerts JG (2013) Immunological profiling as a means to invigorate personalized cancer therapy. Oncoimmunology 2(8), e25236

    Article  PubMed  PubMed Central  Google Scholar 

  210. Kershaw MH et al (2013) Enhancing immunotherapy using chemotherapy and radiation to modify the tumor microenvironment. Oncoimmunology 2(9), e25962

    Article  PubMed  PubMed Central  Google Scholar 

  211. Galluzzi L et al (2012) The secret ally: immunostimulation by anticancer drugs. Nat Rev Drug Discov 11(3):215–233

    Article  CAS  PubMed  Google Scholar 

  212. Ko HJ et al (2007) A combination of chemoimmunotherapies can efficiently break self-tolerance and induce antitumor immunity in a tolerogenic murine tumor model. Cancer Res 67(15):7477–7486

    Article  CAS  PubMed  Google Scholar 

  213. Suzuki E et al (2005) Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res 11(18):6713–6721

    Article  CAS  PubMed  Google Scholar 

  214. Fridlender ZG et al (2010) Chemotherapy delivered after viral immunogene therapy augments antitumor efficacy via multiple immune-mediated mechanisms. Mol Ther 18(11):1947–1959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Nowak AK, Robinson BW, Lake RA (2003) Synergy between chemotherapy and immunotherapy in the treatment of established murine solid tumors. Cancer Res 63(15):4490–4496

    CAS  PubMed  Google Scholar 

  216. Belani CP et al (2013) Phase 2 trial of erlotinib with or without PF-3512676 (CPG 7909, a Toll-like receptor 9 agonist) in patients with advanced recurrent EGFR-positive non-small cell lung cancer. Cancer Biol Ther 14(7):557–563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Yamada K et al (2010) Phase I study of TLR9 agonist PF-3512676 in combination with carboplatin and paclitaxel in patients with advanced non-small-cell lung cancer. Cancer Sci 101(1):188–195

    Article  CAS  PubMed  Google Scholar 

  218. Wang YY et al (2011) The variation of CD4+ CD25+ regulatory T cells in the periphery blood and tumor microenvironment of non-small cell lung cancer patients and the downregulation effects induced by CpG ODN. Target Oncol 6(3):147–154

    Article  PubMed  Google Scholar 

  219. Bottomley A et al (2008) Symptom and quality of life results of an international randomised phase III study of adjuvant vaccination with Bec2/BCG in responding patients with limited disease small-cell lung cancer. Eur J Cancer 44(15):2178–2184

    Article  CAS  PubMed  Google Scholar 

  220. Gupta P et al (2008) Targeted combinatorial therapy of non-small cell lung carcinoma using a GST-fusion protein of full-length or truncated MDA-7/IL-24 with Tarceva. J Cell Physiol 215(3):827–836

    Article  CAS  PubMed  Google Scholar 

  221. Galustian C, Dalgleish A (2009) Lenalidomide: a novel anticancer drug with multiple modalities. Expert Opin Pharmacother 10(1):125–133

    Article  CAS  PubMed  Google Scholar 

  222. Elkinson S, McCormack PL (2013) Pomalidomide: first global approval. Drugs 73(6):595–604

    Article  CAS  PubMed  Google Scholar 

  223. Bass KK, Mastrangelo MJ (1998) Immunopotentiation with low-dose cyclophosphamide in the active specific immunotherapy of cancer. Cancer Immunol Immunother 47(1):1–12

    Article  CAS  PubMed  Google Scholar 

  224. Ghiringhelli F et al (2007) Metronomic cyclophosphamide regimen selectively depletes CD4+ CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother 56(5):641–648

    Article  CAS  PubMed  Google Scholar 

  225. Kawai M et al (2005) Inhibitory and stimulatory effects of cyclosporine A on the development of regulatory T cells in vivo. Transplantation 79(9):1073–1077

    Article  CAS  PubMed  Google Scholar 

  226. Litzinger MT et al (2007) IL-2 immunotoxin denileukin diftitox reduces regulatory T cells and enhances vaccine-mediated T-cell immunity. Blood 110(9):3192–3201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Hayes TG et al (2006) Phase I trial of oral talactoferrin alfa in refractory solid tumors. Invest New Drugs 24(3):233–240

    Article  CAS  PubMed  Google Scholar 

  228. Germano G et al (2013) Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell 23(2):249–262

    Article  CAS  PubMed  Google Scholar 

  229. Hoang T et al (2012) Randomized phase III study of thoracic radiation in combination with paclitaxel and carboplatin with or without thalidomide in patients with stage III non-small-cell lung cancer: the ECOG 3598 study. J Clin Oncol 30(6):616–622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Young RJ et al (2012) Analysis of circulating angiogenic biomarkers from patients in two phase III trials in lung cancer of chemotherapy alone or chemotherapy and thalidomide. Br J Cancer 106(6):1153–1159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Kruijtzer CM et al (2002) Phase II and pharmacologic study of weekly oral paclitaxel plus cyclosporine in patients with advanced non-small-cell lung cancer. J Clin Oncol 20(23):4508–4516

    Article  CAS  PubMed  Google Scholar 

  232. Gerena-Lewis M et al (2009) A Phase II trial of Denileukin Diftitox in patients with previously treated advanced non-small cell lung cancer. Am J Clin Oncol 32(3):269–273

    Article  CAS  PubMed  Google Scholar 

  233. Digumarti R et al (2011) A randomized, double-blind, placebo-controlled, phase II study of oral talactoferrin in combination with carboplatin and paclitaxel in previously untreated locally advanced or metastatic non-small cell lung cancer. J Thorac Oncol 6(6):1098–1103

    Article  PubMed  Google Scholar 

  234. Kelly RJ, Giaccone G (2010) The role of talactoferrin alpha in the treatment of non-small cell lung cancer. Expert Opin Biol Ther 10(9):1379–1386

    Article  CAS  PubMed  Google Scholar 

  235. Sessa C et al (2009) Phase I clinical and pharmacokinetic study of trabectedin and cisplatin in solid tumours. Eur J Cancer 45(12):2116–2122

    Article  CAS  PubMed  Google Scholar 

  236. Massuti B et al (2012) Trabectedin in patients with advanced non-small-cell lung cancer (NSCLC) with XPG and/or ERCC1 overexpression and BRCA1 underexpression and pretreated with platinum. Lung Cancer 76(3):354–361

    Article  PubMed  Google Scholar 

  237. Iclozan C et al (2013) Therapeutic regulation of myeloid-derived suppressor cells and immune response to cancer vaccine in patients with extensive stage small cell lung cancer. Cancer Immunol Immunother 62(5):909–918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Hanna N et al (2006) Phase II trial of cetuximab in patients with previously treated non-small-cell lung cancer. J Clin Oncol 24(33):5253–5258

    Article  CAS  PubMed  Google Scholar 

  239. Pirker R et al (2009) Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet 373(9674):1525–1531

    Article  CAS  PubMed  Google Scholar 

  240. Clamon G et al (2005) Lack of trastuzumab activity in nonsmall cell lung carcinoma with overexpression of erb-B2: 39810: a phase II trial of Cancer and Leukemia Group B. Cancer 103(8):1670–1675

    Article  CAS  PubMed  Google Scholar 

  241. Lara PN Jr et al (2004) Trastuzumab plus docetaxel in HER2/neu-positive non-small-cell lung cancer: a California Cancer Consortium screening and phase II trial. Clin Lung Cancer 5(4):231–236

    Article  CAS  PubMed  Google Scholar 

  242. Hassan R et al (2007) Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin given as a bolus I.V. infusion to patients with mesothelin-expressing mesothelioma, ovarian, and pancreatic cancers. Clin Cancer Res 13(17):5144–5149

    Article  CAS  PubMed  Google Scholar 

  243. Barlesi F et al (2013) Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol 31(24):3004–11

    Google Scholar 

  244. Reck M et al (2013) 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 24(1):75–83

    Article  CAS  PubMed  Google Scholar 

  245. Brezicka T et al (2000) Reactivity of monoclonal antibodies with ganglioside antigens in human small cell lung cancer tissues. Lung Cancer 28(1):29–36

    Article  CAS  PubMed  Google Scholar 

  246. Fernandez LE et al (2010) NGcGM3 ganglioside: a privileged target for cancer vaccines. Clin Dev Immunol 2010:814397

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  247. Nemunaitis J et al (2009) Phase II trial of Belagenpumatucel-L, a TGF-beta2 antisense gene modified allogeneic tumor vaccine in advanced non small cell lung cancer (NSCLC) patients. Cancer Gene Ther 16(8):620–624

    Article  CAS  PubMed  Google Scholar 

  248. Butts C et al (2011) 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 137(9):1337–1342

    Article  CAS  PubMed  Google Scholar 

  249. Grant SC et al (1999) 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 5(6):1319–1323

    CAS  PubMed  Google Scholar 

  250. Vazquez AM et al (2012) Racotumomab: an anti-idiotype vaccine related to N-glycolyl-containing gangliosides - preclinical and clinical data. Front Oncol 2:150

    PubMed  PubMed Central  Google Scholar 

  251. Rosenberg SA et al (1985) Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 313(23):1485–1492

    Article  CAS  PubMed  Google Scholar 

  252. Ma Y et al (2012) Cytokine-induced killer cells in the treatment of patients with solid carcinomas: a systematic review and pooled analysis. Cytotherapy 14(4):483–493

    Article  CAS  PubMed  Google Scholar 

  253. Terme M et al (2008) Natural killer cell-directed therapies: moving from unexpected results to successful strategies. Nat Immunol 9(5):486–494

    Article  CAS  PubMed  Google Scholar 

  254. Hirschowitz EA et al (2004) Autologous dendritic cell vaccines for non-small-cell lung cancer. J Clin Oncol 22(14):2808–2815

    Article  PubMed  Google Scholar 

  255. Hirschowitz EA et al (2007) Immunization of NSCLC patients with antigen-pulsed immature autologous dendritic cells. Lung Cancer 57(3):365–372

    Article  PubMed  PubMed Central  Google Scholar 

  256. Um SJ et al (2010) Phase I study of autologous dendritic cell tumor vaccine in patients with non-small cell lung cancer. Lung Cancer 70(2):188–194

    Article  PubMed  Google Scholar 

  257. Madan RA et al (2010) Therapeutic cancer vaccines in prostate cancer: the paradox of improved survival without changes in time to progression. Oncologist 15(9):969–975

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Joost Hegmans .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Lievense, L., Aerts, J., Hegmans, J. (2016). Immune Therapy. In: Ahmad, A., Gadgeel, S. (eds) Lung Cancer and Personalized Medicine. Advances in Experimental Medicine and Biology, vol 893. Springer, Cham. https://doi.org/10.1007/978-3-319-24223-1_4

Download citation

Publish with us

Policies and ethics