Skip to main content
SpringerLink
Log in

Modulation of Signaling Pathways by Immunotherapeutics in Lung Cancer

  • Chapter
  • First Online:
Targeting Cellular Signalling Pathways in Lung Diseases

  • 945 Accesses

Abstract

Lung cancer is the leading cause of mortality for both males and females among all types of cancer. Histologically lung cancer is classified into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Conventional surgery and chemotherapy are often associated with severe toxicity and multiple drug resistance among lung cancer patients. Recent advancement of immunotherapy can elicit immune-mediated destruction of tumor cells. Wide variations of immunotherapeutic approaches were undertaken to stimulate immune response against lung cancer cells including immunomodulators, therapeutic vaccines, and monoclonal antibodies, and those were directed towards checkpoint proteins in cancer cells. Checkpoint inhibitors targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and the programmed death-1 (PD-1) pathway were employed as immunotherapy with the achievement of progression free survival and associated with minimal toxicity among lung cancer patients. Various categories of therapeutic vaccines were employed in lung cancer, and those were associated with improved survival rate and quality of life. Recently, a combination of radiotherapy and immunotherapy was employed in lung cancer patients and found to be more effective with no significant generation of toxicity.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
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

Institutional subscriptions

References

  1. National Cancer Institute (2008) Non-small cell lung and bronchus cancer (invasive) survival rates, by race, sex, diagnosis year, state and age. In: SEER Cancer Statistics Review 1975–2004. National Cancer Institute, Bethesda, MD

    Google Scholar 

  2. Alberg AJ, Ford JG, Samet JM (2007) Epidemiology of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 132:29s–55s

    Article  CAS  PubMed  Google Scholar 

  3. Mountain CF (1997) Revisions in the international system for staging lung cancer. Chest 111:1710–1717

    Article  CAS  PubMed  Google Scholar 

  4. Shepherd FA, Crowley J, Van Houtte P, Postmus PE, Carney D, Chansky K et al (2007) The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer. J Thorac Oncol 2:1067–1077

    Article  PubMed  Google Scholar 

  5. Greenlee R, Murray T, Bloden S, Wingo PA (2000) Cancer statistics. CA Cancer J Clin 50:7–33

    Article  CAS  PubMed  Google Scholar 

  6. Bunn PJ, Kelly K (2000) New combinations in the treatment of lung cancer: a time for optimism. Chest 117:138–143

    Article  Google Scholar 

  7. Barlesi F (2010) Targeted therapies in non-small-cell lung cancer (NSCLC): how to proceed to aim at the good target? Eur J Cardio Thorac 38:37–38

    Article  Google Scholar 

  8. Kim EK, Kim KA, Lee CY, Shim HS (2017) The frequency and clinical impact of HER2 alterations in lung adenocarcinoma. PLoS One 12(2):e0171280

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Yoneda K, Imanishi N, Ichiki Y, Tanaka F (2018) Immune checkpoint inhibitors (ICIs) in non-small cell lung Cancer (NSCLC). J UOEH 40(2):173–189

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Dal Bello MG, Alama A, Coco S, Vanni I, Grossi F (2017) Understanding the checkpoint blockade in lung cancer immunotherapy. Drug Discov Today 22(8):1266–1273

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  14. Butte MJ et al (2007) PD-L1 interacts specifically with B7-1 to inhibit T cell proliferation. Immunity 27:111–122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Shepherd FA, Dancey J, Ramlau R et al (2000) Prospective randomized trial of docetaxel versus best supportive care in patients with non–small-cell lung cancer patients previously treated with platinum-based chemotherapy. J Clin Oncol 18:2095–2103

    Google Scholar 

  16. Fossella FV, DeVore R, Kerr RN et al (2000) Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non–small-cell lung cancer previously treated with platinum-containing chemotherapy. J Clin Oncol 18:2354–2362

    Google Scholar 

  17. Bagley SJ, Bauml JM, Langer CJ (2015) PD-1/PD-L1 immune checkpoint blockade in non-small cell lung cancer. Clin Adv Hematol Oncol 13(10):676–683

    PubMed  Google Scholar 

  18. Herbst RS, Soria JC, al KM (2014) Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515(7528):563–567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Spigel D, Gettinger SN, Horn L et al (2013) Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) [ASCO abstract 8008]. J Clin Oncol 31(15):8008

    Article  Google Scholar 

  20. Garon EB, Rizvi NA, Hui R et al (2015) Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372:2018–2028

    Article  PubMed  Google Scholar 

  21. Reck M, Rodríguez-Abreu D, Robinson AG et al (2016) Pembrolizumab versus chemotherapy for PDL1positive non-small-cell lung cancer. N Engl J Med 375:1823–1833

    Article  CAS  PubMed  Google Scholar 

  22. Hui E, Cheung J, Zhu J et al (2017) T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science 355(6332):1428–1433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wei SC, Anang NAS, Sharma R et al (2019) Combination anti-CTLA-4 plus anti-PD-1 checkpoint blockade utilizes cellular mechanisms partially distinct from monotherapies. Proc Natl Acad Sci U S A 116(45):22699–22709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wada J, Kanwar YS (1997) Identification and characterization of galectin-9, a novel β-galactoside-binding mammalian lectin. J Biol Chem 272:6078–6086

    Article  CAS  PubMed  Google Scholar 

  25. Sundar R et al (2014) Immunotherapy in the treatment of non-small cell lung cancer. Lung Cancer 85:101–109

    Article  PubMed  Google Scholar 

  26. Gao X et al (2012) TIM-3 expression characterizes regulatory T cells in tumor tissues and is associated with lung cancer progression. PLoS One 7:e30676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Anderson AC (2014) Tim-3: an emerging target in the cancer immunotherapy landscape. Cancer Immunol Res 2:393–398

    Article  CAS  PubMed  Google Scholar 

  28. Zhu C et al (2005) The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol 6:1245–1252

    Article  CAS  PubMed  Google Scholar 

  29. Grosso JF et al (2007) LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems. J Clin Invest 117:3383–3392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Huang CT, Workman CG, Flies D, Pan X, Marson AL, Zhou G, Hipkiss EL, Ravi S, Kowalski J, Levitsky HI, Powell JD, Pardoll DM, Drake CG, Vijnali DA (2004) Role of LAG-3 in regulatory T cells. Immunity 21(4):503–513

    Article  CAS  PubMed  Google Scholar 

  31. Blackburn SD et al (2009) Coregulation of CD8+ T cell exhaustion during chronic viral infection by multiple inhibitory receptors. Nat Immunol 10:29–37

    Article  CAS  PubMed  Google Scholar 

  32. Miyazaki T et al (1996) LAG-3 is not responsible for selecting T helper cells in CD4-deficient mice. Int Immunol 8:725–729

    Article  CAS  PubMed  Google Scholar 

  33. Burova E et al (2016) 31st annual meeting and associated programs of the Society for Immunotherapy of Cancer (SITC 2016): part two. J Immunother Cancer 4(Suppl. 1):73

    Google Scholar 

  34. Nirschl CJ, Drake CG (2013) Molecular pathways: co-expression of immune checkpoint molecules: Signalling pathways and implications for cancer immunotherapy. Clin Cancer Res 19:4917–4924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Durham NM et al (2014) Lymphocyte activation gene 3 (LAG-3) modulates the ability of CD4 T-cells to be suppressed in vivo. PLoS One 9:e109080

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. He Y et al (2017) LAG-3 protein expression in non-small cell lung cancer and its relationship with PD-1/PD-L1 and tumor-infiltrating lymphocytes. J Thorax Oncologia 12:814–823

    Article  Google Scholar 

  37. Lanier LL (2008) Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol 9(5):495–502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mingari MC et al (2005) Human cytolytic T lymphocytes expressing HLA class I inhibitory receptors. Curr Opin Immunol 17:312–319

    Article  CAS  PubMed  Google Scholar 

  39. He Y et al (2016) KIR 2 D (L1, L3, L4, S4) and KIR 3 DL1 protein expression in non-small cell lung cancer. Oncotarget 7:82104–82111

    Article  PubMed  PubMed Central  Google Scholar 

  40. Kohrt HE et al (2014) Anti-KIR antibody enhancement of anti-lymphoma activity of natural killer cells as monotherapy and in combination with anti-CD20 antibodies. Blood 123:678–686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Marin-Acevedo JA, Chirila RM, Dronca RS (2019) Immune checkpoint inhibitor toxicities. Mayo Clin Proc 94(7):1321–1329

    Article  CAS  PubMed  Google Scholar 

  42. Kwak JJ, Tirumani SH, Van den Abbeele AD, Koo PJ, Jacene HA (2015) Cancer immunotherapy: imaging assessment of novel treatment response patterns and immune-related adverse events. Radiographics 35:424–437

    Article  PubMed  Google Scholar 

  43. Wang GX, Guo LQ, Gainor JF, Fintelmann FJ (2017) Immune checkpoint inhibitors in lung Cancer: imaging considerations. AJR Am J Roentgenol 209(3):567–575

    Article  PubMed  Google Scholar 

  44. 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 439:682–687

    Article  CAS  PubMed  Google Scholar 

  45. Canaday DH, Parker KE, Aung H, Chen HE, Nunez-Medina D, Burant CJ (2013) Age-dependent changes in the expression of regulatory cell surface ligands in activated human T-cells. BMC Immunol 14:45

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P et al (2015) Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348:124–128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Gandara DR, Paul SM, Kowanetz M, Schleifman E, Zou W et al (2018) Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat Med 24:1441–1448

    Article  CAS  PubMed  Google Scholar 

  48. Khagi Y, Goodman AM, Daniels GA, Patel SP, Sacco AG et al (2017) Hypermutated circulating tumor DNA: correlation with response to checkpoint inhibitor-based immunotherapy. Clin Cancer Res 23:5729–5736

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zheng SG, Wang JH, Stohl W et al (2006) TGF-beta requires CTLA-4 early after T cell activation to induce FoxP3 and generate adaptive CD4+CD25+ regulatory cells. J Immunol 176:3321–3329

    Article  CAS  PubMed  Google Scholar 

  50. Bianco A, Perrotta F, Barra G, Malapelle U, Rocco D, De Palma R (2019) Prognostic factors and biomarkers of responses to immune checkpoint inhibitors in lung cancer. Int J Mol Sci 20(19):4931

    Article  CAS  PubMed Central  Google Scholar 

  51. Pabla S, Conroy JM, Nesline MK et al (2019) Proliferative potential and resistance to immune checkpoint blockade in lung cancer patients. J Immunother Cancer 7(1):27

    Article  PubMed  PubMed Central  Google Scholar 

  52. Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre ML et al (2018) The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 359:104–108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wang R, Yang L, Zhang C, Wang R, Zhang Z, He Q et al (2018) Th17 cell derived IL-17A promoted tumor progression via STAT3/NF-kB/Notch1 signaling in non-small cell lung cancer. Onco Targets Ther 7:e1461303

    Google Scholar 

  54. Hagihara M, Yamashita R, Matsumoto A, Mori T, Inagaki T, Nonogaki T et al (2019) The impact of probiotic Clostridium butyricum MIYAIRI 588 on murine gut metabolic alterations. J Infect Chemother 25:571–577

    Article  CAS  PubMed  Google Scholar 

  55. Hagihara M, Yamashita R, Matsumoto A, Mori T, Kuroki Y, Kudo H et al (2018) The impact of Clostridium butyricum MIYAIRI 588 on the murine gut microbiome and colonic tissue. Anaerobe 54:8–18

    Article  CAS  PubMed  Google Scholar 

  56. Helmink BA, Khan MAW, Hermann A, Gopalakrishnan V, Wargo JA (2019) The microbiome, cancer, and cancer therapy. Nat Med 25:377–388

    Article  CAS  PubMed  Google Scholar 

  57. Tomita Y, Ikeda T, Sakata S et al (2020) Association of probiotic Clostridium butyricum therapy with survival and response to immune checkpoint blockade in patients with lung cancer. Cancer Immunol Res 8:1236–1242. https://doi.org/10.1158/2326-6066.cir-20-0051

    Article  CAS  PubMed  Google Scholar 

  58. Hollingsworth RE, Jansen K (2019) Turning the corner on therapeutic cancer vaccines. NJP Vaccines 4(7):1–10

    Google Scholar 

  59. Giaccone G, Bazhenova LA, Nemunaitis J et al (2015) A phase III study of Belagenpumatucel-L, an allogenic tumor cell vaccine, as maintenance therapy for non-small cell lung cancer. Eur J Cancer 51(16):2321–2329

    Article  CAS  PubMed  Google Scholar 

  60. Kong F, Jirtle RL, Huang DH, Clough RW, Anscher MS (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 

  61. Nemunaitis J, Dillman RO, Schwarzenberger PO et al (2006) Phase II study of belagenpumatucel-L, a transforming growth factor beta-2 antisense gene-modified allogenic tumor cell vaccine in non-small-cell lung cancer. J Clin Oncol 24(29):4721–4730

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  63. Olivers H, Caglevic C, Passiglia F, Taverna S, Smits E, Rolfo C (2018) Vaccine and immune cell therapy in non-small cell lung cancer. J Thorac Dis 10(suppl 13):S1602–S1614

    Article  Google Scholar 

  64. Socola F, Scherfenberg N, Raez LE (2013) Therapeutic vaccines in non-small cell lung cancer. Immuno Target Ther 2:115–124

    Google Scholar 

  65. Suzuki H, Owada Y, Watanabe Y et al (2014) Recent advances in immunotherapy for non-small-cell lung cancer. Hum Vaccines Immunother 10(2):352–357

    Article  CAS  Google Scholar 

  66. Banchereau J, Palucka K (2018) Cancer vaccines on the move. Nat Rev Clin Oncol 15:9–10

    Article  PubMed  Google Scholar 

  67. Cortes-jofre M, Uranga R, Torres Pombert A, Arango Prado MDC, Caballero Aguirrechu I, Pacheco C, Ortiz Reyes RM, Chuecas F, Mas Bermejo PI (2019) Therapeutic vaccines for advanced non-small cell lung cancer. Cochrane Database Syst Rev 2019:1–13

    Google Scholar 

  68. Cuppens K, Vansteenkiste J (2014) Vaccination therapy for non-small-cell lung cancer. Curr Opin Oncol 26(2):165–170

    Article  CAS  PubMed  Google Scholar 

  69. Fernandez CG, Fornaguera C, Borros S (2020) Nanomedicine in non-small cell lung cancer: from conventional treatments of immunotherapy. Cancer 12(1609):1–26

    Google Scholar 

  70. Sienel W, Varwerk C, Linder A et al (2004) Melanoma associated antigen (MAGE)-A3 expression in stages I and II non-small cell lung cancer: results of a multi-center study. Eur J Cardio Thorac Surg 25(1):131–134

    Article  CAS  Google Scholar 

  71. Vansteenkiste J, Zielinski M, Linder A, Dahabreh J, Gonzalez EE, Malinowski w L-BM, Vanakesa T, Jassem J, Kalofonos H 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 

  72. Limacher JM, Quoix E (2012) TG4010: a therapeutic vaccine against MUC1 expressing tumors. Onco Targets Ther 1(5):791–792

    Google Scholar 

  73. Quoix E, Ramlau R, Westeel V, Papai Z, Madroszyk A, Riviere A, Koralewski P, Breton JL, Stoelben E, Braun D 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 

  74. Raina D, Kosugi M, Ahmad R et al (2011) Dependence on the MUC1-C oncoprotein in non-small cell lung cancer cells. Mol Cancer Ther 10(5):806–816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ho SB, Niehans GA, Lyftogt C et al (1993) Heterogenicity of mucin gene expression in normal and neoplastic tissues. Cancer Res 53:641–651

    CAS  PubMed  Google Scholar 

  76. Palmer M, Parker J, Modi S et al (2001) Phase I study of the BLP25 (MUC1) peptide liposomal vaccine for active specific immunotherapy in stage IIIB/IV non-small-cell lung cancer. Clin Lung Cancer 3:49–57

    Article  CAS  PubMed  Google Scholar 

  77. Hirsch FR, Varella-García M, Cappuzzo F (2009) Predictive value of EGFR and HER2 overexpression in advanced non-small-cell lung cancer. Oncogene 28:S32–S37

    Article  CAS  PubMed  Google Scholar 

  78. Luo SY, Lam DC (2013) Oncogenic driver mutations in lung. Transl Respir Med 1:6

    Article  PubMed  PubMed Central  Google Scholar 

  79. Mendelsohn J, Baselga J (2006) Epidermal growth factor receptor targeting in cancer. Semin Oncol 33(4):369–385

    Article  CAS  PubMed  Google Scholar 

  80. Rodriguez PC, Rodriguez G, Gonzalez G, Lage A (2010) Clinical development and perspectives of CIMAvax EGF, Cuban vaccine for non-small-cell lung cancer therapy. MEDICC Rev 12(1):17–23

    Article  PubMed  Google Scholar 

  81. Rotow J, Bivona TG (2017) Understanding and targeting resistance mechanisms in NSCLC. Nat Rev Cancer 17(11):637–658

    Article  CAS  PubMed  Google Scholar 

  82. Saavedra D, Crombet T (2017) CIMAvax-EGF: a new therapeutic vaccine for advanced non-small cell lung cancer patients. Front Immunol 8:269

    Article  PubMed  PubMed Central  Google Scholar 

  83. Toffoli G, De Mattia E, Cecchin E, Biason P, Masier S, Corona G (2007) Pharmacology of epidermal growth factor inhibitors. Int J Biol Markers 22(1):S24–S39

    Article  CAS  PubMed  Google Scholar 

  84. Fiedler K, Lazzaro S, Lutz J, Rauch S, Heidenreich R (2016) MRNA cancer vaccines. Recent Results Cancer Res 209:61–84

    Article  CAS  PubMed  Google Scholar 

  85. Midoux P, Pichon C (2014) Lipid based MRNA vaccine delivery system. Expert Rev Vaccines 14(2):221–234

    Article  PubMed  CAS  Google Scholar 

  86. Sebastian M, Von Boehmer L, Zippelius A, Mayer F, Reck M, Atanackovic D, Thomas M, Schneller F, Stoehlmacher J, Goekkurt E et al (2011) Messenger RNA vaccination in NSCLC: findings from a phase I/IIa clinical trial. J Clin Oncol 2584s:29

    Google Scholar 

  87. Huang J, Kondo H, Marom EM et al (2016) The IASLC lung cancer staging project: proposals for coding T categories for subsolid nodules and assessment of tumor size in part-solid tumors in the forthcoming eighth edition of the TNM classification of lung cancer. J Thorac Oncol 11(8):1204–1223

    Article  Google Scholar 

  88. Calles A, Aguado G, Sandoval C, Alvarez R (2019) The role of immunotherapy in small cell lung cancer. Clin Transl Oncol 21(8):961–976

    Article  CAS  PubMed  Google Scholar 

  89. Winston WT, Maghfoor I (2019) Small Cell Lung Cancer. https://emedicine.medscape.com/article/280104-overview#a5

  90. D’Angelo SP, Pietanza MC (2010) +e molecular pathogenesis of small cell lung cancer. Can Biol Ther 10(1):1–10

    Article  CAS  Google Scholar 

  91. Kahnert K, Kauffmann-Guerrero D, Huber RM (2016) SCLC–state of the art and what does the future have in store? Clin Lung Cancer 17(5):325–333

    Article  PubMed  Google Scholar 

  92. Arriola E, Wheater M, Galea I et al (2016) Outcome and biomarker analysis from a multicenter phase 2 study of ipilimumab in combination with carboplatin and etoposide as first-line therapy for extensive-stage SCLC. J Thor Oncol 11(9):1511–1521

    Article  Google Scholar 

  93. Antonia SJ, Lopez-Martin JA, Bendell J, Ott PA, Taylor M, Eder JP et al (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

    Article  CAS  PubMed  Google Scholar 

  94. Tsiouprou I, Zaharias A, Spyratos D (2019) The role of immunotherapy in extensive stage small-cell lung cancer: a review of the literature. Can Respir J 2019:6860432

    Article  PubMed  PubMed Central  Google Scholar 

  95. Bonanno L, Pavan A, Dieci MV, Di Liso E, Schiavon M, Comacchio G et al (2018) The role of immune microenvironment in small-cell lung cancer: distribution of PD-L1 expression and prognostic role of FOXP3-positive tumour infiltrating lymphocytes. Eur J Cancer 101:191–200

    Article  CAS  PubMed  Google Scholar 

  96. Ishii H, Azuma K, Kawahara A, Yamada K, Imamura Y, Tokito T et al (2015) Significance of programmed cell death-ligand 1 expression and its association with survival in patients with small cell lung cancer. J Thorac Oncol 10(3):426–430

    Article  CAS  PubMed  Google Scholar 

  97. Ancevski HK, Socinski MA, Villaruz LC (2018) PD-L1 testing in guiding patient selection for PD-1/PD-L1 inhibitor therapy in lung cancer. Mol Diagn Ther 22(1):1–10

    Article  CAS  Google Scholar 

  98. He J, Hu Y, Hu M, Li B (2015) Development of PD-1/PD-L1 pathway in tumor immune microenvironment and treatment for non-small cell lung cancer. Sci Rep 5:13110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Piccione EC, Juarez S, Tseng S, Liu J, Stafford M, Narayanan C et al (2016) SIRPa antibody fusion proteins selectively bind and eliminate dual antigen expressing tumor cells. Clin Cancer Res 22:5109–5119

    Article  CAS  PubMed  Google Scholar 

  100. Vonderheide RH (2015) CD47 blockade as another immune checkpoint therapy for cancer. Nat Med 21:1122–1123

    Article  CAS  PubMed  Google Scholar 

  101. Zhang X, Fan J, Wang S et al (2017) Targeting CD47 and autophagy elicited enhanced antitumor effects in non-small cell lung cancer. Cancer Immunol Res 5(5):363–375

    Article  CAS  PubMed  Google Scholar 

  102. Weiskopf K, Jahchan NS, Schnorr PJ, Cristea S, Ring AM, Maute RL et al (2016) CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer. J Clin Invest 126:2610–2620

    Article  PubMed  PubMed Central  Google Scholar 

  103. Horn L, Mansfield AS, Szczesna A et al (2018) First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med 379(23):2220–2229

    Article  CAS  PubMed  Google Scholar 

  104. Rudin C, Shen L, Pietanza MC (2017) P2.04-007 KEYNOTE-604: phase 3 randomized, double-blind trial of pembrolizumab/placebo plus etoposide/platinum for extensive stage-SCLC. J Thorac Oncol 12(11):S2400

    Article  Google Scholar 

  105. Horn L, Reck M, Gettinger SN et al (2016) CheckMate 331: an open-label, randomized phase III trial of nivolumab versus chemotherapy in patients (pts) with relapsed small cell lung cancer (SCLC) after first-line platinum-based chemotherapy (PT-DC). J Clin Oncol 34(15):TPS8578

    Article  Google Scholar 

  106. Ready N, Owonikoko TK, Postmus PE et al (2017) CheckMate 451: a randomized, double-blind, phase III trial of nivolumab (nivo), nivo plus ipilimumab (ipi), or placebo as maintenance therapy in patients (pts) with extensive-stage disease small cell lung cancer (ED-SCLC) after first-line platinum-based doublet chemotherapy (PT-DC). J Clin Oncol 34(15):TPS8579

    Google Scholar 

  107. Ott PA, Elez E, Hiret S et al (2017) Pembrolizumab in patients with extensive-stage small-cell lung cancer: results from the phase ib KEYNOTE-028 study. J Clin Oncol 35(34):3823–3829

    Article  CAS  PubMed  Google Scholar 

  108. Chung HC, Lopez-Martin JA, Kao SCH et al (2018) Phase 2 study of pembrolizumab in advanced small-cell lung cancer (SCLC): KEYNOTE-158. J Clin Oncol 36(15):8506

    Article  Google Scholar 

  109. FDA, FDA Approves Pembrolizumab for Metastatic Small Cell Lung Cancer (2019). https://www.fda.gov/drugs/resourcesinformation-approved-drugs/fda-approvespembrolizumabmetastatic-small-cell-lung-cancer

  110. Ko EC, Raben D, Formenti SC (2018) The integration of radiotherapy with immunotherapy for the treatment of non-small cell lung cancer. Clin Cancer Res 24(23):5792–5806

    Article  CAS  PubMed  Google Scholar 

  111. Yuan Z, Fromm A, Ahmed KA, Grass GD, Yang GQ, Oliver DE et al (2017) Radiotherapy rescue of a nivolumab-refractory immune response in a patient with PD-L1 negative metastatic squamous cell carcinoma of the lung. J Thorac Oncol 12:e135–e136

    Article  PubMed  Google Scholar 

  112. Butts C, Socinski MA, Mitchell PL, Thatcher N, Havel L, Krzakowski M et al (2014) Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small cell lung cancer (START): a randomised, double-blind, phase 3 trial. Lancet Oncol 15:59–68

    Article  CAS  PubMed  Google Scholar 

  113. Mitchell P, Thatcher N, Socinski MA, Wasilewska-Tesluk E, Horwood K, Szczesna A et al (2015) Tecemotide in unresectable stage III non-small-cell lung cancer in the phase III START study: updated overall survival and biomarker analyses. Ann Oncol 26:1134–1142

    Article  CAS  PubMed  Google Scholar 

  114. Shaverdian N, Lisberg AE, Bornazyan K, Veruttipong D, Goldman JW, Formenti SC, Garon EB, Lee P (2017) Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol 18:895–903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Wirsdörfer F, de Leve S, Jendrossek V (2018) Combining radiotherapy and immunotherapy in lung cancer: can we expect limitations due to altered normal tissue toxicity? Int J Mol Sci 20(1):24

    Article  PubMed Central  CAS  Google Scholar 

  116. Lazzari C, Karachaliou N, Bulotta A et al (2018) Combination of immunotherapy with chemotherapy and radiotherapy in lung cancer: is this the beginning of the end for cancer? Ther Adv Med Oncol 10:1758835918762094

    Google Scholar 

  117. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Yokoi T, Chiappori A, Lee KH, deWit M et al (2017) Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 377:1919–1929

    Article  CAS  PubMed  Google Scholar 

  118. Reck M, von Pawel J, Zatloukal P et al (2010) Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol 21:1804–1809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Sandler A, Gray R, Perry MC et al (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542–2550

    Article  CAS  PubMed  Google Scholar 

  120. Simone CB 2nd, Burri SH, Heinzerling JH (2015) Novel radiotherapy approaches for lung cancer: combining radiation therapy with targeted and immunotherapies. Transl Lung Cancer Res 4(5):545–552

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Soria JC, Mauguen A, Reck M et al (2013) Systematic review and meta-analysis of randomised, phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer. Ann Oncol 24:20–30

    Article  PubMed  Google Scholar 

  122. Paz-Ares L, Jiang H, Huang Y, Dennis P (2017) P2.04-002 CASPIAN: phase 3 study of first-line durvalumab ± tremelimumab + platinum-based chemotherapy vs chemotherapy alone in ED-SCLC. J Thorac Oncol 12(11):S2398

    Article  Google Scholar 

  123. ClinicalTrials.gov: a study of rovalpituzumab tesirine (SC16LD6.5) in the frontline treatment of patients with deltalike protein 3-expressing extensive stage small cell lung cancer. https://clinicaltrials.gov/ct2/show/NCT02819999?term=NCT02819999&rank=1

  124. Lashari BH, Vallatharasu Y, Kolandra L, Hamid M, Uprety D (2018) Rovalpituzumabtesirine: a novel DLL3-targeting antibody-drug conjugate. Drugs R D 18(4):255–258

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors acknowledge Department of Zoology, The University of Burdwan.

Conflicts of Interest

There are none.

Author information

Authors and Affiliations

  1. Biomedical Genetics Laboratory, Department of Zoology, The University of Burdwan, Burdwan, West Bengal, India

    Paramita Mandal, Anindita Goswami, Sarmistha Adhikari & Subham Sarkar

Authors
  1. Paramita Mandal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anindita Goswami
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sarmistha Adhikari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Subham Sarkar
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Graduate School of Health, Discipline of Pharmacy, University of Technology Sydney, Sydney, NSW, Australia

    Kamal Dua

  2. Drug Development and Innovation Centre, University of Alberta, Edmonton, AB, Canada

    Raimar Löbenberg

  3. Haematology and Hemotherapy Center, State University of Campinas, Campinas, São Paulo, Brazil

    Ângela Cristina Malheiros Luzo

  4. Graduate School of Health, Discipline of Pharmacy, University of Technology Sydney, Sydney, NSW, Australia

    Shakti Shukla

  5. School of Pharmaceutical Sciences & Division of Research & Development, Lovely Professional University, Phagwara, Punjab, India

    Saurabh Satija

Rights and permissions

Reprints and permissions

Copyright information

© 2021 The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Mandal, P., Goswami, A., Adhikari, S., Sarkar, S. (2021). Modulation of Signaling Pathways by Immunotherapeutics in Lung Cancer. In: Dua, K., Löbenberg, R., Malheiros Luzo, Â.C., Shukla, S., Satija, S. (eds) Targeting Cellular Signalling Pathways in Lung Diseases. Springer, Singapore. https://doi.org/10.1007/978-981-33-6827-9_10

Download citation

Publish with us

Policies and ethics

Search

Navigation