Tuberc Respir Dis.  2018 Jan;81(1):29-41. 10.4046/trd.2017.0120.

Tumor Immunology and Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer

Affiliations
  • 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Daegu Catholic University School of Medicine, Daegu, Korea.
  • 2Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. scott.antonia@moffitt.org

Abstract

Lung cancer is one of the most commonly diagnosed cancers and the leading cause of cancer-related deaths worldwide. Although progress in the treatment of advanced non-small cell lung cancer (NSCLC) has been made over the past decade, the 5-year survival rate in patients with lung cancer remains only 10%-20%. Obviously, new therapeutic options are required for patients with advanced NSCLC and unmet medical needs. Cancer immunotherapy is an evolving treatment modality that uses a patient's own immune systems to fight cancer. Theoretically, cancer immunotherapy can result in long-term cancer remission and may not cause the same side effects as chemotherapy and radiation. Immuno-oncology has become an important focus of basic research as well as clinical trials for the treatment of NSCLC. Immune checkpoint inhibitors are the most promising approach for cancer immunotherapy and they have become the standard of care for patients with advanced NSCLC. This review summarizes basic tumor immunology and the relevant clinical data on immunotherapeutic approaches, especially immune checkpoint inhibitors in NSCLC.

Keyword

Carcinoma, Non-Small-Cell Lung; Immunotherapy; Cell Cycle Checkpoints

MeSH Terms

Allergy and Immunology*
Carcinoma, Non-Small-Cell Lung*
Cell Cycle Checkpoints
Drug Therapy
Humans
Immune System
Immunotherapy
Lung Neoplasms
Standard of Care
Survival Rate

Figure

  • Figure 1 The three phases of the cancer immunoediting process: elimination, equilibrium, and escape. DC: dendritic cell; γδ: γδ T cell; IDO: indoleamine 2,3-dioxygenase; IFN-γ: interferon γ; IL: interleukin; M1: M1 macrophage; M2: M2 macrophage; MDSC: myeloid-derived suppressor cell; NK: natural killer cell; NKT: natural killer T cell; PD-L1: programmed death ligand 1; TGF-β: transforming growth factor β; Treg: regulatory T cell. Modified from Schreiber et al. Science 2011;331:1565-70, with permission of The American Association for the Advancement of Science24.

  • Figure 2 The cancer-immunity cycle. APC: antigen presenting cell; MHC: major histocompatibility complex; TCR: T cell receptors.

  • Figure 3 The immune system activation and checkpoint inhibitors. APC: antigen presenting cell; CTLA-4: cytotoxic T-lymphocyte-associated antigen 4; PD-1: programmed cell death protein 1; PD-L1: programmed death ligand 1; TCR: T cell receptors. Modified from Pardoll. Nat Rev Cancer 2012;12:252-64, with permission of Springer Nature27.


Cited by  1 articles

Current Status of Immunotherapy for Lung Cancer and Future Perspectives
Ho Cheol Kim, Chang-Min Choi
Tuberc Respir Dis. 2020;83(1):14-19.    doi: 10.4046/trd.2019.0039.


Reference

1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015; 136:E359–E386. PMID: 25220842.
Article
2. Korea Central Cancer Registry. Annual report of cancer statistics in Korea in 2013 [Internet]. Goyang: National Cancer Information Center;2016. cited 2016 Jun 20. Available from: http://www.cancer.go.kr/.
3. Korean Statistical Information Service. Statistics Korea [Internet]. Daejeon: Statistics Korea;2016. cited 2016 Jun 20. Available from: http://kosis.kr/.
4. Reck M, Heigener DF, Mok T, Soria JC, Rabe KF. Management of non-small-cell lung cancer: recent developments. Lancet. 2013; 382:709–719. PMID: 23972814.
Article
5. National Comprehensive Cancer Network. NCCN Clinical practice guidelines in oncology: non-small cell lung cancer. Version 9. 2017 [Internet]. Fort Washington: National Comprehensive Cancer Network;2017. cited 2017 Sep 28. Available from: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.
6. Midha A, Dearden S, McCormack R. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). Am J Cancer Res. 2015; 5:2892–2911. PMID: 26609494.
7. Park JY, Jang SH. Epidemiology of lung cancer in Korea: recent trends. Tuberc Respir Dis (Seoul). 2016; 79:58–69. PMID: 27064578.
Article
8. Allemani C, Weir HK, Carreira H, Harewood R, Spika D, Wang XS, et al. Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2). Lancet. 2015; 385:977–1010. PMID: 25467588.
Article
9. Shepherd FA, Douillard JY, Blumenschein GR Jr. Immunotherapy for non-small cell lung cancer: novel approaches to improve patient outcome. J Thorac Oncol. 2011; 6:1763–1773. PMID: 21876456.
Article
10. Thomas A, Hassan R. Immunotherapies for non-small-cell lung cancer and mesothelioma. Lancet Oncol. 2012; 13:e301–e310. PMID: 22748269.
Article
11. Reck M. What future opportunities may immuno-oncology provide for improving the treatment of patients with lung cancer? Ann Oncol. 2012; 23(Suppl 8):viii28–viii34. PMID: 22918925.
Article
12. Brahmer JR. Harnessing the immune system for the treatment of non-small-cell lung cancer. J Clin Oncol. 2013; 31:1021–1028. PMID: 23401435.
Article
13. Massarelli E, Papadimitrakopoulou V, Welsh J, Tang C, Tsao AS. Immunotherapy in lung cancer. Transl Lung Cancer Res. 2014; 3:53–63. PMID: 25806281.
14. Anagnostou VK, Brahmer JR. Cancer immunotherapy: a future paradigm shift in the treatment of non-small cell lung cancer. Clin Cancer Res. 2015; 21:976–984. PMID: 25733707.
Article
15. Carbone DP, Gandara DR, Antonia SJ, Zielinski C, Paz-Ares L. Non-small-cell lung cancer: role of the immune system and potential for immunotherapy. J Thorac Oncol. 2015; 10:974–984. PMID: 26134219.
Article
16. Abbas AK, Lichtman AH, Pillai S. Cellular and molecular immunology. 9th ed. Philadelphia: Saunders/Elsevier;2018.
17. Liu Y, Zeng G. Cancer and innate immune system interactions: translational potentials for cancer immunotherapy. J Immunother. 2012; 35:299–308. PMID: 22495387.
18. Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural innate and adaptive immunity to cancer. Annu Rev Immunol. 2011; 29:235–271. PMID: 21219185.
Article
19. Finn OJ. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Ann Oncol. 2012; 23(Suppl 8):viii6–viii9. PMID: 22918931.
Article
20. Eggermont AM. Can immuno-oncology offer a truly pan-tumour approach to therapy? Ann Oncol. 2012; 23(Suppl 8):viii53–viii57. PMID: 22918930.
Article
21. Burnet M. Cancer: a biological approach. I. The processes of control. Br Med J. 1957; 1:779–786. PMID: 13404306.
22. 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; 410:1107–1111. PMID: 11323675.
23. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002; 3:991–998. PMID: 12407406.
Article
24. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science. 2011; 331:1565–1570. PMID: 21436444.
Article
25. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013; 39:1–10. PMID: 23890059.
Article
26. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011; 480:480–489. PMID: 22193102.
Article
27. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012; 12:252–264. PMID: 22437870.
Article
28. Butt AQ, Mills KH. Immunosuppressive networks and checkpoints controlling antitumor immunity and their blockade in the development of cancer immunotherapeutics and vaccines. Oncogene. 2014; 33:4623–4631. PMID: 24141774.
Article
29. Ruffini E, Asioli S, Filosso PL, Lyberis P, Bruna MC, Macri L, et al. Clinical significance of tumor-infiltrating lymphocytes in lung neoplasms. Ann Thorac Surg. 2009; 87:365–371. PMID: 19161739.
Article
30. Hiraoka K, Miyamoto M, Cho Y, Suzuoki M, Oshikiri T, Nakakubo Y, et al. Concurrent infiltration by CD8+ T cells and CD4+ T cells is a favourable prognostic factor in non-small-cell lung carcinoma. Br J Cancer. 2006; 94:275–280. PMID: 16421594.
Article
31. Petersen RP, Campa MJ, Sperlazza J, Conlon D, Joshi MB, Harpole DH Jr, et al. Tumor infiltrating Foxp3+ regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients. Cancer. 2006; 107:2866–2872. PMID: 17099880.
Article
32. Drake CG, Lipson EJ, Brahmer JR. Breathing new life into immunotherapy: review of melanoma, lung and kidney cancer. Nat Rev Clin Oncol. 2014; 11:24–37. PMID: 24247168.
Article
33. 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. 2013; 31:2396–2403. PMID: 23715567.
Article
34. Vansteenkiste JF, Cho BC, Vanakesa T, De Pas T, Zielinski M, Kim MS, et al. Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016; 17:822–835. PMID: 27132212.
Article
35. Butts C, Socinski MA, Mitchell PL, Thatcher N, Havel L, Krzakowski M, et al. 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. 2014; 15:59–68. PMID: 24331154.
Article
36. Wu YL, Park K, Soo RA, Sun Y, Tyroller K, Wages D, et al. INSPIRE: a phase III study of the BLP25 liposome vaccine (L-BLP25) in Asian patients with unresectable stage III non-small cell lung cancer. BMC Cancer. 2011; 11:430. PMID: 21982342.
Article
37. Quoix E, Lena H, Losonczy G, Forget F, Chouaid C, Papai Z, et al. TG4010 immunotherapy and first-line chemotherapy for advanced non-small-cell lung cancer (TIME): results from the phase 2b part of a randomised, double-blind, placebo-controlled, phase 2b/3 trial. Lancet Oncol. 2016; 17:212–223. PMID: 26727163.
Article
38. Rodriguez PC, Popa X, Martinez O, Mendoza S, Santiesteban E, Crespo T, et al. A phase III clinical trial of the epidermal growth factor vaccine CIMAvax-EGF as switch maintenance therapy in advanced non-small cell lung cancer patients. Clin Cancer Res. 2016; 22:3782–3790. PMID: 26927662.
Article
39. Sasada T, Komatsu N, Suekane S, Yamada A, Noguchi M, Itoh K. Overcoming the hurdles of randomised clinical trials of therapeutic cancer vaccines. Eur J Cancer. 2010; 46:1514–1519. PMID: 20413296.
Article
40. Mellstedt H, Vansteenkiste J, Thatcher N. Vaccines for the treatment of non-small cell lung cancer: investigational approaches and clinical experience. Lung Cancer. 2011; 73:11–17. PMID: 21474197.
Article
41. Cuppens K, Vansteenkiste J. Vaccination therapy for non-small-cell lung cancer. Curr Opin Oncol. 2014; 26:165–170. PMID: 24441502.
Article
42. Makkouk A, Weiner GJ. Cancer immunotherapy and breaking immune tolerance: new approaches to an old challenge. Cancer Res. 2015; 75:5–10. PMID: 25524899.
Article
43. Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015; 373:123–135. PMID: 26028407.
Article
44. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015; 373:1627–1639. PMID: 26412456.
Article
45. Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, et al. First-Line Nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med. 2017; 376:2415–2426. PMID: 28636851.
Article
46. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015; 372:2018–2028. PMID: 25891174.
Article
47. Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016; 387:1540–1550. PMID: 26712084.
Article
48. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016; 375:1823–1833. PMID: 27718847.
Article
49. Brahmer JR, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Progression after the next line of therapy (PFS2) and updated OS among patients (pts) with advanced NSCLC and PD-L1 tumor proportion score (TPS) ≥50% enrolled in KEYNOTE-024. J Clin Oncol. 2017; 35(15 Suppl):9000.
Article
50. Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016; 387:1837–1846. PMID: 26970723.
Article
51. Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017; 389:255–265. PMID: 27979383.
Article
52. Garassino M, Vansteenkiste J, Kim JH, Lena H, Mazieres J, Powderly J, et al. Durvalumab in ≥3rd-line locally advanced or metastatic, EGFR/ALK wild-type NSCLC: results from the phase 2 ATLANTIC study. J Thorac Oncol. 2017; 12(Suppl):S10–S11.
53. Peters S, Gettinger S, Johnson ML, Janne PA, Garassino MC, Christoph D, et al. Phase II trial of atezolizumab as first-line or subsequent therapy for patients with programmed death-ligand 1-selected advanced non-small-cell lung cancer (BIRCH). J Clin Oncol. 2017; 35:2781–2789. PMID: 28609226.
54. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017; 377:1919–1929. PMID: 28885881.
Article
55. 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. 2012; 30:2046–2054. PMID: 22547592.
Article
56. Govindan R, Szczesna A, Ahn MJ, Schneider CP, Gonzalez Mella PF, Barlesi F, et al. Phase III trial of ipilimumab combined with paclitaxel and carboplatin in advanced squamous non-small-cell lung cancer. J Clin Oncol. 2017; 35:3449–3457. PMID: 28854067.
Article
57. Champiat S, Ileana E, Giaccone G, Besse B, Mountzios G, Eggermont A, et al. Incorporating immune-checkpoint inhibitors into systemic therapy of NSCLC. J Thorac Oncol. 2014; 9:144–153. PMID: 24419410.
Article
58. Antonia SJ, Larkin J, Ascierto PA. Immuno-oncology combinations: a review of clinical experience and future prospects. Clin Cancer Res. 2014; 20:6258–6268. PMID: 25341541.
Article
59. Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016; 17:1497–1508. PMID: 27745820.
Article
60. Borghaei H, Langer CJ, Gadgeel S, Papadimitrakopoulou VA, Patnaik A, Powell SF, et al. Updated results from KEYNOTE-021 cohort G: a randomized, phase 2 study of pemetrexed and carboplatin (PC) with or without pembrolizumab (pembro) as first-line therapy for advanced nonsquamous NSCLC. Ann Oncol. 2017; 28(Suppl_5):636–637.
Article
61. Rizvi NA, Hellmann MD, Brahmer JR, Juergens RA, Borghaei H, Gettinger S, et al. Nivolumab in combination with platinum-based doublet chemotherapy for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol. 2016; 34:2969–2979. PMID: 27354481.
Article
62. Hellmann MD, Rizvi NA, Goldman JW, Gettinger SN, Borghaei H, Brahmer JR, et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol. 2017; 18:31–41. PMID: 27932067.
Article
63. Antonia S, Goldberg SB, Balmanoukian A, Chaft JE, Sanborn RE, Gupta A, et al. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol. 2016; 17:299–308. PMID: 26858122.
Article
64. Remon J, Chaput N, Planchard D. Predictive biomarkers for programmed death-1/programmed death ligand immune checkpoint inhibitors in nonsmall cell lung cancer. Curr Opin Oncol. 2016; 28:122–129. PMID: 26756384.
Article
65. Gridelli C, Ardizzoni A, Barberis M, Cappuzzo F, Casaluce F, Danesi R, et al. Predictive biomarkers of immunotherapy for non-small cell lung cancer: results from an Experts Panel Meeting of the Italian Association of Thoracic Oncology. Transl Lung Cancer Res. 2017; 6:373–386. PMID: 28713682.
Article
66. Chae YK, Pan A, Davis AA, Raparia K, Mohindra NA, Matsangou M, et al. Biomarkers for PD-1/PD-L1 blockade therapy in non-small-cell lung cancer: is PD-L1 expression a good marker for patient selection? Clin Lung Cancer. 2016; 17:350–361. PMID: 27137346.
67. Gibney GT, Weiner LM, Atkins MB. Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol. 2016; 17:e542–e551. PMID: 27924752.
Article
68. Sacher AG, Gandhi L. Biomarkers for the clinical use of PD-1/PD-L1 inhibitors in non-small-cell lung cancer: a review. JAMA Oncol. 2016; 2:1217–1222. PMID: 27310809.
69. Hirsch FR, McElhinny A, Stanforth D, Ranger-Moore J, Jansson M, Kulangara K, et al. PD-L1 immunohistochemistry assays for lung cancer: results from phase 1 of the blueprint PD-L1 IHC assay comparison project. J Thorac Oncol. 2017; 12:208–222. PMID: 27913228.
Article
70. Rimm DL, Han G, Taube JM, Yi ES, Bridge JA, Flieder DB, et al. A prospective, multi-institutional, pathologist-based assessment of 4 immunohistochemistry assays for PD-L1 expression in non-small cell lung cancer. JAMA Oncol. 2017; 3:1051–1058. PMID: 28278348.
Article
71. Buttner R, Gosney JR, Skov BG, Adam J, Motoi N, Bloom KJ, et al. Programmed death-ligand 1 immunohistochemistry testing: a review of analytical assays and clinical implementation in non-small-cell lung cancer. J Clin Oncol. 2017; 35:3867–3876. PMID: 29053400.
72. Scheerens H, Malong A, Bassett K, Boyd Z, Gupta V, Harris J, et al. Current status of companion and complementary diagnostics: strategic considerations for development and launch. Clin Transl Sci. 2017; 10:84–92. PMID: 28121072.
Article
73. Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013; 499:214–218. PMID: 23770567.
Article
74. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology: mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015; 348:124–128. PMID: 25765070.
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