Skip to main content

Advertisement

SpringerLink
Log in

The role of immunotherapy in small cell lung cancer

  • Review Article
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Despite decades of research, prognosis for SCLC patients remains poor, and treatment options limited. SCLC is an immunogenic tumor with high somatic mutation rates due to tobacco exposure resulting in potential neo-antigens, the presence of suppressed immune responses, and occurrence of paraneoplastic disorders. The use of T cell immune-checkpoint inhibitors (anti-PD1: nivolumab, pembrolizumab; anti-PD-L1: atezolizumab, durvalumab; anti-CTLA-4: ipilimumab, tremelimumab) have shown promising antitumor activity with the potential to prolong survival in SCLC patients. In fact, atezolizumab when combined with chemotherapy has achieved the milestone of being the first drug to improve survival in patients with newly diagnosed extensive-stage SCLC. Other immunotherapeutic approaches evaluated in clinical trials for SCLC include the use of cytokines, cancer vaccines, antiganglioside therapies, TLR9 inhibition, anti-Notch signaling, and anti-CD47. This review discusses the rationale and clinical evidence of immunotherapy in SCLC, the conflictive clinical results of novel immunotherapeutic agents and combinatorial therapies under evaluation in SCLC patients.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Alvarado-Luna G, Morales-Espinosa D. Treatment for small cell lung cancer, where are we now?—a review. Transl Lung Cancer Res. 2016;5(1):26–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. George J, Lim JS, Jang SJ, Cun Y, Ozretic L, Kong G, et al. Comprehensive genomic profiles of small cell lung cancer. Nature. 2015;524(7563):47–53. https://doi.org/10.1038/nature14664.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Rudin CM, Ismaila N, Hann CL, Malhotra N, Movsas B, Norris K, et al. Treatment of small-cell lung cancer: American society of clinical oncology endorsement of the American college of chest physicians guideline. J Clin Oncol. 2015;33(34):4106–11. https://doi.org/10.1200/jco.2015.63.7918.

    Article  CAS  PubMed  Google Scholar 

  4. Früh M, De Ruysscher D, Popat S, Crinò L, Peters S, Felip E, et al. Small-cell lung cancer (SCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(suppl_6):99–105. https://doi.org/10.1093/annonc/mdt178.

    Article  Google Scholar 

  5. Artal Cortés Á, Dómine Gómez M, Font Pous A, García Campelo R, Cobo Dolls M, Isla Casado D. SEOM clinical guidelines for the treatment of small-cell lung cancer. Clin Transl Oncol. 2010;12(1):27–31. https://doi.org/10.1007/s12094-010-0463-2.

    Article  PubMed  Google Scholar 

  6. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1–10. https://doi.org/10.1016/j.immuni.2013.07.012.

    Article  CAS  PubMed  Google Scholar 

  7. Darnell RB. Onconeural antigens and the paraneoplastic neurologic disorders: at the intersection of cancer, immunity, and the brain. Proc Natl Acad Sci USA. 1996;93(10):4529–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Maddison P, Newsom-Davis J, Mills KR, Souhami RL. Favourable prognosis in Lambert-Eaton myasthenic syndrome and small-cell lung carcinoma. Lancet. 1999;353(9147):117–8. https://doi.org/10.1016/S0140-6736(05)76153-5.

    Article  CAS  PubMed  Google Scholar 

  9. Spigel DR, Socinski MA. Rationale for chemotherapy, immunotherapy, and checkpoint blockade in SCLC: beyond traditional treatment approaches. J Thorac Oncol. 2013;8(5):587–98. https://doi.org/10.1097/JTO.0b013e318286cf88.

    Article  CAS  PubMed  Google Scholar 

  10. Wang W, Hodkinson P, McLaren F, Mackean MJ, Williams L, Howie SEM, et al. Histologic assessment of tumor-associated CD45(+) cell numbers is an independent predictor of prognosis in small cell lung cancer. Chest. 2013;143(1):146–51. https://doi.org/10.1378/chest.12-0681.

    Article  PubMed  Google Scholar 

  11. Koyama K, Kagamu H, Miura S, Hiura T, Miyabayashi T, Itoh R, et al. Reciprocal CD41 T-cell balance of effector CD62Llow CD41 and CD62LhighCD251 CD41 regulatory T cells in small cell lung cancer reflects disease stage. Clin Cancer Res. 2008;14(21):6770–9. https://doi.org/10.1158/1078-0432.Ccr-08-1156.

    Article  CAS  PubMed  Google Scholar 

  12. Ishii H, Azuma K, Kawahara A, Yamada K, Imamura Y, Tokito T, et al. Significance of programmed cell death-ligand 1 expression and its association with survival in patients with small cell lung cancer. J Thorac Oncol. 2015;10(3):426–30. https://doi.org/10.1097/JTO.0000000000000414.

    Article  CAS  PubMed  Google Scholar 

  13. Peifer M, Fernández-Cuesta L, Sos ML, George J, Seidel D, Kasper LH et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet. 2012;44:1104. https://doi.org/10.1038/ng.2396. https://www.nature.com/articles/ng.2396#supplementary-information.

  14. Weiss GJ, Byron SA, Aldrich J, Sangal A, Barilla H, Kiefer JA, et al. A prospective pilot study of genome-wide exome and transcriptome profiling in patients with small cell lung cancer progressing after first-line therapy. PLoS One. 2017;12(6):e0179170. https://doi.org/10.1371/journal.pone.0179170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hellmann MD, Callahan MK, Awad MM, Calvo E, Ascierto PA, Atmaca A, et al. Tumor mutational burden and efficacy of nivolumab monotherapy and in combination with ipilimumab in small-cell lung cancer. Cancer Cell. 2018;33(5):853. https://doi.org/10.1016/j.ccell.2018.04.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gazdar AF, Bunn PA, Minna JD. Small-cell lung cancer: what we know, what we need to know and the path forward. Nat Rev Cancer. 2017;17:725. https://doi.org/10.1038/nrc.2017.87. https://www.nature.com/articles/nrc.2017.87#supplementary-information.

  17. Sabari JK, Lok BH, Laird JH, Poirier JT, Rudin CM. Unravelling the biology of SCLC: implications for therapy. Nat Rev Clin Oncol. 2017;14:549. https://doi.org/10.1038/nrclinonc.2017.71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yarchoan M, Johnson III BA, Lutz ER, Laheru DA, Jaffee EM. Targeting neoantigens to augment antitumour immunity. Nat Rev Cancer. 2017;17:209. https://doi.org/10.1038/nrc.2016.154.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Efremova M, Finotello F, Rieder D, Trajanoski Z. Neoantigens generated by individual mutations and their role in cancer immunity and immunotherapy. Front Immunol. 2017. https://doi.org/10.3389/fimmu.2017.01679.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Dudley JC, Lin MT, Le DT, Eshleman JR. Microsatellite Instability as a Biomarker for PD-1 Blockade. Clin Cancer Res. 2016;22(4):813–20. https://doi.org/10.1158/1078-0432.Ccr-15-1678.

    Article  CAS  PubMed  Google Scholar 

  21. Goodman AM, Kato S, Bazhenova L, Patel SP, Frampton GM, Miller V, et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther. 2017;16(11):2598–608. https://doi.org/10.1158/1535-7163.Mct-17-0386.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Doyle A, Martin WJ, Funa K, Gazdar A, Carney D, Martin SE, et al. Markedly decreased expression of class I histocompatibility antigens, protein, and mRNA in human small-cell lung cancer. J Exp Med. 1985;161(5):1135–51.

    Article  CAS  PubMed  Google Scholar 

  23. He Y, Rozeboom L, Rivard CJ, Ellison K, Dziadziuszko R, Yu H, et al. MHC class II expression in lung cancer. Lung Cancer. 2017;112:75–80. https://doi.org/10.1016/j.lungcan.2017.07.030.

    Article  PubMed  Google Scholar 

  24. Schalper KA, Carvajal-Hausdorf DE, McLaughlin JF, Altan M, Chiang AC, Velcheti V et al. Objective measurement and significance of PD-L1, B7-H3, B7-H4 and TILs in small cell lung cancer (SCLC). J Clin Oncol. 2016;34(15_suppl):8566. https://doi.org/10.1200/jco.2016.34.15_suppl.8566.

    Article  Google Scholar 

  25. Antonia SJ, Mirza N, Fricke I, Chiappori A, Thompson P, Williams N, et al. Combination of p53 cancer vaccine with chemotherapy in patients with extensive stage small cell lung cancer. Clin Cancer Res. 2006;12(3 Pt 1):878–87. https://doi.org/10.1158/1078-0432.CCR-05-2013.

    Article  CAS  PubMed  Google Scholar 

  26. Rivalland G, Walkiewicz M, Wright GM, John T. Small cell lung cancer: the immune microenvironment and prognostic impact of checkpoint expression. J Clin Oncol. 2017;35(15_suppl):8569. https://doi.org/10.1200/jco.2017.35.15_suppl.8569.

    Article  Google Scholar 

  27. Clamon G, Herndon J, Perry MC, Ozer H, Kreisman H, Maher T, et al. Interleukin-2 activity in patients with extensive small-cell lung cancer: a phase II trial of Cancer and Leukemia Group B. J Natl Cancer Inst. 1993;85(4):316–20.

    Article  CAS  PubMed  Google Scholar 

  28. Clamon G, Herndon J, Akerley W, Green M. Subcutaneous interleukin-2 as initial therapy for patients with extensive small cell lung cancer. Lung Cancer. 1998;19(1):25–9. https://doi.org/10.1016/S0169-5002(97)00070-6.

    Article  CAS  PubMed  Google Scholar 

  29. Zarogoulidis K, Ziogas E, Papagiannis A, Charitopoulos K, Dimitriadis K, Economides D, et al. Interferon alpha-2a and combined chemotherapy as first line treatment in SCLC patients: a randomized trial. Lung Cancer. 1996;15(2):197–205.

    Article  CAS  PubMed  Google Scholar 

  30. Zarogoulidis K, Ziogas E, Boutsikou E, Zarogoulidis P, Darwiche K, Kontakiotis T, et al. Immunomodifiers in combination with conventional chemotherapy in small cell lung cancer: a phase II, randomized study. Drug Des, Dev Ther. 2013;7:611–7. https://doi.org/10.2147/dddt.S43184.

    Article  CAS  Google Scholar 

  31. Mattson K, Niiranen A, Pyrhonen S, Holsti LR, Holsti P, Kumpulainen E, et al. Natural interferon alfa as maintenance therapy for small cell lung cancer. Eur J Cancer. 1992;28a(8–9):1387–91.

    Article  CAS  PubMed  Google Scholar 

  32. Jett JR, Maksymiuk AW, Su JQ, Mailliard JA, Krook JE, Tschetter LK, et al. Phase III trial of recombinant interferon gamma in complete responders with small-cell lung cancer. J Clin Oncol. 1994;12(11):2321–6. https://doi.org/10.1200/jco.1994.12.11.2321.

    Article  CAS  PubMed  Google Scholar 

  33. Kelly K, Crowley JJ, Bunn PA Jr, Hazuka MB, Beasley K, Upchurch C, et al. Role of recombinant interferon alfa-2a maintenance in patients with limited-stage small-cell lung cancer responding to concurrent chemoradiation: a Southwest Oncology Group study. J Clin Oncol. 1995;13(12):2924–30. https://doi.org/10.1200/jco.1995.13.12.2924.

    Article  CAS  PubMed  Google Scholar 

  34. van Zandwijk N, Groen HJ, Postmus PE, Burghouts JT, ten Velde GP, Ardizzoni A, et al. 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. 1997;33(11):1759–66.

    Article  PubMed  Google Scholar 

  35. Pillai RN, Aisner J, Dahlberg SE, Rogers JS, DiPaola RS, Aisner S, et al. Interferon alpha plus 13-cis-retinoic acid modulation of BCL-2 plus paclitaxel for recurrent small-cell lung cancer (SCLC): an Eastern Cooperative Oncology Group study (E6501). Cancer Chemother Pharmacol. 2014;74(1):177–83. https://doi.org/10.1007/s00280-014-2427-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Shengle Z, Carlos C-C, Zhang S, Reuter VE, Sucharita A, Bradley HW, et al. Selection of tumor antigens as targets for immune attack using immunohistochemistry: I. Focus on gangliosides. Int J Cancer. 1997;73(1):42–9. https://doi.org/10.1002/(sici)1097-0215(19970926)73:1%3c42:aid-ijc8%3e3.0.co;2-1.

    Article  Google Scholar 

  37. Krug LM, Ragupathi G, Hood C, Kris MG, Miller VA, Allen JR, et al. Vaccination of patients with small-cell lung cancer with synthetic fucosyl GM-1 conjugated to keyhole limpet hemocyanin. Clin Cancer Res. 2004;10(18 Pt 1):6094–100. https://doi.org/10.1158/1078-0432.CCR-04-0482.

    Article  CAS  PubMed  Google Scholar 

  38. Krug LM, Ragupathi G, Ng KK, Hood C, Jennings HJ, Guo Z, et al. Vaccination of small cell lung cancer patients with polysialic acid or N-propionylated polysialic acid conjugated to keyhole limpet hemocyanin. Clin Cancer Res. 2004;10(3):916–23.

    Article  CAS  PubMed  Google Scholar 

  39. Krug LM, Ragupathi G, Hood C, George C, Hong F, Shen R, et al. Immunization with N-propionyl polysialic acid-KLH conjugate in patients with small cell lung cancer is safe and induces IgM antibodies reactive with SCLC cells and bactericidal against group B meningococci. Cancer Immunol Immunother. 2012;61(1):9–18. https://doi.org/10.1007/s00262-011-1083-6.

    Article  CAS  PubMed  Google Scholar 

  40. Chada S, Mhashilkar A, Roth JA, Gabrilovich D. Development of vaccines against self-antigens: the p53 paradigm. Curr Opin Drug Discov Devel. 2003;6(2):169–73.

    CAS  PubMed  Google Scholar 

  41. Vierboom MP, Nijman HW, Offringa R, van der Voort EI, van Hall T, van den Broek L, et al. Tumor eradication by wild-type p53-specific cytotoxic T lymphocytes. J Exp Med. 1997;186(5):695–704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zwaveling S, Vierboom MP, Ferreira Mota SC, Hendriks JA, Ooms ME, Sutmuller RP, et al. Antitumor efficacy of wild-type p53-specific CD4(+) T-helper cells. Cancer Res. 2002;62(21):6187–93.

    CAS  PubMed  Google Scholar 

  43. Chiappori AA, Soliman H, Janssen WE, Antonia SJ, Gabrilovich DI. INGN-225: a dendritic cell-based p53 vaccine (Ad.p53-DC) in small cell lung cancer: observed association between immune response and enhanced chemotherapy effect. Expert Opin Biol Ther. 2010;10(6):983–91. https://doi.org/10.1517/14712598.2010.484801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):480–9. https://doi.org/10.1038/nature10673.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13(4):227–42. https://doi.org/10.1038/nri3405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Apetoh L, Ladoire S, Coukos G, Ghiringhelli F. Combining immunotherapy and anticancer agents: the right path to achieve cancer cure? Ann Oncol. 2015;26(9):1813–23. https://doi.org/10.1093/annonc/mdv209.

    Article  CAS  PubMed  Google Scholar 

  47. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252. https://doi.org/10.1038/nrc3239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704. https://doi.org/10.1146/annurev.immunol.26.021607.090331.

    Article  CAS  PubMed  Google Scholar 

  49. Reck M, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Ann Oncol. 2013;24(1):75–83. https://doi.org/10.1093/annonc/mds213.

    Article  CAS  PubMed  Google Scholar 

  50. Arriola E, Wheater M, Galea I, Cross N, Maishman T, Hamid D, et al. 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 Thorac Oncol. 2016;11(9):1511–21. https://doi.org/10.1016/j.jtho.2016.05.028.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Reck M, Luft A, Szczesna A, Havel L, Kim SW, Akerley W, et al. Phase III randomized trial of ipilimumab plus etoposide and platinum versus placebo plus etoposide and platinum in extensive-stage small-cell lung cancer. J Clin Oncol. 2016;34(31):3740–8. https://doi.org/10.1200/JCO.2016.67.6601.

    Article  CAS  PubMed  Google Scholar 

  52. Antonia SJ, Lopez-Martin JA, Bendell J, Ott PA, Taylor M, Eder JP, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016;17(7):883–95. https://doi.org/10.1016/s1470-2045(16)30098-5.

    Article  CAS  PubMed  Google Scholar 

  53. Hellmann MD, Ott PA, Zugazagoitia J, Ready NE, Hann CL, De Braud FG, et al. Nivolumab (nivo) ± ipilimumab (ipi) in advanced small-cell lung cancer (SCLC): first report of a randomized expansion cohort from CheckMate 032. J Clin Oncol. 2017;35(15_suppl):8503. https://doi.org/10.1200/jco.2017.35.15_suppl.8503.

    Article  Google Scholar 

  54. National Comprehensive Cancer Network. Small Cell Lung Cancer (Version 2.2018). https://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf. Accessed 15 Jun 2018.

  55. Horn L, Reck M, Gettinger SN, Spigel DR, Antonia SJ, Rupnow BA, et al. 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. 2016;34(15_suppl):TPS8578. https://doi.org/10.1200/jco.2016.34.15_suppl.tps8578.

    Article  Google Scholar 

  56. Ready N, Owonikoko TK, Postmus PE, Reck M, Peters S, Pieters A, et al. 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. 2016;34(15_suppl):TPS8579. https://doi.org/10.1200/jco.2016.34.15_suppl.tps8579.

    Article  Google Scholar 

  57. De Ruysscher D, Pujol JL, Popat S, Reck M, Le Pechoux C, Liston A, et al. STIMULI: a randomised open-label phase II trial of consolidation with nivolumab and ipilimumab in limited-stage SCLC after standard of care chemo-radiotherapy conducted by ETOP and IFCT. Ann Oncol. 2016;27(suppl_6):1430TiP-TiP. https://doi.org/10.1093/annonc/mdw389.08.

    Article  Google Scholar 

  58. Ott PA, Elez E, Hiret S, Kim DW, Morosky A, Saraf S, et al. Pembrolizumab in patients with extensive-stage small-cell lung cancer: results from the phase Ib KEYNOTE-028 Study. J Clin oncol. 2017;35(34):3823–9. https://doi.org/10.1200/JCO.2017.72.5069.

    Article  CAS  PubMed  Google Scholar 

  59. Chung HC, Lopez-Martin JA, Kao SC-H, Miller WH, Ros W, Gao B et al. Phase 2 study of pembrolizumab in advanced small-cell lung cancer (SCLC): KEYNOTE-158. J Clin Oncol. 2018;36(15_suppl):8506-. https://doi.org/10.1200/jco.2018.36.15_suppl.8506.

  60. Gadgeel SM, Pennell NA, Fidler MJ, Halmos B, Bonomi P, Stevenson J, et al. Phase II study of maintenance pembrolizumab in patients with extensive-stage small cell lung cancer (SCLC). J Thorac Oncol. 2018. https://doi.org/10.1016/j.jtho.2018.05.002.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Rudin CM, Shen L, Pietanza MC. KEYNOTE-604: Phase 3 trial of pembrolizumab plus etoposide/platinum (EP) for first-line treatment of extensive stage small-cell lung cancer (ES-SCLC). Ann Oncol. 2017;28(suppl_5):mdx386.008. https://doi.org/10.1093/annonc/mdx386.008.

    Article  Google Scholar 

  62. Sequist LV, Chiang A, Gilbert J, Gordon M, Conkling PR, Thompson D, et al. Clinical activity, safety and predictive biomarkers results from a phase Ia atezolizumab (atezo) trial in extensive-stage small cell lung cancer (ES-SCLC). Ann Oncol. 2016;27(suppl_6):1425PD-PD. https://doi.org/10.1093/annonc/mdw389.03.

    Article  Google Scholar 

  63. Pujol JL, Greillier L, Audigier Valette C, Moro-Sibilot D, Uwer L, Hureaux J, et al. A randomized non-comparative phase II study of anti–PD-L1 atezolizumab or chemotherapy as second-line therapy in patients with small cell lung cancer: results from the IFCT-1603 trial. Ann Oncol. 2018;29(Suppl 8):1664O. https://doi.org/10.1093/annonc/mdy298.

    Article  Google Scholar 

  64. Horn L, Reck M, Mok TSK, Johnson M, Waterkamp D, Lam S, et al. A Phase III study of atezolizumab with carboplatin plus etoposide in patients with extensive-stage small cell lung cancer (IMpower133). Ann Oncol. 2016;27(suppl_6):1431TiP-TiP. https://doi.org/10.1093/annonc/mdw389.09.

    Article  Google Scholar 

  65. Horn L, Mansfield AS, Szczęsna A, Havel L, Krzakowski M, Hochmair MJ et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379:2220–9. https://doi.org/10.1056/nejmoa1809064.

    Article  CAS  PubMed  Google Scholar 

  66. Pawel JV, Vynnychenko I, Jiang H, Huang Y, Dennis PA. A phase II, open-label, multi-arm study of novel combinations of immunotherapies or DDR inhibitors in platinum-refractory, extensive disease small-cell lung cancer (ED-SCLC): BALTIC. J Clin Oncol. 2017;35(15_suppl):TPS8585-TPS. https://doi.org/10.1200/jco.2017.35.15_suppl.tps8585.

    Article  Google Scholar 

  67. Paz-Ares L, Jiang H, Huang Y, Dennis P. CASPIAN: phase 3 study of first-line durvalumab ± tremelimumab + platinum-based chemotherapy vs chemotherapy alone in ED-SCLC. J Thorac Oncol. 2017;12(11):S2398. https://doi.org/10.1016/j.jtho.2017.11.015.

    Article  Google Scholar 

  68. Jiao S, Xia W, Yamaguchi H, Wei Y, Chen MK, Hsu JM, et al. PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression. Clin Cancer Res. 2017;23(14):3711–20. https://doi.org/10.1158/1078-0432.CCR-16-3215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Krebs M, Ross K, Kim S, De Jonge M, Barlesi F, Postel-Vinay S, et al. An open-label, multitumor phase II basket study of olaparib and durvalumab (MEDIOLA): results in patients with relapsed SCLC. J Thorac Oncol. 2017;12(11):S2044–S5. https://doi.org/10.1016/j.jtho.2017.09.1040.

    Article  Google Scholar 

  70. Schmidt M, Hagner N, Marco A, Konig-Merediz SA, Schroff M, Wittig B. Design and structural requirements of the potent and safe TLR-9 agonistic immunomodulator MGN1703. Nucleic Acid Ther. 2015;25(3):130–40. https://doi.org/10.1089/nat.2015.0533.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Thomas M, Ponce-Aix S, Navarro Mendivil A, Riera Knorrenschild J, Schmidt M, Krikow M, et al. Top-line data from the randomized phase 2 IMPULSE study in small-cell lung cancer (SCLC): Immunotherapeutic maintenance treatment with lefitolimod. Ann Oncol. 2017;28(suppl_5):mdx386. https://doi.org/10.1093/annonc/mdx386.

    Article  Google Scholar 

  72. Saunders LR, Bankovich AJ, Anderson WC, Aujay MA, Bheddah S, Black K, et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med. 2015;7(302):302ra136. https://doi.org/10.1126/scitranslmed.aac9459.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Rudin CM, Pietanza MC, Bauer TM, Ready N, Morgensztern D, Glisson BS, et al. Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study. Lancet Oncol. 2017;18(1):42–51. https://doi.org/10.1016/s1470-2045(16)30565-4.

    Article  CAS  PubMed  Google Scholar 

  74. Carbone DP, Morgensztern D, Moulec SL, Santana-Davila R, Ready N, Hann CL, et al. Efficacy and safety of rovalpituzumab tesirine in patients with DLL3-expressing, ≥ 3rd line small cell lung cancer: results from the phase 2 TRINITY study. J Clin Oncol. 2018;36(15_suppl):8507. https://doi.org/10.1200/jco.2018.36.15_suppl.8507.

    Article  Google Scholar 

  75. Daniel DB, Rudin CM, Hart L, Spigel DR, Edelman MJ, Goldschmidt J, et al. Results of a randomized, placebo-controlled, phase 2 study of tarextumab (TRXT, anti-Notch2/3) in combination with etoposide and platinum (EP) in patients (pts) with untreated extensive-stage small-cell lung cancer (ED-SCLC). Ann Oncol. 2017;28(suppl_5):mdx386.004. https://doi.org/10.1093/annonc/mdx386.004.

    Article  Google Scholar 

  76. Chu QSC, Markman B, Leighl N, Krug L, Rudin C, Lathers D, et al. A phase 1/2 trial of a monoclonal antibody targeting fucosyl GM1 in relapsed/refractory small cell lung cancer (SCLC): safety and preliminary efficacy. Ann Oncol. 2016;27(suppl_6):1427PD. https://doi.org/10.1093/annonc/mdw389.05.

    Article  Google Scholar 

  77. Chu QSC, van Herpen C, Leighl NB, Markman B, Clarke S, Juergens RA, et al. Initial results of BMS-986012, a first-in-class fucosyl-GM1 mAb, in combination with nivolumab, in pts with relapsed/refractory (rel/ref) small-cell lung cancer (SCLC). Ann Oncol. 2017;28(suppl_5):mdx386.002. https://doi.org/10.1093/annonc/mdx386.002.

    Article  Google Scholar 

  78. Mueller BM, Romerdahl CA, Gillies SD, Reisfeld RA. Enhancement of antibody-dependent cytotoxicity with a chimeric anti-GD2 antibody. J Immunol. 1990;144(4):1382–6.

    CAS  PubMed  Google Scholar 

  79. Navid F, Santana VM, Barfield RC. Anti-GD2 antibody therapy for GD2-expressing tumors. Curr Cancer Drug Targets. 2010;10(2):200–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Dhillon S. Dinutuximab: first global approval. Drugs. 2015;75(8):923–7. https://doi.org/10.1007/s40265-015-0399-5.

    Article  CAS  PubMed  Google Scholar 

  81. Castel V, Segura V, Canete A. Treatment of high-risk neuroblastoma with anti-GD2 antibodies. Clin Transl Oncol. 2010;12(12):788–93. https://doi.org/10.1007/s12094-010-0600-y.

    Article  CAS  PubMed  Google Scholar 

  82. Weiskopf K. Cancer immunotherapy targeting the CD47/SIRPalpha axis. Eur J Cancer. 2017;76:100–9. https://doi.org/10.1016/j.ejca.2017.02.013.

    Article  CAS  PubMed  Google Scholar 

  83. Xiang Y-R, Liu L. Eating cancer cells by blocking CD47 signaling: cancer therapy by targeting the innate immune checkpoint. Cancer Transl Med. 2017;3(6):200–8. https://doi.org/10.4103/ctm.ctm_26_17.

    Article  CAS  Google Scholar 

  84. Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, et al. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci USA. 2012;109(17):6662–7. https://doi.org/10.1073/pnas.1121623109.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Weiskopf K, Jahchan NS, Schnorr PJ, Cristea S, Ring AM, Maute RL, et al. CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer. J Clin Invest. 2016;126(7):2610–20. https://doi.org/10.1172/JCI81603.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Navarro A, Felip E. Pembrolizumab in advanced pretreated small cell lung cancer patients with PD-L1 expression: data from the KEYNOTE-028 trial: a reason for hope? Transl Lung Cancer Res. 2017;6(Suppl 1):S78–83. https://doi.org/10.21037/tlcr.2017.10.04.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Giaccone G, Debruyne C, Felip E, Chapman PB, Grant SC, Millward M, et al. 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. 2005;23(28):6854–64. https://doi.org/10.1200/jco.2005.17.186.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Medical Oncology Department, Hospital General Universitario Gregorio Marañon, Calle del Doctor Esquerdo, 46, 28007, Madrid, Spain

    A. Calles, G. Aguado, C. Sandoval & R. Álvarez

  2. Instituto de Investigacion Sanitaria Gregorio Marañon, Madrid, Spain

    A. Calles & R. Álvarez

Authors
  1. A. Calles
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G. Aguado
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C. Sandoval
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. Álvarez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. Calles.

Ethics declarations

Conflict of interest

AC has received honorary/consulting fees from AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche/Genentech, Eli Lilly and Company, Novartis, Merck Sharp & Dohme, and Bristol-Myers Squibb. The rest of the authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Informed consent is not applicable to this article.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Calles, A., Aguado, G., Sandoval, C. et al. The role of immunotherapy in small cell lung cancer. Clin Transl Oncol 21, 961–976 (2019). https://doi.org/10.1007/s12094-018-02011-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-018-02011-9

Keywords

Search

Navigation