Skip to main content

Advertisement

SpringerLink
Log in

Epigenetic Therapeutics and Their Impact in Immunotherapy of Lung Cancer

  • Epigenetics (ATY Lau, Section Editor)
  • Published:
Current Pharmacology Reports Aims and scope Submit manuscript

Abstract

Lung cancer is the leading cause of cancer-related death in the USA and worldwide. Novel therapeutic developments are critically necessary to improve outcomes for this disease. Aberrant epigenetic change plays an important role in lung cancer development and progression. Therefore, drugs targeting the epigenome are being investigated in the treatment of lung cancer. Monotherapy of epigenetic therapeutics such as DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi) have so far not shown any apparent benefit while one of the clinical trials with the combinations of DNMTi and HDACi showed a small positive signal for treating lung cancer. Combinations of DNMTi and HDACi with chemotherapies have some efficacy but are often limited by increased toxicities. Preclinical data and clinical trial results suggest that combining epigenetic therapeutics with targeted therapies might potentially improve outcomes in lung cancer patients. Furthermore, several clinical studies suggest that the HDACi vorinostat could be used as a radiosensitizer in lung cancer patients receiving radiation therapy. Immune checkpoint blockade therapies are revolutionizing lung cancer management. However, only a minority of lung cancer patients experience long-lasting benefits from immunotherapy. The role of epigenetic reprogramming in boosting the effects of immunotherapy is an area of active investigation. Preclinical studies and early clinical trial results support this approach which may improve lung cancer treatment, with potentially prolonged survival and tolerable toxicity. In this review, we discuss the current status of epigenetic therapeutics and their combination with other antineoplastic therapies, including novel immunotherapies, in lung cancer management.

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

Similar content being viewed by others

References

  1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55(2):74–108.

    Article  PubMed  Google Scholar 

  2. Yang P, Allen MS, Aubry MC, Wampfler JA, Marks RS, Edell ES, et al. Clinical features of 5,628 primary lung cancer patients: experience at Mayo Clinic from 1997 to 2003. Chest. 2005;128(1):452–62. https://doi.org/10.1378/chest.128.1.452.

    Article  PubMed  Google Scholar 

  3. 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 Thoracic Oncol. 2015;10(7):974–84. https://doi.org/10.1097/JTO.0000000000000551.

    Article  CAS  Google Scholar 

  4. Schrump DS, Fischette MR, Nguyen DM, Zhao M, Li X, Kunst TF, et al. Phase I study of decitabine-mediated gene expression in patients with cancers involving the lungs, esophagus, or pleura. Clin Cancer Res. 2006;12(19):5777–85. https://doi.org/10.1158/1078-0432.CCR-06-0669.

    Article  CAS  PubMed  Google Scholar 

  5. https://clinicaltrials.gov/ct2/show/NCT00413075.

  6. Kummar S, Gutierrez M, Gardner ER, Donovan E, Hwang K, Chung EJ, et al. Phase I trial of MS-275, a histone deacetylase inhibitor, administered weekly in refractory solid tumors and lymphoid malignancies. Clin Cancer Res: Off J Am Assoc Cancer Res. 2007;13(18 Pt 1):5411–7. https://doi.org/10.1158/1078-0432.CCR-07-0791.

    Article  CAS  Google Scholar 

  7. Gore L, Rothenberg ML, O'Bryant CL, Schultz MK, Sandler AB, Coffin D, et al. A phase I and pharmacokinetic study of the oral histone deacetylase inhibitor, MS-275, in patients with refractory solid tumors and lymphomas. Clin Cancer Res: Off J Am Assoc Cancer Res. 2008;14(14):4517–25. https://doi.org/10.1158/1078-0432.CCR-07-1461.

    Article  CAS  Google Scholar 

  8. https://clinicaltrials.gov/ct2/show/NCT00020202?term=NCT00020202&rank=1.

  9. Traynor AM, Dubey S, Eickhoff JC, Kolesar JM, Schell K, Huie MS, et al. Vorinostat (NSC# 701852) in patients with relapsed non-small cell lung cancer: a Wisconsin Oncology Network phase II study. J Thorac Oncol: off Publ Int Assoc Study Lung Cancer. 2009;4(4):522–6.

    Article  Google Scholar 

  10. Juergens RA, Wrangle J, Vendetti FP, Murphy SC, Zhao M, Coleman B, et al. Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov. 2011;1(7):598–607. https://doi.org/10.1158/2159-8290.CD-11-0214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. https://clinicaltrials.gov/ct2/show/NCT01207726?term=NCT01207726&rank=1.

  12. https://clinicaltrials.gov/ct2/show/NCT01886573?term=NCT01886573&rank=1.

  13. https://clinicaltrials.gov/ct2/show/NCT01935947?term=NCT01935947&rank=1.

  14. Chu BF, Karpenko MJ, Liu Z, Aimiuwu J, Villalona-Calero MA, Chan KK, et al. Phase I study of 5-aza-2′-deoxycytidine in combination with valproic acid in non-small-cell lung cancer. Cancer Chemother Pharmacol. 2013;71(1):115–21. https://doi.org/10.1007/s00280-012-1986-8.

    Article  CAS  PubMed  Google Scholar 

  15. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002;3(6):415–28. https://doi.org/10.1038/nrg816.

    CAS  PubMed  Google Scholar 

  16. Cheng X, Blumenthal RM. Mammalian DNA methyltransferases: a structural perspective. Structure. 2008;16(3):341–50. https://doi.org/10.1016/j.str.2008.01.004.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Baylin SB, Jones PA. A decade of exploring the cancer epigenome—biological and translational implications. Nat Rev Cancer. 2011;11(10):726–34. https://doi.org/10.1038/nrc3130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003;349(21):2042–54. https://doi.org/10.1056/NEJMra023075.

    Article  CAS  PubMed  Google Scholar 

  19. Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128(4):683–92. https://doi.org/10.1016/j.cell.2007.01.029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. McGrath J, Trojer P. Targeting histone lysine methylation in cancer. Pharmacol Ther. 2015;150:1–22. https://doi.org/10.1016/j.pharmthera.2015.01.002.

    Article  CAS  PubMed  Google Scholar 

  21. Shames DS, Girard L, Gao B, Sato M, Lewis CM, Shivapurkar N, et al. A genome-wide screen for promoter methylation in lung cancer identifies novel methylation markers for multiple malignancies. PLoS Med. 2006;3(12):e486. https://doi.org/10.1371/journal.pmed.0030486.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Belinsky SA, Klinge DM, Dekker JD, Smith MW, Bocklage TJ, Gilliland FD, et al. Gene promoter methylation in plasma and sputum increases with lung cancer risk. Clin Cancer Res: Off J Am Assoc Cancer Res. 2005;11(18):6505–11. https://doi.org/10.1158/1078-0432.CCR-05-0625.

    Article  CAS  Google Scholar 

  23. Sorm F, Vesely J. Effect of 5-aza-2′-deoxycytidine against leukemic and hemopoietic tissues in AKR mice. Neoplasma. 1968;15(4):339–43.

    CAS  PubMed  Google Scholar 

  24. Sorm F, Piskala A, Cihak A, Vesely J. 5-Azacytidine, a new, highly effective cancerostatic. Experientia. 1964;20(4):202–3.

    Article  CAS  PubMed  Google Scholar 

  25. Jones PA, Taylor SM. Cellular differentiation, cytidine analogs and DNA methylation. Cell. 1980;20(1):85–93.

    Article  CAS  PubMed  Google Scholar 

  26. Wilson VL, Jones PA, Momparler RL. Inhibition of DNA methylation in L1210 leukemic cells by 5-aza-2′-deoxycytidine as a possible mechanism of chemotherapeutic action. Cancer Res. 1983;43(8):3493–6.

    CAS  PubMed  Google Scholar 

  27. Momparler RL, Bouchard J, Onetto N, Rivard GE. 5-aza-2′-deoxycytidine therapy in patients with acute leukemia inhibits DNA methylation. Leuk Res. 1984;8(2):181–5.

    Article  CAS  PubMed  Google Scholar 

  28. Momparler RL, Bouffard DY, Momparler LF, Dionne J, Belanger K, Ayoub J. Pilot phase I-II study on 5-aza-2′-deoxycytidine (Decitabine) in patients with metastatic lung cancer. Anti-Cancer Drugs. 1997;8(4):358–68.

    Article  CAS  PubMed  Google Scholar 

  29. Momparler RL, Ayoub J. Potential of 5-aza-2′-deoxycytidine (Decitabine) a potent inhibitor of DNA methylation for therapy of advanced non-small cell lung cancer. Lung Cancer. 2001;34(Suppl 4):S111–5.

    Article  PubMed  Google Scholar 

  30. Aparicio A, Eads CA, Leong LA, Laird PW, Newman EM, Synold TW, et al. Phase I trial of continuous infusion 5-aza-2′-deoxycytidine. Cancer Chemother Pharmacol. 2003;51(3):231–9. https://doi.org/10.1007/s00280-002-0563-y.

    CAS  PubMed  Google Scholar 

  31. Khan N, Jeffers M, Kumar S, Hackett C, Boldog F, Khramtsov N, et al. Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors. Biochem J. 2008;409(2):581–9. https://doi.org/10.1042/BJ20070779.

    Article  CAS  PubMed  Google Scholar 

  32. Jenuwein T, Allis CD. Translating the histone code. Science. 2001;293(5532):1074–80. https://doi.org/10.1126/science.1063127.

    Article  CAS  PubMed  Google Scholar 

  33. Taddei A, Maison C, Roche D, Almouzni G. Reversible disruption of pericentric heterochromatin and centromere function by inhibiting deacetylases. Nat Cell Biol. 2001;3(2):114–20. https://doi.org/10.1038/35055010.

    Article  CAS  PubMed  Google Scholar 

  34. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76. https://doi.org/10.1016/j.cell.2006.07.024.

    Article  CAS  PubMed  Google Scholar 

  35. Watson JD, Baker TA, Bell SP, Gann A, Levine M, Losick R. Molecular biology of the gene, seventh edition. New York: Pearson Education, Inc.; 2014

  36. Vendetti FP, Rudin CM. Epigenetic therapy in non-small-cell lung cancer: targeting DNA methyltransferases and histone deacetylases. Expert Opin Biol Ther. 2013;13(9):1273–85. https://doi.org/10.1517/14712598.2013.819337.

    Article  CAS  PubMed  Google Scholar 

  37. Gigek CO, Chen ES, Calcagno DQ, Wisnieski F, Burbano RR, Smith MA. Epigenetic mechanisms in gastric cancer. Epigenomics. 2012;4(3):279–94. https://doi.org/10.2217/epi.12.22.

    Article  CAS  PubMed  Google Scholar 

  38. Osada H, Tatematsu Y, Saito H, Yatabe Y, Mitsudomi T, Takahashi T. Reduced expression of class II histone deacetylase genes is associated with poor prognosis in lung cancer patients. Int J Cancer. 2004;112(1):26–32. https://doi.org/10.1002/ijc.20395.

    Article  CAS  PubMed  Google Scholar 

  39. Minamiya Y, Ono T, Saito H, Takahashi N, Ito M, Mitsui M, et al. Expression of histone deacetylase 1 correlates with a poor prognosis in patients with adenocarcinoma of the lung. Lung Cancer. 2011;74(2):300–4. https://doi.org/10.1016/j.lungcan.2011.02.019.

    Article  PubMed  Google Scholar 

  40. Esteller M. Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet. 2007;8(4):286–98. https://doi.org/10.1038/nrg2005.

    Article  CAS  PubMed  Google Scholar 

  41. Baylin SB, Jones PA. Epigenetic determinants of cancer. Cold Spring Harb Perspect Biol. 2016;8(9). https://doi.org/10.1101/cshperspect.a019505.

  42. Cai Y, Geutjes EJ, de Lint K, Roepman P, Bruurs L, Yu LR, et al. The NuRD complex cooperates with DNMTs to maintain silencing of key colorectal tumor suppressor genes. Oncogene. 2014;33(17):2157–68. https://doi.org/10.1038/onc.2013.178.

    Article  CAS  PubMed  Google Scholar 

  43. Shah MH, Binkley P, Chan K, Xiao J, Arbogast D, Collamore M, et al. Cardiotoxicity of histone deacetylase inhibitor depsipeptide in patients with metastatic neuroendocrine tumors. Clin Cancer Res: Off J Am Assoc Cancer Res. 2006;12(13):3997–4003. https://doi.org/10.1158/1078-0432.CCR-05-2689.

    Article  CAS  Google Scholar 

  44. Otterson GA, Hodgson L, Pang H, Vokes EE. Phase II study of the histone deacetylase inhibitor Romidepsin in relapsed small cell lung cancer (Cancer and Leukemia Group B 30304). J Thorac Oncol: Off Publ Int Assoc Study Lung Cancer. 2010;5(10):1644–8. https://doi.org/10.1097/JTO.0b013e3181ec1713.

    Article  Google Scholar 

  45. Schrump DS, Fischette MR, Nguyen DM, Zhao M, Li X, Kunst TF, et al. Clinical and molecular responses in lung cancer patients receiving Romidepsin. Clin Cancer Res: Off J Am Assoc Cancer Res. 2008;14(1):188–98. https://doi.org/10.1158/1078-0432.CCR-07-0135.

    Article  CAS  Google Scholar 

  46. de Marinis F, Atmaca A, Tiseo M, Giuffreda L, Rossi A, Gebbia V, et al. A phase II study of the histone deacetylase inhibitor panobinostat (LBH589) in pretreated patients with small-cell lung cancer. J Thorac Oncol: Off Publ Int Assoc Study Lung Cancer. 2013;8(8):1091–4. https://doi.org/10.1097/JTO.0b013e318293d88c.

    Article  Google Scholar 

  47. Owonikoko TK, Ramalingam SS, Kanterewicz B, Balius TE, Belani CP, Hershberger PA. Vorinostat increases carboplatin and paclitaxel activity in non-small-cell lung cancer cells. Int J Cancer. 2010;126(3):743–55. https://doi.org/10.1002/ijc.24759.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kanzaki M, Kakinuma H, Kumazawa T, Inoue T, Saito M, Narita S, et al. Low concentrations of the histone deacetylase inhibitor, depsipeptide, enhance the effects of gemcitabine and docetaxel in hormone refractory prostate cancer cells. Oncol Rep. 2007;17(4):761–7.

    CAS  PubMed  Google Scholar 

  49. Ramalingam SS, Maitland ML, Frankel P, Argiris AE, Koczywas M, Gitlitz B, et al. Carboplatin and paclitaxel in combination with either vorinostat or placebo for first-line therapy of advanced non-small-cell lung cancer. J Clin Oncol: Off J Am Soc Clin Oncol. 2010;28(1):56–62. https://doi.org/10.1200/JCO.2009.24.9094.

    Article  CAS  Google Scholar 

  50. Jones SF, Infante JR, Thompson DS, Mohyuddin A, Bendell JC, Yardley DA, et al. A phase I trial of oral administration of panobinostat in combination with paclitaxel and carboplatin in patients with solid tumors. Cancer Chemother Pharmacol. 2012;70(3):471–5.

    Article  CAS  PubMed  Google Scholar 

  51. Waqar SN. Belinostat in combination with carboplatin and paclitaxel in patients with chemotherapy-naive metastatic lung cancer. WCLC 2016. 2016;abstract no 5996.

  52. Jones DR, Moskaluk CA, Gillenwater HH, Petroni GR, Burks SG, Philips J, et al. Phase I trial of induction histone deacetylase and proteasome inhibition followed by surgery in non-small-cell lung cancer. J Thorac Oncol: Off Publ Int Assoc Study Lung Cancer. 2012;7(11):1683–90. https://doi.org/10.1097/JTO.0b013e318267928d.

    Article  CAS  Google Scholar 

  53. Erasmus JJ, Rohren E, Swisher SG. Prognosis and reevaluation of lung cancer by positron emission tomography imaging. Proc Am Thorac Soc. 2009;6(2):171–9. https://doi.org/10.1513/pats.200806-059LC.

    Article  PubMed  Google Scholar 

  54. https://clinicaltrials.gov/ct2/show/NCT00901537?term=NCT00901537&rank=1.

  55. https://clinicaltrials.gov/ct2/show/NCT01478685?term=NCT01478685&rank=1.

  56. https://clinicaltrials.gov/ct2/show/NCT01090830?term=NCT01090830&rank=1.

  57. https://clinicaltrials.gov/ct2/show/NCT00907179?term=NCT00907179&rank=1.

  58. Tarhini AA, Zahoor H, McLaughlin B, Gooding WE, Schmitz JC, Siegfried JM, et al. Phase I trial of carboplatin and etoposide in combination with panobinostat in patients with lung cancer. Anticancer Res. 2013;33(10):4475–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. https://clinicaltrials.gov/ct2/show/NCT01336842?term=NCT01336842&rank=1.

  60. https://clinicaltrials.gov/ct2/show/NCT00702572?term=NCT00702572&rank=1.

  61. https://clinicaltrials.gov/ct2/show/NCT00697476?term=NCT00697476&rank=1.

  62. https://clinicaltrials.gov/ct2/show/NCT00423449?term=NCT00423449&rank=1.

  63. https://clinicaltrials.gov/ct2/show/NCT00565227?term=NCT00565227&rank=1.

  64. https://clinicaltrials.gov/ct2/show/NCT01413750?term=NCT01413750&rank=1.

  65. https://clinicaltrials.gov/ct2/show/NCT00473889?term=NCT00473889&rank=1.

  66. https://clinicaltrials.gov/ct2/show/NCT00094978?term=NCT00094978&rank=1.

  67. Hoang T, Campbell TC, Zhang C, Kim K, Kolesar JM, Oettel KR, et al. Vorinostat and bortezomib as third-line therapy in patients with advanced non-small cell lung cancer: a Wisconsin Oncology Network Phase II study. Investig New Drugs. 2014;32(1):195–9. https://doi.org/10.1007/s10637-013-9980-5.

    Article  CAS  Google Scholar 

  68. https://clinicaltrials.gov/ct2/show/NCT00996515?term=NCT00996515&rank=1.

  69. https://clinicaltrials.gov/ct2/show/NCT01545947?term=NCT01545947&rank=1.

  70. Anderson JL. Trial of the HDAC inhibitor belinostat in combination with erlotinib in patients with non-small cell lung cancer. WCLC 2013. 2013;Poster Session 3(P 3.11 (abstract no. 2369)).

  71. Witta SE, Jotte RM, Konduri K, Neubauer MA, Spira AI, Ruxer RL, et al. Randomized phase II trial of erlotinib with and without entinostat in patients with advanced non-small-cell lung cancer who progressed on prior chemotherapy. J Clin Oncol: Off J Am Soc Clin Oncol. 2012;30(18):2248–55. https://doi.org/10.1200/JCO.2011.38.9411.

    Article  CAS  Google Scholar 

  72. https://clinicaltrials.gov/ct2/show/NCT00738751?term=NCT00738751&rank=1.

  73. https://clinicaltrials.gov/ct2/show/NCT01005797?term=NCT01005797&rank=1.

  74. Gerber DE, Boothman DA, Fattah FJ, Dong Y, Zhu H, Skelton RA, et al. Phase 1 study of romidepsin plus erlotinib in advanced non-small cell lung cancer. Lung Cancer. 2015;90(3):534–41. https://doi.org/10.1016/j.lungcan.2015.10.008.

    Article  PubMed  PubMed Central  Google Scholar 

  75. https://clinicaltrials.gov/ct2/show/NCT00503971?term=NCT00503971&rank=1.

  76. https://clinicaltrials.gov/ct2/show/NCT00251589?term=NCT00251589&rank=1.

  77. https://clinicaltrials.gov/ct2/show/NCT02151721?term=NCT02151721&rank=1.

  78. Han JY, Lee SH, Lee GK, Yun T, Lee YJ, Hwang KH, et al. Phase I/II study of gefitinib (Iressa((R))) and vorinostat (IVORI) in previously treated patients with advanced non-small cell lung cancer. Cancer Chemother Pharmacol. 2015;75(3):475–83. https://doi.org/10.1007/s00280-014-2664-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. https://clinicaltrials.gov/ct2/show/NCT00635791?term=NCT00635791&rank=1.

  80. https://clinicaltrials.gov/ct2/show/NCT01628471?term=NCT01628471&rank=1.

  81. https://clinicaltrials.gov/ct2/show/NCT00037817?term=NCT00037817&rank=1.

  82. Song H, Li CW, Labaff AM, Lim SO, Li LY, Kan SF, et al. Acetylation of EGF receptor contributes to tumor cell resistance to histone deacetylase inhibitors. Biochem Biophys Res Commun. 2011;404(1):68–73. https://doi.org/10.1016/j.bbrc.2010.11.064.

    Article  CAS  PubMed  Google Scholar 

  83. Tanimoto A, Takeuchi S, Arai S, Fukuda K, Yamada T, Roca X, et al. Histone deacetylase 3 inhibition overcomes BIM deletion polymorphism-mediated osimertinib resistance in EGFR-mutant lung cancer. Clin Cancer Res: Off J Am Assoc Cancer Res. 2016; https://doi.org/10.1158/1078-0432.CCR-16-2271.

  84. Fukuda K, Takeuchi S, Katayama R, Nanjo S, Yamada T, Suzuki T et al.. HDAC inhibition overcomes crizotinib-resistance by mesenchymal-epithelial transition (MET) in EML4-ALK lung cancer cells. WCLC 2016. 2016;abstract MA07.10.

  85. Nicholson J, Jevons SJ, Groselj B, Ellermann S, Konietzny R, Kerr M, et al. E3 ligase cIAP2 mediates downregulation of MRE11 and radiosensitization in response to HDAC inhibition in bladder cancer. Cancer Res. 2017;77(11):3027–39. https://doi.org/10.1158/0008-5472.CAN-16-3232.

    Article  CAS  PubMed  Google Scholar 

  86. Kim JG, Bae JH, Kim JA, Heo K, Yang K, Yi JM. Combination effect of epigenetic regulation and ionizing radiation in colorectal cancer cells. PLoS One. 2014;9(8):e105405. https://doi.org/10.1371/journal.pone.0105405.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Artacho-Cordon F, Rios-Arrabal S, Olivares-Urbano MA, Storch K, Dickreuter E, Munoz-Gamez JA, et al. Valproic acid modulates radiation-enhanced matrix metalloproteinase activity and invasion of breast cancer cells. Int J Radiat Biol. 2015;91(12):946–56. https://doi.org/10.3109/09553002.2015.1087067.

    Article  CAS  PubMed  Google Scholar 

  88. Decker RH, Gettinger SN, Glazer PM, Wilson LD. Vorinostat, a histone deacetylase inhibitor, in combination with thoracic radiotherapy in advanced non-small cell lung cancer: a dose escalation study. Int J Radiat Oncol. 2011;81(2):2.

    Article  Google Scholar 

  89. Choi CYH, Wakelee HA, Neal JW, Pinder-Schenck MC, Michael YH-H, Chang SD et al. Vorinostat and concurrent stereotactic radiosurgery for non-small cell lung cancer brain metastases: a phase I dose escalation trial. Int J Radiat Oncol. 2017.

  90. Shi W, Lawrence YR, Choy H, Werner-Wasik M, Andrews DW, Evans JJ, et al. Vorinostat as a radiosensitizer for brain metastasis: a phase I clinical trial. J Neuro-Oncol. 2014;118(2):313–9. https://doi.org/10.1007/s11060-014-1433-2.

    Article  CAS  Google Scholar 

  91. Rizvi NA, Mazieres J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015;16(3):257–65. https://doi.org/10.1016/S1470-2045(15)70054-9.

    Article  CAS  PubMed  Google Scholar 

  92. 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(17):1627–39. https://doi.org/10.1056/NEJMoa1507643.

    Article  CAS  PubMed  Google Scholar 

  93. Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural innate and adaptive immunity to cancer. Annu Rev Immunol. 2011;29:235–71. https://doi.org/10.1146/annurev-immunol-031210-101324.

    Article  CAS  PubMed  Google Scholar 

  94. 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 

  95. Palucka K, Banchereau J. Cancer immunotherapy via dendritic cells. Nat Rev Cancer. 2012;12(4):265–77. https://doi.org/10.1038/nrc3258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Ostrand-Rosenberg S. Immune surveillance: a balance between protumor and antitumor immunity. Curr Opin Genet Dev. 2008;18(1):11–8. https://doi.org/10.1016/j.gde.2007.12.007.

  97. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science. 2011;331(6024):1565–70. https://doi.org/10.1126/science.1203486.

    Article  CAS  PubMed  Google Scholar 

  98. Shepherd FA, Douillard JY, Blumenschein GR Jr. Immunotherapy for non-small cell lung cancer: novel approaches to improve patient outcome. J Thorac Oncol: Off Publ Int Assoc Study Lung Cancer. 2011;6(10):1763–73. https://doi.org/10.1097/JTO.0b013e31822e28fc.

    Article  Google Scholar 

  99. Forde PM, Reiss KA, Zeidan AM, Brahmer JR. What lies within: novel strategies in immunotherapy for non-small cell lung cancer. Oncologist. 2013;18(11):1203–13. https://doi.org/10.1634/theoncologist.2013-0171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Woo EY, Yeh H, Chu CS, Schlienger K, Carroll RG, Riley JL, et al. Cutting edge: regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J Immunol. 2002;168(9):4272–6.

    Article  CAS  PubMed  Google Scholar 

  101. 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  PubMed  Google Scholar 

  102. Zhang Y, Huang S, Gong D, Qin Y, Shen Q. Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer. Cell Mol Immunol. 2010;7(5):389–95. https://doi.org/10.1038/cmi.2010.28.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Chen YB, Mu CY, Huang JA. Clinical significance of programmed death-1 ligand-1 expression in patients with non-small cell lung cancer: a 5-year-follow-up study. Tumori. 2012;98(6):751–5. https://doi.org/10.1700/1217.13499.

    PubMed  Google Scholar 

  104. Mu CY, Huang JA, Chen Y, Chen C, Zhang XG. 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. 2011;28(3):682–8. https://doi.org/10.1007/s12032-010-9515-2.

    Article  CAS  PubMed  Google Scholar 

  105. Konishi J, Yamazaki K, Azuma M, Kinoshita I, Dosaka-Akita H, Nishimura M. B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res: Off J Am Assoc Cancer Res. 2004;10(15):5094–100. https://doi.org/10.1158/1078-0432.CCR-04-0428.

    Article  CAS  Google Scholar 

  106. Rajan A, Kim C, Heery CR, Guha U, Gulley JL. Nivolumab, anti-programmed death-1 (PD-1) monoclonal antibody immunotherapy: role in advanced cancers. Hum Vaccin Immunother. 2016;12(9):2219–31. https://doi.org/10.1080/21645515.2016.1175694.

    Article  PubMed  PubMed Central  Google Scholar 

  107. 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(2):123–35. https://doi.org/10.1056/NEJMoa1504627.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. 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(10066):255–65. https://doi.org/10.1016/S0140-6736(16)32517-X.

    Article  PubMed  Google Scholar 

  109. 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(21):2018–28. https://doi.org/10.1056/NEJMoa1501824.

    Article  PubMed  Google Scholar 

  110. Heninger E, Krueger TE, Lang JM. Augmenting antitumor immune responses with epigenetic modifying agents. Front Immunol. 2015;6:29. https://doi.org/10.3389/fimmu.2015.00029.

    PubMed  PubMed Central  Google Scholar 

  111. Sigalotti L, Fratta E, Coral S, Maio M. Epigenetic drugs as immunomodulators for combination therapies in solid tumors. Pharmacol Ther. 2014;142(3):339–50. https://doi.org/10.1016/j.pharmthera.2013.12.015.

    Article  CAS  PubMed  Google Scholar 

  112. Wrangle J, Wang W, Koch A, Easwaran H, Mohammad HP, Vendetti F, et al. Alterations of immune response of non-small cell lung cancer with azacytidine. Oncotarget. 2013;4(11):2067–79. 10.18632/oncotarget.1542.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Zheng H, Zhao W, Yan C, Watson CC, Massengill M, Xie M, et al. HDAC inhibitors enhance T-cell chemokine expression and augment response to PD-1 immunotherapy in lung adenocarcinoma. Clin Cancer Res: Off J Am Assoc Cancer Res. 2016;22(16):4119–32. https://doi.org/10.1158/1078-0432.CCR-15-2584.

    Article  CAS  Google Scholar 

  114. Ma T, Galimberti F, Erkmen CP, Memoli V, Chinyengetere F, Sempere L, et al. Comparing histone deacetylase inhibitor responses in genetically engineered mouse lung cancer models and a window of opportunity trial in patients with lung cancer. Mol Cancer Ther. 2013;12(8):1545–55. https://doi.org/10.1158/1535-7163.MCT-12-0933.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Peng D, Kryczek I, Nagarsheth N, Zhao L, Wei S, Wang W, et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature. 2015;527(7577):249–53. https://doi.org/10.1038/nature15520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Kim K, Skora AD, Li Z, Liu Q, Tam AJ, Blosser RL, et al. Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc Natl Acad Sci U S A. 2014;111(32):11774–9. https://doi.org/10.1073/pnas.1410626111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Weiser TS, Guo ZS, Ohnmacht GA, Parkhurst ML, Tong-On P, Marincola FM, et al. Sequential 5-Aza-2 deoxycytidine-depsipeptide FR901228 treatment induces apoptosis preferentially in cancer cells and facilitates their recognition by cytolytic T lymphocytes specific for NY-ESO-1. J Immunother. 2001;24(2):151–61.

    Article  CAS  PubMed  Google Scholar 

  118. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65. https://doi.org/10.1056/NEJMoa1200694.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54. https://doi.org/10.1056/NEJMoa1200690.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Brahmer JR, Horn L, Antonia SJ, Spigel DR, Gandhi L, Sequist LV, et al. Survival and long-term follow-up of the phase I trial of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in patients (pts) with previously treated advanced non-small cell lung cancer (NSCLC). ASCO Meeting Abstracts 2013. 2013;31(15_suppl):8030.

    Google Scholar 

  121. Johnson ML, Adjei AA, Opyrchal M, Ramalingam S, Janne PA, Dominguez G et al. Dose escalation/confirmation results of ENCORE 601, a phase Ib/II, open-label study of entinostat (ENT) in combination with pembrolizumab (PEMBRO) in patients with non-small cell lung cancer (NSCLC). 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016). 2016;part two: National Harbor(abstract no. 215).

  122. Johnson ML, Gonzalez R, Opyrchal M, Gabrilovich D, Ordentlich P, Brouwer S et al. ENCORE 601: a phase II study of entinostat (ENT) in combination with pembrolizumab (PEMBRO) in patients with melanoma. ASCO Annual Meeting. 2017;35, (suppl; abstract no 9529).

  123. http://www.syndax.com/wp-content/uploads/2017/05/SNDX-General-Releases-5.16.17.pdf.

  124. Levy BP, Giaccone G, Besse B, Begic D, Wu X, Fandi A et al. A phase II multicenter, randomized, placebo-controlled, double-blind study of CC-486 plus pembrolizumab (pembro) vs pembro plus placebo (PBO) in previously treated patients (pts) with locally advanced/metastatic non-small cell lung cancer (NSCLC). ASCO Meeting abstract no TPS9107. 2016.

  125. https://clinicaltrials.gov/ct2/show/NCT02635061?term=NCT02635061&rank=1.

  126. https://clinicaltrials.gov/ct2/show/NCT02909452?term=NCT02909452&rank=1.

  127. https://clinicaltrials.gov/ct2/show/NCT02453620?term=NCT02453620&rank=1.

  128. https://clinicaltrials.gov/ct2/show/NCT02638090?term=NCT02638090&rank=1.

  129. https://clinicaltrials.gov/ct2/show/NCT01928576?term=NCT01928576&rank=1.

  130. https://clinicaltrials.gov/ct2/show/NCT02959437?term=NCT02959437&rank=1.

  131. Kang K, Schrump D, Thomas A, Schalper K, Saunthararajah Y, Velcheti V. Tetrahydrouridine-decitabine for non-cytotoxic epigenetic therapy of NSCLC to enhance immunotherapeutic effect of anti-PD1 in vivo. ASCO Meeting abstract no 11552. 2017.

  132. https://clinicaltrials.gov/ct2/show/NCT02250326?term=NCT02250326&rank=1.

Download references

Author information

Author notes

  1. Ju Hwan Cho and Filiz Oezkan contributed equally.

Authors and Affiliations

  1. Arthur G. James Cancer Hospital Comprehensive Cancer Center, The Ohio State University, 460 W 12th Avenue, Biomedical Research Tower, Columbus, OH, 43210, USA

    Ju Hwan Cho, Filiz Oezkan, Michael Koenig, Gregory A. Otterson & Kai He

  2. Department of Interventional Pneumology, Ruhrlandklinik, West German Lung Center, University Hospital, University Duisburg-Essen, Tueschener Weg 40, 45239, Essen, Germany

    Filiz Oezkan

  3. Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh, UPMC Cancer Pavilion, 5150 Centre Avenue, Pittsburgh, PA, 15232, USA

    James Gordon Herman

Authors
  1. Ju Hwan Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Filiz Oezkan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael Koenig
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gregory A. Otterson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. James Gordon Herman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kai He
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kai He.

Ethics declarations

Conflict of Interest

The authors have no conflicts of interest to declare.

Human and Animal Rights and Informed Consent

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

Additional information

This article is part of the Topical Collection on Epigenetics

Electronic supplementary material

ESM 1

(DOCX 39 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cho, J.H., Oezkan, F., Koenig, M. et al. Epigenetic Therapeutics and Their Impact in Immunotherapy of Lung Cancer. Curr Pharmacol Rep 3, 360–373 (2017). https://doi.org/10.1007/s40495-017-0110-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40495-017-0110-5

Keywords

Search

Navigation