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Targeted Therapy in Head and Neck Cancer: An Update on Current Clinical Developments in Epidermal Growth Factor Receptor-Targeted Therapy and Immunotherapies

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Abstract

Most patients diagnosed with head and neck squamous cell carcinoma (HNSCC) will present with locally advanced disease, requiring multimodality therapy. Despite this curative approach, a significant subset of these patients will develop locoregional failure and/or distant metastases. Despite significant progress in the treatment and subsequent prognosis of locally advanced HNSCC, the prognosis of those patients with recurrent and/or metastatic (R/M) HNSCC is poor, with short-lived responses to palliative chemotherapy and few therapeutic agents available. The discovery of the integral role of epidermal growth factor receptor overexpression in the pathogenesis of HNSCC, coupled with emerging data on the role of tumor evasion of the immune system, has opened new pathways in the development of novel therapeutic agents for the treatment of R/M HNSCC. As a result, cetuximab, a monoclonal antibody targeting epidermal growth factor receptor, as well as pembrolizumab and nivolumab, monoclonal antibodies targeting programmed cell death 1 (PD-1), are now US Food and Drug Administration approved for the treatment of R/M HNSCC. This review will detail the data supporting the use of these agents, as well as clinical trials evaluating the efficacy of other novel and promising drugs.

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References

  1. Davies L, Welch HG. Epidemiology of head and neck cancer in the United States. Otolaryngol Head Neck Surg. 2006;135:451–7.

    Article  PubMed  Google Scholar 

  2. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    Article  PubMed  Google Scholar 

  3. Seiwert TY, Cohen EE. State-of-the-art management of locally advanced head and neck cancer. Br J Cancer. 2005;92:1341–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Marur S, Forastiere AA. Head and neck cancer: changing epidemiology, diagnosis, and treatment. Mayo Clin Proc. 2008;83:489–501.

    Article  PubMed  Google Scholar 

  5. Sacco AG, Cohen EE. Current treatment options for recurrent or metastatic head and neck squamous cell carcinoma. J Clin Oncol. 2015;33:3305–13.

    Article  CAS  PubMed  Google Scholar 

  6. Schantz SPHL, Forastiere A. Cancer: principles and practice of oncology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2001. p. 797–860.

    Google Scholar 

  7. Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359:1116–27.

    Article  CAS  PubMed  Google Scholar 

  8. Mehra R, Seiwert TY, Mahipal A, Weiss J, et al. Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC): pooled analyses after long-term follow-up in KEYNOTE-012. Presented at the American Society of Clinical Oncology Annual Meeting, June 3–7, 2016, Chicago (IL).

  9. Chow LQM, Haddad R, Gupta S, et al. Antitumor Activity of Pembrolizumab in Biomarker-Unselected Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Results From the Phase Ib KEYNOTE-012 Expansion Cohort. J Clin Oncol. 2016;34(32):3838–3845

    Article  Google Scholar 

  10. Tanguy Y Seiwert, Barbara Burtness, Ranee Mehra et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol 2016;17 (7):956–965

    Article  CAS  PubMed  Google Scholar 

  11. Sacco AG, Worden FP. Molecularly targeted therapy for the treatment of head and neck cancer: a review of the ErbB family inhibitors. Onco Targets Ther. 2016;9:1927–43.

    PubMed  PubMed Central  Google Scholar 

  12. Dassonville O, Formento JL, Francoual M, et al. Expression of epidermal growth factor receptor and survival in upper aerodigestive tract cancer. J Clin Oncol. 1993;11:1873–8.

    Article  CAS  PubMed  Google Scholar 

  13. Rubin Grandis J, Melhem MF, Barnes EL, et al. Quantitative immunohistochemical analysis of transforming growth factor-alpha and epidermal growth factor receptor in patients with squamous cell carcinoma of the head and neck. Cancer. 1996;78:1284–92.

    Article  CAS  PubMed  Google Scholar 

  14. Santini J, Formento JL, Francoual M, et al. Characterization, quantification, and potential clinical value of the epidermal growth factor receptor in head and neck squamous cell carcinomas. Head Neck. 1991;13:132–9.

    Article  CAS  PubMed  Google Scholar 

  15. Rubin Grandis J, Melhem MF, Gooding WE, et al. Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst. 1998;90:824–32.

    Article  CAS  PubMed  Google Scholar 

  16. Bazley LA, Gullick WJ. The epidermal growth factor receptor family. Endocr Relat Cancer. 2005;12(Suppl. 1):S17–27.

    Article  CAS  PubMed  Google Scholar 

  17. Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer. 2005;5:341–54.

    Article  CAS  PubMed  Google Scholar 

  18. Egloff AM, Grandis JR. Targeting epidermal growth factor receptor and SRC pathways in head and neck cancer. Semin Oncol. 2008;35:286–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Baselga J, Arteaga CL. Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol. 2005;23:2445–59.

    Article  CAS  PubMed  Google Scholar 

  20. Ganly I, Talbot S, Carlson D, et al. Identification of angiogenesis/metastases genes predicting chemoradiotherapy response in patients with laryngopharyngeal carcinoma. J Clin Oncol. 2007;25:1369–76.

    Article  CAS  PubMed  Google Scholar 

  21. Ang KK, Berkey BA, Tu X, et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res. 2002;62:7350–6.

    CAS  PubMed  Google Scholar 

  22. Takikita M, Xie R, Chung JY, et al. Membranous expression of Her3 is associated with a decreased survival in head and neck squamous cell carcinoma. J Transl Med. 2011;9:126.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Xia W, Lau YK, Zhang HZ, et al. Combination of EGFR, HER-2/neu, and HER-3 is a stronger predictor for the outcome of oral squamous cell carcinoma than any individual family members. Clin Cancer Res. 1999;5:4164–74.

    CAS  PubMed  Google Scholar 

  24. Bowers G, Reardon D, Hewitt T, et al. The relative role of ErbB1-4 receptor tyrosine kinases in radiation signal transduction responses of human carcinoma cells. Oncogene. 2001;20:1388–97.

    Article  CAS  PubMed  Google Scholar 

  25. Schmidt-Ullrich RK, Mikkelsen RB, Dent P, et al. Radiation-induced proliferation of the human A431 squamous carcinoma cells is dependent on EGFR tyrosine phosphorylation. Oncogene. 1997;15:1191–7.

    Article  CAS  PubMed  Google Scholar 

  26. Contessa JN, Hampton J, Lammering G, et al. Ionizing radiation activates Erb-B receptor dependent Akt and p70 S6 kinase signaling in carcinoma cells. Oncogene. 2002;21:4032–41.

    Article  CAS  PubMed  Google Scholar 

  27. Dittmann K, Mayer C, Fehrenbacher B, et al. Radiation-induced epidermal growth factor receptor nuclear import is linked to activation of DNA-dependent protein kinase. J Biol Chem. 2005;280:31182–9.

    Article  CAS  PubMed  Google Scholar 

  28. Bozec A, Peyrade F, Fischel JL, et al. Emerging molecular targeted therapies in the treatment of head and neck cancer. Expert Opin Emerg Drugs. 2009;14:299–310.

    Article  CAS  PubMed  Google Scholar 

  29. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354:567–78.

    Article  CAS  PubMed  Google Scholar 

  30. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 2010;11:21–8.

    Article  CAS  PubMed  Google Scholar 

  31. Burtness B, Goldwasser MA, Flood W, et al. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol. 2005;23:8646–54.

    Article  PubMed  Google Scholar 

  32. Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol. 2007;25:2171–7.

    Article  CAS  PubMed  Google Scholar 

  33. Yang XD, Jia XC, Corvalan JR, et al. Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer therapy. Crit Rev Oncol Hematol. 2001;38:17–23.

    Article  CAS  PubMed  Google Scholar 

  34. Wirth LJ, Dakhil SR, Kornek G, et al. PARTNER: a randomized phase II study of docetaxel/cisplatin (doc/cis) chemotherapy with or without panitumumab (pmab) as first-line treatment (tx) for recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). Presented at the American Society of Clinical Oncology Annual Meeting, May 31–June 4, 2013, Chicago (IL).

  35. Li D, Ambrogio L, Shimamura T, et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene. 2008;27:4702–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Solca F, Dahl G, Zoephel A, et al. Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther. 2012;343:342–50.

    Article  CAS  PubMed  Google Scholar 

  37. Machiels JP, Haddad RI, Fayette J, et al. Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head and Neck 1): an open-label, randomised phase 3 trial. Lancet Oncol. 2015;16:583–94.

    Article  CAS  PubMed  Google Scholar 

  38. Cohen EEW, Licitra LF, Gauler TC, et al. Biomarker analysis in recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients (pts) treated with second-line afatinib versus methotrexate (MTX): LUX-Head and Neck 1 (LUX-H&N1). Presented at the American Society of Clinical Oncology Annual Meeting, May 29–June 2, 2015, Chicago (IL).

  39. Seiwert TY, Fayette J, Cupissol D, et al. A randomized, phase II study of afatinib versus cetuximab in metastatic or recurrent squamous cell carcinoma of the head and neck. Ann Oncol. 2014;25:1813–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Machiels JP, Menis J, Lia M, Fortpied C, et al. Activity of afatinib administered in a window pre-operative study in squamous cell carcinoma of the head and neck (SCCHN): EORTC-90111. Presented at the American Society of Clinical Oncology Annual Meeting, June 3–7, 2016, Chicago (IL).

  41. Gonzales AJ, Hook KE, Althaus IW, et al. Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor. Mol Cancer Ther. 2008;7:1880–9.

    Article  CAS  PubMed  Google Scholar 

  42. Abdul Razak AR, Soulieres D, Laurie SA, et al. A phase II trial of dacomitinib, an oral pan-human EGF receptor (HER) inhibitor, as first-line treatment in recurrent and/or metastatic squamous-cell carcinoma of the head and neck. Ann Oncol. 2013;24:761–9.

    Article  CAS  PubMed  Google Scholar 

  43. Adamo V, Franchina T, Adamo B, et al. Gefitinib in lung cancer therapy: clinical results, predictive markers of response and future perspectives. Cancer Biol Ther. 2009;8:206–12.

    Article  CAS  PubMed  Google Scholar 

  44. Patel PN, Vyas R, Mehta M. Efficacy and toxicity of gefitinib in palliative treatment in recurrent squamous cell carcinoma of head and neck in poor performance elderly patients. Presented at the European Society of Medical Oncology Congress, September 29, 2014, Madrid.

  45. Stewart JS, Cohen EE, Licitra L, et al. Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck [corrected]. J Clin Oncol. 2009;27:1864–71.

    Article  CAS  PubMed  Google Scholar 

  46. Argiris A, Ghebremichael M, Gilbert J, et al. Phase III randomized, placebo-controlled trial of docetaxel with or without gefitinib in recurrent or metastatic head and neck cancer: an eastern cooperative oncology group trial. J Clin Oncol. 2013;31:1405–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Cohen MH, Johnson JR, Chen YF, et al. FDA drug approval summary: erlotinib (Tarceva) tablets. Oncologist. 2005;10:461–6.

    Article  CAS  PubMed  Google Scholar 

  48. Tarceva® (erlotinib tablets) [package insert]. South San Francisco: Genentech, Inc.; 2013.

  49. Soulieres D, Senzer NN, Vokes EE, et al. Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol. 2004;22:77–85.

    Article  CAS  PubMed  Google Scholar 

  50. Siu LL, Soulieres D, Chen EX, et al. Phase I/II trial of erlotinib and cisplatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: a Princess Margaret Hospital phase II consortium and National Cancer Institute of Canada Clinical Trials Group Study. J Clin Oncol. 2007;25:2178–83.

    Article  CAS  PubMed  Google Scholar 

  51. Kim ES, Kies MS, Glisson BS, et al. Final results of a phase II study of erlotinib, docetaxel and cisplatin in patients with recurrent/metastatic head and neck cancer. Presented at the American Society of Clinical Oncology Annual Meeting, June 1–5, 2007, Chicago (IL).

  52. Thomas F, Rochaix P, Benlyazid A, et al. Pilot study of neoadjuvant treatment with erlotinib in nonmetastatic head and neck squamous cell carcinoma. Clin Cancer Res. 2007;13:7086–92.

    Article  CAS  PubMed  Google Scholar 

  53. Herchenhorn D, Dias FL, Viegas CM, et al. Phase I/II study of erlotinib combined with cisplatin and radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 2010;78:696–702.

    Article  CAS  PubMed  Google Scholar 

  54. Hainsworth JD, Spigel DR, Greco FA, et al. Combined modality treatment with chemotherapy, radiation therapy, bevacizumab, and erlotinib in patients with locally advanced squamous carcinoma of the head and neck: a phase II trial of the Sarah Cannon oncology research consortium. Cancer J. 2011;17:267–72.

    Article  CAS  PubMed  Google Scholar 

  55. Martins RG, Parvathaneni U, Bauman JE, et al. Cisplatin and radiotherapy with or without erlotinib in locally advanced squamous cell carcinoma of the head and neck: a randomized phase II trial. J Clin Oncol. 2013;31:1415–21.

    Article  CAS  PubMed  Google Scholar 

  56. Kondo N, Tsukuda M, Ishiguro Y, et al. Antitumor effects of lapatinib (GW572016), a dual inhibitor of EGFR and HER-2, in combination with cisplatin or paclitaxel on head and neck squamous cell carcinoma. Oncol Rep. 2010;23:957–63.

    Article  CAS  PubMed  Google Scholar 

  57. Tykerb® (lapatinib) tablets [package insert]. Research Triangle Park: GlaxoSmithKline; 2012.

  58. Del Campo JM, Hitt R, Sebastian P, et al. Effects of lapatinib monotherapy: results of a randomised phase II study in therapy-naive patients with locally advanced squamous cell carcinoma of the head and neck. Br J Cancer. 2011;105:618–27.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. de Souza JA, Davis DW, Zhang Y, et al. A phase II study of lapatinib in recurrent/metastatic squamous cell carcinoma of the head and neck. Clin Cancer Res. 2012;18:2336–43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Wedge SR, Ogilvie DJ, Dukes M, et al. ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res. 2002;62:4645–55.

    CAS  PubMed  Google Scholar 

  61. Caprelsa® (vandetanib) tablets [prescribing information]. Wilmington: AstraZeneca Pharmaceuticals LP; 2011.

  62. Limaye S, Riley S, Zhao S, et al. A randomized phase II study of docetaxel with or without vandetanib in recurrent or metastatic squamous cell carcinoma of head and neck (SCCHN). Oral Oncol. 2013;49:835–41.

    Article  CAS  PubMed  Google Scholar 

  63. Shinohara T, Taniwaki M, Ishida Y, et al. Structure and chromosomal localization of the human PD-1 gene (PDCD1). Genomics. 1994;23:704–6.

    Article  CAS  PubMed  Google Scholar 

  64. Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704.

    Article  CAS  PubMed  Google Scholar 

  65. Ishida Y, Agata Y, Shibahara K, et al. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. Embo J. 1992;1:3887–95.

    Google Scholar 

  66. Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 2007;19:813–24.

    Article  CAS  PubMed  Google Scholar 

  67. Nishimura H, Nose M, Hiai H, et al. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999;11:141–51.

    Article  CAS  PubMed  Google Scholar 

  68. Intlekofer AM, Thompson CB. At the bench: preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy. J Leukoc Biol. 2013;94:25–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Day CL, Kaufmann DE, Kiepiela P, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. 2006;443:350–4.

    Article  CAS  PubMed  Google Scholar 

  70. Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439:682–7.

    Article  CAS  PubMed  Google Scholar 

  71. Yamazaki T, Akiba H, Iwai H, et al. Expression of programmed death 1 ligands by murine T cells and APC. J Immunol. 2002;169:5538–45.

    Article  CAS  PubMed  Google Scholar 

  72. Keir ME, Liang SC, Guleria I, et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med. 2006;203:883–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Liang SC, Latchman YE, Buhlmann JE, et al. Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses. Eur J Immunol. 2003;33:2706–16.

    Article  CAS  PubMed  Google Scholar 

  74. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2:261–8.

    Article  CAS  PubMed  Google Scholar 

  75. Blank C, Kuball J, Voelkl S, et al. Blockade of PD-L1 (B7-H1) augments human tumor-specific T cell responses in vitro. Int J Cancer. 2006;119:317–27.

    Article  CAS  PubMed  Google Scholar 

  76. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192:1027–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Parry RV, Chemnitz JM, Frauwirth KA, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2005;25:9543–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Seo SK, Seo HM, Jeong HY, et al. Co-inhibitory role of T-cell-associated B7-H1 and B7-DC in the T-cell immune response. Immunol Lett. 2006;102:222–8.

    Article  CAS  PubMed  Google Scholar 

  79. Quezada SA, Peggs KS. Exploiting CTLA-4, PD-1 and PD-L1 to reactivate the host immune response against cancer. Br J Cancer. 2013;108:1560–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Boni C, Fisicaro P, Valdatta C, et al. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J Virol. 2007;81:4215–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Urbani S, Amadei B, Tola D, et al. Restoration of HCV-specific T cell functions by PD-1/PD-L1 blockade in HCV infection: effect of viremia levels and antiviral treatment. J Hepatol. 2008;48:548–58.

    Article  CAS  PubMed  Google Scholar 

  82. Norris S, Coleman A, Kuri-Cervantes L, et al. PD-1 expression on natural killer cells and CD8(+) T cells during chronic HIV-1 infection. Viral Immunol. 2012;25:329–32.

    Article  CAS  PubMed  Google Scholar 

  83. Das S, Suarez G, Beswick EJ, et al. Expression of B7-H1 on gastric epithelial cells: its potential role in regulating T cells during Helicobacter pylori infection. J Immunol. 2006;176:3000–9.

    Article  CAS  PubMed  Google Scholar 

  84. Lepenies B, Jacobs T. The role of negative costimulators during parasitic infections. Endocr Metab Immune Disord Drug Targets. 2008;8:279–88.

    Article  CAS  PubMed  Google Scholar 

  85. Jacobsen ED. Restoring antitumor immunity via PD-1 blockade after autologous stem-cell transplantation for diffuse large B-cell lymphoma. J Clin Oncol. 2013;31:4268–70.

    Article  CAS  PubMed  Google Scholar 

  86. Amarnath S, Mangus CW, Wang JC, et al. The PDL1-PD1 axis converts human TH1 cells into regulatory T cells. Sci Transl Med. 2011;3:111ra120.

  87. Ferris RL. Immunology and immunotherapy of head and neck cancer. J Clin Oncol. 2015;33:3293–304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Zandberg DP, Strome SE. The role of the PD-L1:PD-1 pathway in squamous cell carcinoma of the head and neck. Oral Oncol. 2014;50:627–32.

    Article  CAS  PubMed  Google Scholar 

  89. Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008;8:467–77.

    Article  CAS  PubMed  Google Scholar 

  90. Jebreel A, Mistry D, Loke D, et al. Investigation of interleukin 10, 12 and 18 levels in patients with head and neck cancer. J Laryngol Otol. 2007;121:246–52.

    Article  CAS  PubMed  Google Scholar 

  91. Moutsopoulos NM, Wen J, Wahl SM. TGF-beta and tumors: an ill-fated alliance. Curr Opin Immunol. 2008;20:234–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Cheng F, Wang HW, Cuenca A, et al. A critical role for Stat3 signaling in immune tolerance. Immunity. 2003;19:425–36.

    Article  CAS  PubMed  Google Scholar 

  93. Duffy SA, Taylor JM, Terrell JE, et al. Interleukin-6 predicts recurrence and survival among head and neck cancer patients. Cancer. 2008;113:750–7.

    Article  PubMed  Google Scholar 

  94. Snyderman CH, Milanovich M, Wagner RL, et al. Prognostic significance of prostaglandin E2 production in fresh tissues of head and neck cancer patients. Head Neck. 1995;17:108–13.

    Article  CAS  PubMed  Google Scholar 

  95. Camacho M, Leon X, Fernandez-Figueras MT, et al. Prostaglandin E(2) pathway in head and neck squamous cell carcinoma. Head Neck. 2008;30:1175–81.

    Article  PubMed  Google Scholar 

  96. Harris SG, Padilla J, Koumas L, et al. Prostaglandins as modulators of immunity. Trends Immunol. 2002;23:144–50.

    Article  CAS  PubMed  Google Scholar 

  97. Seiwert TY, Cohen EE. Targeting angiogenesis in head and neck cancer. Semin Oncol. 2008;35:274–85.

    Article  PubMed  Google Scholar 

  98. Johnson BF, Clay TM, Hobeika AC, et al. Vascular endothelial growth factor and immunosuppression in cancer: current knowledge and potential for new therapy. Expert Opin Biol Ther. 2007;7:449–60.

    Article  CAS  PubMed  Google Scholar 

  99. Alhamarneh O, Amarnath SM, Stafford ND, et al. Regulatory T cells: what role do they play in antitumor immunity in patients with head and neck cancer? Head Neck. 2008;30:251–61.

    Article  PubMed  Google Scholar 

  100. Strauss L, Bergmann C, Gooding W, et al. The frequency and suppressor function of CD4+ CD25highFoxp3+ T cells in the circulation of patients with squamous cell carcinoma of the head and neck. Clin Cancer Res. 2007;13:6301–11.

    Article  CAS  PubMed  Google Scholar 

  101. Strauss L, Bergmann C, Szczepanski M, et al. A unique subset of CD4+ CD25highFoxp3+ T cells secreting interleukin-10 and transforming growth factor-beta1 mediates suppression in the tumor microenvironment. Clin Cancer Res. 2007;13:4345–54.

    Article  CAS  PubMed  Google Scholar 

  102. Strauss L, Bergmann C, Whiteside TL. Functional and phenotypic characteristics of CD4+ CD25highFoxp3+ Treg clones obtained from peripheral blood of patients with cancer. Int J Cancer. 2007;121:2473–83.

    Article  CAS  PubMed  Google Scholar 

  103. Ostrand-Rosenberg S, Sinha P. Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol. 2009;82:4499–506.

    Article  CAS  Google Scholar 

  104. Komohara Y, Jinushi M, Takeya M. Clinical significance of macrophage heterogeneity in human malignant tumors. Cancer Sci. 2014;105:1–8.

    Article  CAS  PubMed  Google Scholar 

  105. O’Brien PM, Saveria Campo M. Evasion of host immunity directed by papillomavirus-encoded proteins. Virus Res. 2002;88:103–17.

    Article  PubMed  Google Scholar 

  106. Stanley M. Immunobiology of HPV and HPV vaccines. Gynecol Oncol. 2008;109:S15–21.

    Article  CAS  PubMed  Google Scholar 

  107. Bhat P, Mattarollo SR, Gosmann C, et al. Regulation of immune responses to HPV infection and during HPV-directed immunotherapy. Immunol Rev. 2011;239:85–98.

    Article  CAS  PubMed  Google Scholar 

  108. Gildener-Leapman N, Ferris RL, Bauman JE. Promising systemic immunotherapies in . Oral Oncol. 2013;49:1089–96.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Lyford-Pike S, Peng S, Young GD, et al. Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated . Cancer Res. 2013;73:1733–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Badoual C, Hans S, Merillon N, et al. PD-1-expressing tumor-infiltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck cancer. Cancer Res. 2013;73:128–38.

    Article  CAS  PubMed  Google Scholar 

  111. Nasman A, Romanitan M, Nordfors C, et al. Tumor infiltrating CD8+ and Foxp3+ lymphocytes correlate to clinical outcome and human papillomavirus (HPV) status in tonsillar cancer. PLoS One. 2012;7:e38711.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. King EV, Ottensmeier CH, Thomas GJ. The immune response in HPV+ oropharyngeal cancer. Oncoimmunology. 2014;3:e27254.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Herrero R, Quint W, Hildesheim A, et al. Reduced prevalence of oral human papillomavirus (HPV) 4 years after bivalent HPV vaccination in a randomized clinical trial in Costa Rica. PLoS One. 2013;8:e68329.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Uppaluri R, Zolkind P, Lin T, Nussenbaum B, et al. Immunotherapy with pembrolizumab in surgically resectable . Presented at the American Society of Clinical Oncology Annual Meeting, June 3–7, 2016, Chicago (IL).

  115. Ferris RL, Blumenschein G Jr, Fayette J, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375(19):1856–67.

    Article  PubMed  CAS  Google Scholar 

  116. Seiwert T, Weiss J, Baxi SS, et al. A phase 3, randomized, open-label study of first-line durvalumab (MEDI4736) ± tremelimumab versus standard of care (SoC; EXTREME regimen) in recurrent/metastatic (R/M) SCCHN: KESTREL. Presented at the 2016 American Society of Clinical Oncology Annual Meeting, June 3-7, 2016, Chicago (IL).

  117. Zandberg DP, Jarkowski A, Emeribe UA, Goswami T, Melillo G. A phase 2, multicenter, single-arm, global study of MEDI4736 monotherapy in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): HAWK (NCT02207530). Presented at the American Society of Clinical Oncology Annual Meeting, May 29-June 2, 2015, Chicago (IL).

  118. Chow LQM, Eaton KD, Baik C, et al. Phase Ib trial of TLR8 agonist VTX-2237 in combination with cetuximab in patients with recurrent or metastatic squamous cell carcinomas of the head and neck (SCCHN). Presented at the Multidisciplinary Head and Neck Cancer Symposium, 20–22 Feb 2014, Scottsdale (AZ).

  119. Chow LQ, Morishima C, Eaton KD, et al. Phase 1b trial of the Toll-like receptor 8 agonist, motolimod (VTX-2337), combined with cetuximab in patients with recurrent or metastatic SCCHN. Clin Cancer Res. 2016. doi:10.1158/1078-0432.CCR-16-1934. [Epub ahead of print].

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Jonathan Moreira, Alexander Tobias, Michael P. O’Brien, and Mark Agulnik have no conflicts of interest directly relevant to the content of this article.

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Moreira, J., Tobias, A., O’Brien, M.P. et al. Targeted Therapy in Head and Neck Cancer: An Update on Current Clinical Developments in Epidermal Growth Factor Receptor-Targeted Therapy and Immunotherapies. Drugs 77, 843–857 (2017). https://doi.org/10.1007/s40265-017-0734-0

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