Влияние ассоциированности опухоли с вирусом папилломы человека на результаты иммунотерапии у пациентов с рецидивным и метастатическим плоскоклеточным раком головы и шеи

Вирус папилломы человека (ВПЧ), преимущественно 16-го (реже 18-го) типа, ассоциирован с развитием плоскоклеточного рака ротоглотки (ПРР). Согласно данным литературы, от 25 до 70 % всех случаев данного заболевания связаны с ВПЧ-инфекцией. В США и некоторых странах европейского союза частота ВПЧ-ассоциированного ПРР достигает 60-70 % всех случаев плоскоклеточного рака головы и шеи. Для ВПЧ-положительного ПРР характерны благоприятный прогноз и более высокие показатели выживаемости по сравнению с ВПЧ-отрицательным ПРР. Эти варианты данной патологии по-разному классифицируются в Tumor, Nodus and Metastasis (TNM) 8-го издания. Значительная разница в показателях выживаемости и прогнозе заболевания стала причиной проведения исследований, направленных на изучение возможности деинтенсификации стандартного лечения ПРР с целью минимизации нежелательных явлений без потери эффективности. Несмотря на более благоприятное клиническое течение, у 15 % пациентов с ВПЧ-ассоциированным ПРР даже после стандартной терапии развиваются рецидивы и/или регионарные/ отдаленные метастазы, что связано с неблагоприятным прогнозом. Современные схемы лечения рецидивного/метастатического плоскоклеточного рака головы и шеи включают иммунотерапию, результаты которой также могут зависеть от ВПЧ-статуса опухоли. Несмотря на то что в клинические исследования, посвященные изучению эффективности иммунопрепаратов, входят пациенты с ВПЧ-положительными опухолями, данные о результатах лечения являются неоднозначными, к тому же молекулярные механизмы влияния ВПЧ на иммунный ответ в полной мере не изучены.

В статье обобщены данные о влиянии положительного ВПЧ-стасуса на эффективность иммунотерапии пациентов с прогрессирующим/метастатическим плоскоклеточным раком головы и шеи.

1. De Sanjose S., Quint W.G., Alemany L. et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol 2010;11(11):1048—56. DOI: 10.1016/S1470-2045(10)70230-8

2. Chaturvedi A.K., Engels E.A., Pfeiffer R.M. et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol 2011;29(32):4294-301. DOI: 10.1200/JCO.2011.36.4596

3. Nasman A., Attner P., Hammarstedt L. et al. Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma? Int J Cancer 2009;125(2):362-6. DOI: 10.1002/ijc.24339

4. Gillison M.L., Broutian T., Pickard R.K. et al. Prevalence of oral HPV infection in the United States, 2009-2010. JAMA 2012;307(7):693-703. DOI: 10.1001/jama.2012.101

5. Mehanna H., Beech T., Nicholson T. et al. Prevalence of human papillomavirus in oropharyngeal and nonoropharyngeal head and neck cancer - systematic review and meta-analysis of trends by time and region. Head Neck 2013;35(5):747-55. DOI: 10.1002/hed.22015

6. Marklund L., Holzhauser S., de Flon C. et al. Survival of patients with oropharyngeal squamous cell carcinomas (OPSCC) in relation to TNM 8 - risk of incorrect downstaging of HPV-mediated non- tonsillar, non-base of tongue carcinomas. Eur J Cancer 2020;139:192-200. DOI: 10.1016/j.ejca.2020.08.003

7. Gillison M.L., Koch W.M., Capone R.B. et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 2000;92(9):709-20. DOI: 10.1093/jnci/92.9.709

8. Amin M., Edge S., Greene F. et al. AJCC Cancer Staging Manual, 8th edn. New York: Springer, 2017.

9. Masterson L., Moualed D., Liu Z.W. et al. De-escalation treatment protocols for human papillomavirus-associated oropharyngeal squamous cell carcinoma: a systematic review and meta-analysis of current clinical trials. Eur J Cancer 2014;50(15):2636-48. DOI: 10.1016/j.ejca.2014.07.001

10. Economopoulou P., Kotsantis I., Psyrri A. Special issue about head and neck cancers: HPV positive cancers. Int J Mol Sci 2020;21(9):3388. DOI: 10.3390/ijms21093388

11. Gillison M.L., Trotti A.M., Harris J. et al. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. Lancet 2019;393(10166):40-50. DOI: 10.1016/s0140-6736(18)32779-x

12. Liu C., Mann D., Sinha U.K., Kokot N.C. The molecular mechanisms of increased radiosensitivity of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC): an extensive review. J Otolaryngol Head Neck Surg 2018;47(1):59. DOI: 10.1186/s40463-018-0302-y

13. Ang K.K., Harris J., Wheeler R. et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;363(1):24-35. DOI: 10.1056/NEJMoa0912217

14. Posner M.R., Lorch J.H., Goloubeva O. et al. Survival and human papillomavirus in oropharynx cancer in TAX 324: a subset analysis from an international phase III trial. Ann Oncol 2011;22(5):1071-7. DOI: 10.1093/annonc/mdr006

15. Roselló À., Albuquerque R., Roselló-Llabrés X. et al. Transoral robotic surgery vs open surgery in head and neck cancer. A systematic review of the literature. Med Oral Patol Oral Cir Bucal 2020;25(5):e599-607. DOI: 10.4317/medoral.23632

16. Economopoulou P., De Bree R., Kotsantis I., Psyrri A. Diagnostic tumor markers in head and neck squamous cell carcinoma (HNSCC) in the clinical setting. Front Oncol 2019;9:827. DOI: 10.3389/fonc.2019.00827

17. Bossi P., Miceli R., Benasso M. et al. Impact of treatment expertise on the outcome of patients with head and neck cancer treated within 6 randomized trials. Head Neck 2018;40(12):2648-56. DOI: 10.1002/hed.25389

18. Szturz P., Wouters K., Kiyota N. et al. Weekly low-dose versus three-weekly high-dose cisplatin for concurrent chemoradiation in locoregionally advanced non-nasopharyngeal head and neck cancer: a systematic review and meta-analysis of aggregate data. Oncologist 2017;22(9):1056-66. DOI: 10.1634/theoncologist.2017-0015

19. Vermorken J.B., Mesia R., Rivera F. et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008;359(11):1116-27. DOI: 10.1056/NEJMoa0802656

20. Mehanna H., Robinson M., Hartley A. et al. On behalf of the de-escalate HPV trial group. Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus - positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial. Lancet 2019;393(10166):51-60. DOI: 10.1016/S0140-6736(18)32752-1

21. Gleber-Netto F.O., Rao X., Guo T. et al. Variations in HPV function are associated with survival in squamous cell carcinoma. JCI Insight 2019;4(1):e124762. DOI: 10.1172/jci.insight.124762

22. Brennan S., Baird A.M., O'Regan E., Sheils O. The role of human papilloma virus in dictating outcomes in head and neck squamous cell carcinoma. Front Mol Biosci 2021;8:677900. DOI: 10.3389/fmolb.2021.677900

23. Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 2015;517(7536):576-82. DOI: 10.1038/nature14129

24. Reder H., Wagner S., Gamerdinger U. et al. Genetic alterations in human papillomavirus-associated oropharyngeal squamous cell carcinoma of patients with treatment failure. Oral Oncol 2019;93:59-65. DOI: 10.1016/j.oraloncology.2019.04.013

25. Harbison R.A., Kubik M., Konnick E.Q. et al. The mutational landscape of recurrent versus nonrecurrent human papillomavirus- related oropharyngeal cancer. JCI Insight 2018;3(14):e99327. DOI: 10.1172/jci.insight.99327

26. Isaacsson Velho P.H., Castro G., Chung C.H. Targeting the PI3K pathway in head and neck squamous cell carcinoma. Am Soc Clin Oncol Educ Book 2015:123-8. DOI: 10.14694/EdBook_AM.2015.35.123

27. Lechien J.R., Seminerio I., Descamps G. et al. Impact of HPV infection on the immune system in oropharyngeal and non- oropharyngeal squamous cell carcinoma: a systematic review. Cells 2019;8(9):1061. DOI: 10.3390/cells8091061

28. Turksma A.W., Bontkes H.J., van den Heuvel H. et al. Effector memory T-cell frequencies in relation to tumour stage, location and HPV status in HNSCC patients. Oral Dis 2013;19(6):577-84. DOI: 10.1111/odi.12037

29. Kareer R., Ahuja S., Chaudhary N., Arora R. Association of PD-L1 and p16 expression with clinicopathological parameters in oral cavity and oropharyngeal squamous cell carcinoma. Pathol Res Pract 2023;241:154266. DOI: 10.1016/j.prp.2022.154266

30. Machiels J.P., Rene Leemans C., Golusinski W. et al. Squamous cell carcinoma of the oral cavity, larynx, oropharynx and hypopharynx: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2020;31(11):1462-75. DOI: 10.1016/j.annonc.2020.07.011

31. Mandal R., §enbabaoglu Y., Desrichard A. et al. The Head and Neck Cancer Immune Landscape and its Immunotherapeutic Implications. JCI Insight 2016;1(17):e89829. DOI: 10.1172/jci.insight.89829

32. Wang Y., Xu Y., Hua Q. et al. Novel prognostic model based on im-mune signature for head and neck squamous cell carcinoma. BioMed Res Int 2020;2020:4725314. DOI: 10.1155/2020/4725314

33. Zhang F., Liu Y., Yang Y., Yang K. Development and Validation of a fourteen-innate immunity-related gene pairs signature for predicting prognosis head and neck squamous cell carcinoma. BMC Cancer 2020;20(1):1015. DOI: 10.1186/s12885-020-07489-7

34. Varilla V., Atienza J., Dasanu C.A. Immune alterations and immunotherapy prospects in head and neck cancer. Expert Opin Biol Ther 2013;13(9):1241-56. DOI: 10.1517/14712598.2013.810716

35. Wang H., Zhao Q., Zhang Y. et al. Immunotherapy advances in locally advanced and recurrent/metastatic head and neck squamous cell carcinoma and its relationship with human papillomavirus. Front Immunol 2021;12:652054. DOI: 10.3389/fimmu.2021.652054

36. Clancy K., Hamill C.S., O'Neill W.Q. et al. Impact of p16 status and anatomical site in anti-PD-1 immunotherapy-treated recurrent/ metastatic head and neck squamous cell carcinoma patients. Cancers (Basel) 2021;13(19):4861. DOI: 10.3390/cancers13194861

37. Kanaan H., Kourie H.R., Awada A.H. Are virus-induced cancers more sensitive to checkpoint inhibitors? Future Oncol 2016;12(23):2665-8. DOI: 10.2217/fon-2016-028

38. Näsman 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(6):e38711. DOI: 10.1371/journal.pone.0038711

39. Green V.L., Michno A., Stafford N.D., Greenman J. Increased prevalence of tumour infiltrating immune cells in oropharyngeal tumours in comparison to other subsites: relationship to peripheral immunity. Cancer Immunol Immunother 2013;62(5):863-73. DOI: 10.1007/s00262-013-1395-9

40. Matlung S.E., Wilhelmina van Kempen P.M., Bovenschen N. et al. Differences in T-cell infiltrates and survival between HPV+ and HPV- oropharyngeal squamous cell carcinoma. Future Sci OA 2016;2(1):Fso88. DOI: 10.4155/fso.15.88

41. Welters M.J.P., Ma W., Santegoets S. et al. Intratumoral HPV16- specific T cells constitute a type i-oriented tumor microenvironment to improve survival in HPV16-driven oropharyngeal cancer. Clin Cancer Res 2018;24(3):634-47. DOI: 10.1158/1078-0432.CCR-17-2140

42. Heusinkveld M., Goedemans R., Briet R.J. et al. Systemic and local human papillomavirus 16-specific T-cell immunity in patients with head and neck cancer. Int J Cancer 2012;131(2):E74-85. DOI: 10.1002/ijc.26497

43. Wood O., Woo J., Seumois G. et al. Gene expression analysis of TIL rich HPV-driven head and neck tumors reveals a distinct B-cell signature when compared to HPV independent tumors. Oncotarget 2016;7(35):56781-97. DOI: 10.18632/oncotarget.10788

44. Schoenfeld J.D., Gjini E., Rodig S.J. et al. Evaluating the PD-1 axis and immune effector cell infiltration in oropharyngeal squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2018;102(1):137-45. DOI: 10.1016/j.ijrobp.2018.05.002

45. Oliveira-Costa J.P., de Carvalho A.F., da Silveira G.G. et al. Gene expression patterns through oral squamous cell carcinoma development: PD-L1 expression in primary tumor and circulating tumor cells. Oncotarget 2015;6(25):20902-20. DOI: 10.18632/oncotarget.3939

46. Lyford-Pike S., Peng S., Young G.D. et al. Evidence for a Role of the PD-1:PD-L1 pathway in immune resistance of HPV- associated head and neck squamous cell carcinoma. Cancer Res 2013;73(6):1733-41. DOI: 10.1158/0008-5472.CAN-12-2384

47. Green S.E., McCusker M.G., Mehra R. Emerging immune checkpoint inhibitors for the treatment of head and neck cancers. Expert Opin Emerg Drugs 2020;25(4):501-14. DOI: 10.1080/14728214.2020.1852215

48. Sunshine J., Taube J.M. PD-1/PD-L1 inhibitors. Curr Opin Pharmacol 2015;23:32-8. DOI: 10.1016/j.coph.2015.05.011

49. Ferris R.L., Blumenschein G., Fayette J. et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 2016;375(19):1856-67. DOI: 10.1056/NEJMoa1602252

50. Gulley J.L., Repasky E.A., Wood L.S., Butterfield L.H. Highlights of the 31st Annual Meeting of the Society for Immunotherapy of Cancer (Sitc), 2016. J Immunother Cancer 2017;5(1):55. DOI: 10.1186/s40425-017-0262-1

51. Adusumilli P.S., Cha E., Cornfeld M. et al. New cancer immunotherapy agents in development: a report from an associated program of the 31st annual meeting of the Society for Immunotherapy of Cancer, 2016. J Immunother Cancer 2017;5:50. DOI: 10.1186/s40425-017-0253-2

52. Massarelli E., William W., Johnson F. et al. Combining immune checkpoint blockade and tumor-specific vaccine for patients with incurable human papillomavirus 16-related cancer: a phase 2 clinical trial. JAMA Oncol 2019;5(1):67-73. DOI: 10.1001/jamaoncol.2018.4051

53. Seiwert T.Y., Burtness B., Mehra R. 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):956-65. DOI: 10.1016/S1470-2045(16)30066-3

54. Cohen E.E.W., Soulieres D., Le Tourneau C. et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet 2019;393(10167):156-67. DOI: 10.1016/S0140-6736(18)31999-8

55. Soulieres D., Harrington K.J., Le Tourneau C. et al. Pembrolizumab (pembro) vs standard-of-care (SOC) in previously treated recurrent/ metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): 6-year follow-up of KEYNOTE-040. Ann Oncol 2022;33(Suppl_7):S295-322. DOI: 10.1016/annonc/annonc1056

56. Burtness B., Harrington K.J., Greil R. et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet 2019;394(10212):1915-28. DOI: 10.1016/s0140-6736(19)32591-7

57. Harrington K.J., Burtness B., Greil R. et al. Pembrolizumab with or without chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma: updated results of the phase III KEYNOTE-048 study. JCO 2023;41(4):790-802. DOI: 10.1200/JCO.21.02508.

58. Colevas A.D., Bahleda R., Braiteh F. et al. Safety and clinical activity of atezolizumab in head and neck cancer: results from a phase I trial. Ann Oncol. 2018;29(11):2247—53. DOI: 10.1093/annonc/mdy411

59. Prendergast G.C., Malachowski W.J., Mondal A. et al. Indoleamine 2,3-dioxygenase and its therapeutic inhibition in cancer. Int Rev Cell Mol Biol 2018;336:175-203. DOI: 10.1016/bs.ircmb.2017.07.004

60. Godin-Ethier J., Hanafi L.A., Piccirillo C.A., Lapointe R. Indoleamine 2,3-dioxygenase expression in human cancers: clinical and immunologic perspectives. Clin Cancer Res 2011;17(22): 6985-91. DOI: 10.1158/1078-0432.CCR-11-1331

61. Nayak-Kapoor A., Hao Z., Sadek R. et al. Phase Ia study of the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor navoximod (GDC-0919) in patients with recurrent advanced solid tumors. J Immunother Cancer 2018;6(1):61. DOI: 10.1186/s40425-018-0351-9

62. Mitchell T.C., Hamid O., Smith D.C. et al. Epacadostat plus pembrolizumab in patients with advanced solid tumors: phase I results from a multicenter, open-label phase i/ii trial (ECHO-202/ KEYNOTE-037). J Clin Oncol 2018;36(32):3223-30. DOI: 10.1200/JCO.2018.78.9602

63. Outh-Gauer S., Alt M., Le Tourneau C. et al. Immunotherapy in head and neck cancers: a new challenge for immunologists, pathologists and clinicians. Cancer Treat Rev 2018;65:54-64. DOI: 10.1016/j.ctrv.2018.02.008

64. Yearley J., Gibson C., Yu N. et al. PD-L2 expression in human tumors: relevance to anti-PD-1 therapy in cancer. Clin Cancer Res 2017;23:(12):3158-67. DOI: 10.1158/1078-0432.CCR-16-1761

65. Stanley M. HPV-immune response to infection and vaccination. Infect Agent Cancer 2010;5:19. DOI: 10.1186/1750-9378-5-19

66. Whiteside T.L. Immune responses to cancer: are they potential biomarkers of prognosis? Front Oncol 2013;3:107. DOI: 10.3389/fonc.2013.00107

67. Nguyen N., Bellile E., Thomas D. et al. Tumor infiltrating lymphocytes and survival in patients with head and neck squamous cell carcinoma. Head Neck 2016;38(7):1074-84. DOI: 10.1002/hed.24406

68. Chow L.Q.M., 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):3838-45. DOI: 10.1200/jco.2016.68.1478

69. Bauml J., Seiwert T.Y., Pfister D.G. et al. Pembrolizumab for platinum- and cetuximab-refractory head and neck cancer: results from a single-arm, phase II study. J Clin Oncol 2017;35(14):1542-9. DOI: 10.1200/JCO.2016.70.1524

70. Pfister D.G., Haddad R.I., Worden F.P. et al. Biomarkers predictive of response to pembrolizumab in head and neck cancer. Cancer Med 2023;12(6):6603-14. DOI: 10.1002/cam4.5434

71. Kumar B., Cordell K.G., Leeet J.S. al. EGFR, p16, HPV titer, Bcl-xL and p53, sex, and Smoking as indicators of response to therapy and survival in oropharyngeal cancer. JCO 2008;26(19):3128-37. DOI: 10.1200/JCO.2007.12.7662

72. Sato F., Ono T., Kawahara A. et al. Prognostic impact of p16 and PD-L1 expression in patients with oropharyngeal squamous cell carcinoma receiving a definitive treatment. J Clin Pathol 2019;72(8):542-9. DOI: 10.1136/jclinpath-2019-205818

73. Galvis M.M., Borges G.A., Oliveira T.B. et al. Immunotherapy improves efficacy and safety of patients with HPV positive and negative head and neck cancer: A systematic review and meta-analysis. Crit Rev Oncol Hematol 2020;150:102966. DOI: 10.1016/j.critrevonc.2020.102966