Иммунотерапия гепатоцеллюлярного рака: начало и перспективы

Гепатоцеллюлярный рак (ГЦР) является значимой проблемой современной онкологии. До недавнего времени лекарственная терапия местно-распространенного и диссеминированного ГЦР была ограничена единственным препаратом – сорафенибом. Более глубокое понимание ключевых механизмов канцерогенеза и ускользания опухоли от иммунного ответа послужило основанием для изучения возможностей иммунотерапии в лечении злокачественных опухолей и ГЦР в частности. Первые клинические исследования показали, что иммунотерапия позволяет существенно улучшить непосредственные и отдаленные результаты лечения больных местно-распространенным и метастатическим ГЦР при управляемом профиле токсичности. В настоящее время в качестве второй линии лечения после прогрессирования заболевания на терапии сорафенибом зарегистрировано уже 2 ингибитора контрольных точек иммунного ответа – анти-PD-1-препараты ниволумаб и пембролизумаб. Одновременное появление нескольких новых лекарственных препаратов определяет необходимость проведения клинических исследований по выявлению оптимальных сочетаний препаратов и последовательности их использования в различных клинических ситуациях.

1. Parkin D.M., Bray F., Ferlay J., Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74-108.

2. Altekruse S.F., McGlynn K.A., Reichman M.E. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J ClinOncol. 2009;27:1485-91.

3. Cheng A.-L. et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebocontrolled trial. Lancet. Oncol. Elsevier. 2009;10(1):25–34.

4. Llovet J.J.M. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 2008;359(4):378–390.

5. Parkin D.M., Bray F., Ferlay J., Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.

6. Li F.J., Zhang Y., Jin G.X., Yao L., Wu E.Q. Expression of LAG-3 is coincident with the impaired effector function of HBV-specific CD8(+) T cell in HCC patients. Immunol Lett. 2013;150:116-22.

7. Huz J.I., Melis M., Sarpel U. Spontaneous regression of hepatocellular carcinoma is most often associated with tumor hypoxia or a systemic inflammatory response. HPB (Oxford). 2012;14:500-5.

8. Gao Q., Qiu S.J., Fan J., Zhou J., Wang X.Y., Xiao Y.S. et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J ClinOncol. 2007;25:2586-93.

9. Han Y., Yang Y., Chen Z., Jiang Z., Gu Y., Liu Y. et al. Human hepatocellular carcinoma-infiltrating CD4+CD69+Foxp3- regulatory T cell suppresses T cell response via membrane-bound TGF-β1. J Mol Med (Berl). 2014;92:539-50.

10. Ormandy L.A., Hillemann T., Wedemeyer H., Manns M.P., Greten T.F., Korangy F. Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res. 2005;65:2457-64.

11. Barathan M., Gopal K., Mohamed R., Ellegard R., Saeidi A., Vadivelu J. et al. Chronic hepatitis C virus infection triggers spontaneous differential expression of biosignatures associated with T cell exhaustion and apoptosis signaling in peripheral blood mononucleocytes. Apoptosis. 2015;20:466-80.

12. Li F.J., Zhang Y., Jin G.X., Yao L., Wu E.Q. Expression of LAG-3 is coincident with the impaired effector function of HBV-specific CD8(+) T cell in HCC patients. Immunol Lett. 2013;150:116-22.

13. Pfizer Announces Discontinuation of Phase III Clinical Trial for Patients with Advanced Melanoma. Pfizer.com. 1 April 2008. Retrieved 5 December 2015.

14. Sangro B., Gomez-Martin C., de la Mata M., Inarrairaegui M., Garralda E., Barrera P. et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol. 2013;59:81-8.

15. El-Koueiry A.B., Sangro B., Yau T., Crocenzi T.S., Welling III T.H., Yeo W. et al. I. Phase 1/2 safety and antitumor activity of Nivolumab in patients with advanced hepatocellular carcinoma: interim analysis of the Checkmate-040 dose escalation study. In: Proceedings of the 52th Annual Meeting of the American Society of Clinical Oncology; 2016 June 4-8; Chicago. ASCO 2016. Abstract nr 4012.

16. Zhu A.X., Finn R.S., Edeline J., Cattan S., Ogasawara S., Palmer D. et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, openlabel phase 2 trial. Lancet Oncol. 2018;19:940–52.

17. https://clinicaltrials.gov.

18. https://www.clinicaltrialsregister.eu/ctr-search/trial.

19. Wainberg Z.A., Segal N.H., Jaeger D., et al. Safety and clinical activity of durvalumab monotherapy in patients with hepatocellular carcinoma (HCC). J ClinOncol. 2017;35(suppl; abstr 4071).

20. Kelley R.K., Abou-Alfa Gh.K., Bendell J.C., Kim T.-Y. et al. Phase I/II study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): Phase I safety and efficacy analyses. ClinOncol. 2017;35(suppl;abstr 4071-4073).

21. Boige V., Malka D., Bourredjem A. et al. Efficacy, safety, and biomarkers of single-agent bevacizumab therapy in patients with advanced hepatocellular carcinoma. Oncologist. 2012;17:1063-72.

22. Frenette C. Current status of bevacizumab for advanced hepatocellular carcinoma. Chin ClinOncol. 2012;1:13.

23. Motz G.T., Santoro S.P., Wang L.P. et al. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat Med. 2014;20:607-17.

24. Oelkrug C., Ramage J.M. Enhancement of T cell recruitment and infiltration into tumors. Clin Exp Immunol. 2014;178:1-8.

25. Wainberg Z.A., Segal N.H., Jaeger D. et al. Safety and clinical activity of durvalumab monotherapy in patients with hepatocellular carcinoma (HCC). J Clin Oncol. 2017;35 (suppl; abstr 4071).

26. Roland C.L., Lynn K.D., Toombs J.E. et al. Cytokine levels correlate with immune cell infiltration after anti-VEGF therapy in preclinical mouse models of breast cancer. PLoS ONE. 2009;4:e7669.

27. Voron T., Colussi O., Marcheteau E. et al. VEGFA modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J ExpMed. 2015;212:139-48.

28. Wallin J.J., Bendell J.C., Funke R. et al. Atezolizumab in combination with bevacizumab enhances antigenspecificTcell migration in metastatic renal cell carcinoma. Nat Comm. 2016;7:1-8.

29. Ikeda M., Sung M.W., Kudo M., Kobayashi M., Baron A.D., Finn R.S. et al. A phase 1b trial of lenvatinib (LEN) plus pembrolizumab (PEM) in patients (pts) with unresectable hepatocellular carcinoma (uHCC). J Clin Oncol. 2018;36(suppl; abstr 4076).

30. De Martin E., Michot J.-M., Papouin B., Champiat S., Mateus C., Lambotte O. et al. Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors. J Hepatol. 2018;68:1181–1190.

31. Bruix J., Qin S., Merle P., Granito A., Huang Y.H., Bodoky G. et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389:56-66.

32. Finn R.S., Merle P., Granito A., Huang Y.-H., Bodoky G., Pracht M. et al. Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: additional analyses from the phase 3 RESORCE trial. Journal of Hepatology. 2018. doi: https://doi.org/10.1016/j.jhep.2018.04.010.