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Review

PD-L1, TMB, and other potential predictors of response to immunotherapy for hepatocellular carcinoma: how can they assist drug clinical trials?

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Pages 415-423 | Received 02 Jul 2021, Accepted 23 Aug 2021, Published online: 30 Aug 2021

References

  • Villanueva A. Hepatocellular Carcinoma. N Engl J Med. 2019 Apr 11;380(15):1450–1462. PMID: 30970190.
  • Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391(10127):1301–1304.
  • Waidmann O, Trojan J. Novel drugs in clinical development for hepatocellular carcinoma. Expert Opin Investig Drugs. 2015 24;24(8):1075–1082. Epub 2015 Jun 24. PMID: 26108356.
  • Pfister D, Núñez NG, Pinyol R, et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature. 2021 Apr;592(7854):450–456. Epub 2021 Mar 24. PMID: 33762733; PMCID: PMC8046670.
  • Noonan A, Pawlik TM. Hepatocellular carcinoma: an update on investigational drugs in phase I and II clinical trials. Expert Opin Investig Drugs. 2019 Nov;28(11):941–949. Epub 2019 Oct 12. PMID: 31590579.
  • De Lorenzo S, Tovoli F, Barbera MA, et al. Metronomic capecitabine vs. best supportive care in Child-Pugh B hepatocellular carcinoma: a proof of concept. Sci Rep. 2018 Jul 3;8(1):9997. PMID: 29968763; PMCID: PMC6030080.
  • Faivre S, Rimassa L, Finn RS. Molecular therapies for HCC: looking outside the box. J Hepatol. 2020 Feb;72(2):342–352. PMID: 31954496.
  • Rizzo A, Dadduzio V, Ricci AD, et al., Lenvatinib plus pembrolizumab: the next frontier for the treatment of hepatocellular carcinoma? Expert Opin Investig Drugs. 2021 Jun 30:1–8. Epub ahead of print. PMID: 34167433. https://doi.org/10.1080/13543784.2021.1948532.
  • Ingles Garces AH, Au L, Mason R, et al. Building on the anti-PD1/PD-L1 backbone: combination immunotherapy for cancer. Expert Opin Investig Drugs. 2019 Aug;28(8):695–708. Epub 2019 Aug 6. PMID: 31359805.
  • Alsaab HO, Sau S, Alzhrani R, et al. PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome. Front Pharmacol. 2017 Aug;23(8):561. PMID: 28878676; PMCID: PMC5572324.
  • Llovet JM, Montal R, Sia D, et al. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat Rev Clin Oncol. 2018 Oct;15(10):599–616. PMID: 30061739.
  • Rizzo A, Ricci AD, Brandi G. Atezolizumab in advanced hepatocellular carcinoma: good things come to those who wait. Immunotherapy. 2021 Jun;13(8):637–644. Epub 2021 Apr 6. PMID: 33820447.
  • Scientific KM. Rationale for combined immunotherapy with PD-1/PD-L1 antibodies and VEGF inhibitors in advanced hepatocellular carcinoma. Cancers (Basel). 2020 Apr 27;12(5):1089. PMID: 32349374; PMCID: PMC7281246.
  • Finkelmeier F, Waidmann O, Trojan J. Nivolumab for the treatment of hepatocellular carcinoma. Expert Rev Anticancer Ther. 2018 Dec;18(12):1169–1175. Epub 2018 Oct 22. PMID: 30304963.
  • El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017 Jun 24;389(10088):2492–2502. Epub 2017 Apr 20. PMID: 28434648; PMCID: PMC7539326.
  • Zhu AX, Finn RS, Edeline J, et al. KEYNOTE-224 investigators. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018 Jul;19(7):940–952. Epub 2018 Jun 3. Erratum in: Lancet Oncol. 2018 Sep;19(9):e440.PMID: 29875066.
  • Cheng H, Sun G, Chen H, et al. Trends in the treatment of advanced hepatocellular carcinoma: immune checkpoint blockade immunotherapy and related combination therapies. Am J Cancer Res. 2019 Aug 1;9(8):1536–1545. PMID: 31497341; PMCID: PMC6726979
  • Ma AEA, Facciorusso A, Nayfeh T, et al. Immune checkpoint inhibitors for unresectable hepatocellular carcinoma. Vaccines (Basel). 2020 Oct 19;8(4):616. PMID: 33086471; PMCID: PMC7712941.
  • Finn RS, Qin S, Ikeda M, et al. IMbrave150 investigators. Atezolizumab plus Bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020 May 14;382(20):1894–1905. PMID: 32402160.
  • Cheng AL, Hsu C, Chan SL, et al. Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma. J Hepatol. 2020 Feb;72(2):307–319. PMID: 31954494.
  • Finn RS, Qin S, Ikeda M, et al., IMbrave150: updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC). J Clin Oncol. 39(3_suppl): 267. 2021.
  • Pinter M, Jain RK, Duda DG. The current landscape of immune checkpoint blockade in hepatocellular carcinoma: a review. JAMA Oncol. 2020 Oct 22. Epub ahead of print. PMID: 33090190. DOI:https://doi.org/10.1001/jamaoncol.2020.3381.
  • Hato T, Zhu AX, Duda DG. Rationally combining anti-VEGF therapy with checkpoint inhibitors in hepatocellular carcinoma. Immunotherapy. 2016;8(3):299–313. Epub 2016 Feb 11. PMID: 26865127; PMCID: PMC5619018.
  • Kelley RK. Atezolizumab plus Bevacizumab - A landmark in liver cancer. N Engl J Med. 2020 May 14;382(20):1953–1955. PMID: 32402168.
  • Rizzo A, Ricci AD, Brandi G. Immune-based combinations for advanced hepatocellular carcinoma: shaping the direction of first-line therapy. Future Oncol. 2021 Mar;17(7):755–757. Epub 2021 Jan 29. PMID: 33508960.
  • Park R, Eshrat F, Al-Jumayli M, et al. Immuno-oncotherapeutic approaches in advanced hepatocellular carcinoma. Vaccines (Basel). 2020 Aug 8;8(3):447. PMID: 32784389; PMCID: PMC7563532.
  • Pinato DJ, Guerra N, Fessas P, et al. Immune-based therapies for hepatocellular carcinoma. Oncogene. 2020 Apr;39(18):3620–3637. Epub 2020 Mar 10. PMID: 32157213; PMCID: PMC7190571.
  • Rizzo A, Brandi G. Biochemical predictors of response to immune checkpoint inhibitors in unresectable hepatocellular carcinoma. Cancer Treat Res Commun. 2021;27:100328. Epub 2021 Feb 2. PMID: 33549983.
  • Reck M. Pembrolizumab as first-line therapy for metastatic non-small-cell lung cancer. Immunotherapy. 2018 Feb;10(2):93–105. Epub 2017 Nov 17. PMID: 29145737.
  • Reck M, Rodríguez-Abreu D, Robinson AG, et al. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537–546. Epub 2019 Jan 8. PMID: 30620668.
  • Paz-Ares L, Spira A, Raben D, et al. Outcomes with durvalumab by tumour PD-L1 expression in unresectable, stage III non-small-cell lung cancer in the PACIFIC trial. Ann Oncol. 2020 Mar 21;31(6):798–806. S0923-7534(20)36374-2. Epub ahead of print. PMID: 32209338.
  • Ilie M, Hofman V, Dietel M, et al. Assessment of the PD-L1 status by immunohistochemistry: challenges and perspectives for therapeutic strategies in lung cancer patients. Virchows Arch. 2016 May;468(5):511–525. Epub 2016 Feb 25. PMID: 26915032.
  • Zhang S, Bai X, Shan F. The progress and confusion of anti-PD1/PD-L1 immunotherapy for patients with advanced non-small cell lung cancer. Int Immunopharmacol. 2020 Mar;80:106247. Epub 2020 Jan 31. PMID: 32007710.
  • Rizzo A, Ricci AD, Brandi G. PD-L1, TMB, MSI, and other predictors of response to immune checkpoint inhibitors in biliary tract cancer. Cancers (Basel). 2021 Feb 1;13(3):558. PMID: 33535621; PMCID: PMC7867133.
  • Lei J, Zhang D, Yao C, et al. Development of a predictive immune-related gene signature associated with hepatocellular carcinoma patient prognosis. Cancer Control. 2020 Jan-Dec;27(1):1073274820977114. PMID: 33269615.
  • Calderaro J, Rousseau B, Amaddeo G, et al. Programmed death ligand 1 expression in hepatocellular carcinoma: relationship With clinical and pathological features. Hepatology. 2016;64(6):2038–2046.
  • Macek Jilkova Z, Aspord C, Decaens T. Predictive Factors for Response to PD-1/PD-L1 checkpoint inhibition in the field of hepatocellular carcinoma: current status and challenges. Cancers (Basel). 2019 Oct 14;11(10):1554. PMID: 31615069; PMCID: PMC6826488.
  • Yau T, Park J, Finn R, et al. CheckMate 459, A randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Ann Oncol. 2019;30:v874–v875.
  • Wu M, Xia X, Hu J, et al. WSX1 act as a tumor suppressor in hepatocellular carcinoma by downregulating neoplastic PD-L1 expression. Nat Commun. 2021 Jun 9;12(1):3500. PMID: 34108491.
  • Pls UJ, Nagalo BM, Ahn DH, et al. Combination immunotherapy for hepatocellular carcinoma: where are we currently? Semin Liver Dis. 2021 May;41(2):136–141. Epub 2021 May 6. PMID: 33957697.
  • Samstein RM, Lee CH, Shoushtari AN, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet. 2019 Feb;51(2):202–206. Epub 2019 Jan 14. PMID: 30643254; PMCID: PMC6365097.
  • Chan TA, Yarchoan M, Jaffee E, et al. Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann Oncol. 2019 Jan 1;30(1):44–56. PMID: 30395155; PMCID: PMC6336005.
  • Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012 Mar 22;12(4):252–264. PMID: 22437870; PMCID: PMC4856023.
  • Van Den Bulk J, Verdegaal EM, De Miranda NF. Cancer immunotherapy: broadening the scope of targetable tumours. Open Biol. 2018 Jun 8;8(6):180037. PMID: 29875199; PMCID: PMC6030119.
  • Merino DM, McShane LM, Fabrizio D, et al. TMB harmonization consortium. Establishing guidelines to harmonize tumor mutational burden (TMB): in silico assessment of variation in TMB quantification across diagnostic platforms: phase I of the friends of cancer research TMB harmonization project. J Immunother Cancer. 2020 Mar 8;8(1):e000147. PMID: 32217756; PMCID: PMC7174078.
  • Shrestha R, Prithviraj P, Anaka M, et al. Monitoring immune checkpoint regulators as predictive biomarkers in hepatocellular carcinoma. Front Oncol. 2018 Jul 13;8:269. PMID: 30057891; PMCID: PMC6053505.
  • Ang C, Klempner SJ, Ali SM, et al. Prevalence of established and emerging biomarkers of immune checkpoint inhibitor response in advanced hepatocellular carcinoma. Oncotarget. 2019 Jun 18;10(40):4018–4025. PMID: 31258846; PMCID: PMC6592287.
  • Tang X, Fan L, Chen G, et al. Higher level of tumor mutational burden and 11q13 amplification in Chinese hepatocellular carcinoma patients. Cancer Res. 2018;78(13 Supplement):4349.
  • Liu L, Bai X, Wang J, et al. Combination of TMB and CNA stratifies prognostic and predictive responses to immunotherapy across metastatic cancer. Clin Cancer Res. 2019 Dec 15;25(24):7413–7423. Epub 2019 Sep 12. PMID: 31515453.
  • Chae YK, Davis AA, Agte S, et al. Clinical implications of circulating tumor DNA tumor mutational burden (ctDNA TMB) in non-small cell lung cancer. Oncologist. 2019 Jun;24(6):820–828. Epub 2019 Mar 13. PMID: 30867242; PMCID: PMC6656496.
  • Wong CN, Fessas P, Dominy K, et al. Qualification of tumour mutational burden by targeted next-generation sequencing as a biomarker in hepatocellular carcinoma. Liver Int. 2020 Oct 23. Epub ahead of print. PMID: 33098208. DOI:https://doi.org/10.1111/liv.14706.
  • Slatko BE, Gardner AF, Ausubel FM. Overview of next-generation sequencing technologies. Curr Protoc Mol Biol. 2018 Apr;122(1):e59. PMID: 29851291; PMCID: PMC6020069.
  • Baretti M, Le DT. DNA mismatch repair in cancer. Pharmacol Ther. 2018 Sep;189:45–62. Epub 2018 Apr 15. PMID: 29669262.
  • Chang L, Chang M, Chang HM, et al. Microsatellite instability: a predictive biomarker for cancer immunotherapy. Appl Immunohistochem Mol Morphol. 2018 Feb;26(2):e15–e21. PMID: 28877075.
  • Hause RJ, Pritchard CC, Shendure J, et al. Classification and characterization of microsatellite instability across 18 cancer types. Nat Med. 2016 Nov;22(11):1342–1350. Epub 2016 Oct 3. Erratum in: Nat Med. 2017 Oct 6;23 (10):1241. Erratum in: Nat Med. 2018 Apr 10;24(4):525.PMID: 27694933.
  • Rotte A. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. J Exp Clin Cancer Res. 2019 Jun 13;38(1):255. PMID: 31196207; PMCID: PMC6567914.
  • Svrcek M, Lascols O, Cohen R, et al. MSI/MMR-deficient tumor diagnosis: which standard for screening and for diagnosis? Diagnostic modalities for the colon and other sites: differences between tumors. Bull Cancer. 2019 Feb;106(2):119–128. Epub 2019 Feb 1. PMID: 30713006.
  • Kazachkov Y, Yoffe B, Khaoustov VI, et al. Microsatellite instability in human hepatocellular carcinoma: relationship to p53 abnormalities. Liver. 1998 Jun;18(3):156–161. PMID: 9716224.
  • Togni R, Bagla N, Muiesan P, et al. Microsatellite instability in hepatocellular carcinoma in non-cirrhotic liver in patients older than 60 years. Hepatol Res. 2009 Mar;39(3):266–273. Epub 2008 Nov 5. PMID: 19054153.
  • Goumard C, Desbois-Mouthon C, Wendum D, et al. Low levels of microsatellite instability at simple repeated sequences commonly occur in human hepatocellular carcinoma. Cancer Genomics Proteomics. 2017 Sep-Oct;14(5):329–339. PMID: 28871000; PMCID: PMC5611519.
  • Zucman-Rossi J, Villanueva A, JC N, et al. Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology. 2015 Oct;149(5):1226–1239.e4. Epub 2015 Jun 20. PMID: 26099527.
  • Levy SE, Myers RM. Advancements in next-generation sequencing. Annu Rev Genomics Hum Genet. 2016 Aug 31;17(1):95–115. Epub 2016 Jun 9. PMID: 27362342.
  • Stratton MR, Campbell PJ, Futreal PA. The cancer genome. Nature. 2009 Apr 9;458(7239):719–724. PMID: 19360079; PMCID: PMC2821689.
  • Astolfi A, Nannini M, Indio V, et al. Genomic database analysis of uterine leiomyosarcoma mutational profile. Cancers (Basel). 2020 Jul 31;12(8):2126. PMID: 32751892; PMCID: PMC7464219.
  • Berger MF, Mardis ER. The emerging clinical relevance of genomics in cancer medicine. Nat Rev Clin Oncol. 2018 Jun;15(6):353–365. PMID: 29599476; PMCID: PMC6658089.
  • Jj H, Nandakumar S, Armenia J, et al. Prospective genotyping of hepatocellular carcinoma: clinical implications of next-generation sequencing for matching patients to targeted and immune therapies. Clin Cancer Res. 2019 Apr 1;25(7):2116–2126. Epub 2018 Oct 29. PMID: 30373752; PMCID: PMC6689131.
  • Ruiz de Galarreta M, Bresnahan E, Molina-Sánchez P, et al. β-catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma. Cancer Discov. 2019 Aug 9;9(8):1124–1141. Epub 2019 Jun 11. PMID: 31186238; PMCID: PMC6677618.
  • Sia D, Jiao Y, Martinez-Quetglas I, et al. Identification of an immune-specific class of hepatocellular carcinoma, based on molecular features. Gastroenterology. 2017 Sep;153(3):812–826. Epub 2017 Jun 15. PMID: 28624577.
  • von Felden J, Craig AJ, Garcia-Lezana T, et al. Mutations in circulating tumor DNA predict primary resistance to systemic therapies in advanced hepatocellular carcinoma. Oncogene. 2021 Jan;40(1):140–151. Epub 2020 Oct 23. PMID: 33097857.
  • Long J, Wang A, Bai Y, et al. Development and validation of a TP53-associated immune prognostic model for hepatocellular carcinoma. EBioMedicine. 2019 Apr;42:363–374. Epub 2019 Mar 16. PMID: 30885723; PMCID: PMC6491941.
  • Hu ZQ, Xin HY, Luo CB, et al. Associations among the mutational landscape, immune microenvironment, and prognosis in Chinese patients with hepatocellular carcinoma. Cancer Immunol Immunother. 2021 Feb;70(2):377–389. Epub 2020 Aug 6. PMID: 32761426.
  • Yang H, Sun L, Guan A, et al. TP53 neoantigen and the immune microenvironment in long-term survivors of hepatocellular carcinoma. Cancer Immunol Immunother. 2021 Mar;70(3):667–677. Epub 2020 Sep 2. PMID: 32876735.
  • O’Connor MJ. Targeting the DNA damage response in cancer. Mol Cell. 2015 Nov 19;60(4):547–560. PMID: 26590714.
  • Brandsma I, Fleuren EDG, Williamson CT, et al. Directing the use of DDR kinase inhibitors in cancer treatment. Expert Opin Investig Drugs. 2017 Dec;26(12):1341–1355. Epub 2017 Oct 14. PMID: 28984489; PMCID: PMC6157710.
  • Ricci AD, Rizzo A, The BG. DNA damage repair (DDR) pathway in biliary tract cancer (BTC): a new Pandora’s box? ESMO Open. 2020 Sep;5(5):e001042. PMID: 32994319; PMCID: PMC7526276.
  • Jeggo PA, Pearl LH, Carr AM. DNA repair, genome stability and cancer: a historical perspective. Nat Rev Cancer. 2016 Jan;16(1):35–42. Epub 2015 Dec 15. PMID: 26667849.
  • Pilié PG, Tang C, Mills GB, et al. State-of-the-art strategies for targeting the DNA damage response in cancer. Nat Rev Clin Oncol. 2019 Feb;16(2):81–104. PMID: 30356138.
  • Ricci AD, Rizzo A, Brandi G. DNA damage response alterations in gastric cancer: knocking down a new wall. Future Oncol. 2021 Mar;17(8):865–868. Epub 2021 Jan 29. PMID: 33508962.
  • Zhang Y, Zhang L, Xu Y, et al. Immune-related long noncoding RNA signature for predicting survival and immune checkpoint blockade in hepatocellular carcinoma. J Cell Physiol. 2020 Dec;235(12):9304–9316. Epub 2020 Apr 24. PMID: 32330311.
  • Peng L, Chen Z, Chen Y, et al. MIR155HG is a prognostic biomarker and associated with immune infiltration and immune checkpoint molecules expression in multiple cancers. Cancer Med. 2019 Dec;8(17):7161–7173. DOI:https://doi.org/10.1002/cam4.2583 Epub 2019 Sep 30. PMID: 31568700; PMCID: PMC6885872.
  • Yuan M, Wang Y, Sun Q, et al. Identification of a nine immune-related lncRNA signature as a novel diagnostic biomarker for hepatocellular carcinoma. Biomed Res Int. 2021 Jan 5;2021::9798231. PMID: 33506049; PMCID: PMC7808810.
  • Xu Q, Wang Y, Huang W. Identification of immune-related lncRNA signature for predicting immune checkpoint blockade and prognosis in hepatocellular carcinoma. Int Immunopharmacol. 2021 Mar;92:107333. Epub 2021 Jan 21. PMID: 33486322.
  • Matson V, Fessler J, Bao R, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science. 2018 Jan 5;359(6371):104–108. PMID: 29302014; PMCID: PMC6707353.
  • Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018 Jan 5;359(6371):97–103. Epub 2017 Nov 2. PMID: 29097493; PMCID: PMC5827966.
  • Lambring CB, Siraj S, Patel K, et al. Impact of the microbiome on the immune system. Crit Rev Immunol. 2019;39(5):313–328. PMID: 32422014; PMCID: PMC7362776.
  • Gharaibeh RZ, Jobin C. Microbiota and cancer immunotherapy: in search of microbial signals. Gut. 2019 Mar;68(3):385–388. Epub 2018 Dec 8. PMID: 30530851; PMCID: PMC6580757.
  • Elkrief A, Derosa L, Zitvogel L, et al. The intimate relationship between gut microbiota and cancer immunotherapy. Gut Microbes. 2019;10(3):424–428. Epub 2018 Oct 19. PMID: 30339501; PMCID: PMC6546322.
  • Rooks MG, Garrett WS. Gut microbiota, metabolites and host immunity. Nat Rev Immunol. 2016 May 27;16(6):341–352. PMID: 27231050; PMCID: PMC5541232.
  • Yu LX, Schwabe RF. The gut microbiome and liver cancer: mechanisms and clinical translation. Nat Rev Gastroenterol Hepatol. 2017 Sep;14(9):527–539. Epub 2017 Jul 5. PMID: 28676707; PMCID: PMC6467288.
  • Schwabe RF, Greten TF. Gut microbiome in HCC - Mechanisms, diagnosis and therapy. J Hepatol. 2020 Feb;72(2):230–238. PMID: 31954488.
  • Guven DC, Aktas BY, Simsek C, et al. Gut microbiota and cancer immunotherapy: prognostic and therapeutic implications. Future Oncol. 2020 Mar;16(9):497–506. Epub 2020 Feb 26. PMID: 32100550.
  • Khan MAW, Ologun G, Arora R, et al. Gut microbiome modulates response to cancer immunotherapy. Dig Dis Sci. 2020 Mar;65(3):885–896. PMID: 32067144; PMCID: PMC7678709.
  • Wang J, Yang HR, Wang DJ, et al. Association between the gut microbiota and patient responses to cancer immune checkpoint inhibitors. Oncol Lett. 2020 Dec;20(6):342. Epub 2020 Oct 8. PMID: 33123253; PMCID: PMC7583737.
  • Sacdalan DB, Lucero JA. The association between inflammation and immunosuppression: implications for ICI biomarker development. Onco Targets Ther. 2021 Mar 18;14:2053–2064. PMID: 33776452; PMCID: PMC7987319.
  • Zheng Y, Wang T, Tu X, et al. Gut microbiome affects the response to anti-PD-1 immunotherapy in patients with hepatocellular carcinoma. J Immunother Cancer. 2019 Jul 23;7(1):193. PMID: 31337439; PMCID: PMC6651993.
  • Fessler J, Matson V, Gajewski TF. Exploring the emerging role of the microbiome in cancer immunotherapy. J Immunother Cancer. 2019 Apr 17;7(1):108. PMID: 30995949; PMCID: PMC6471869.
  • Makuku R, Khalili N, Razi S, et al. Current and future perspectives of PD-1/PDL-1 blockade in cancer immunotherapy. J Immunol Res. 2021 Feb 22;2021:6661406. PMID: 33681388; PMCID: PMC7925068.
  • Boilève A, Hilmi M, Delaye M, et al. Biomarkers in Hepatobiliary Cancers: what is Useful in Clinical Practice? Cancers (Basel). 2021 May 30;13(11):2708. PMID: 34070929; PMCID: PMC8198554.
  • Koulouris A, Tsagkaris C, Spyrou V, et al. An overview of the changing landscape of treatment options. J Hepatocell Carcinoma. 2021 May 13;8:387–401. PMID: 34012929; PMCID: PMC8128500.
  • Zhang T, Merle P, Wang H, et al. Combination therapy for advanced hepatocellular carcinoma: do we see the light at the end of the tunnel? Hepatobiliary Surg Nutr. 2021 Apr;10(2):180–192. PMID: 33898559; PMCID: PMC8050575.
  • Zayac A, Almhanna K. Hepatobiliary cancers and immunotherapy: where are we now and where are we heading? Transl Gastroenterol Hepatol. 2020 Jan 5;5:8. PMID: 32190776; PMCID: PMC7061229.
  • Rizzo A, Ricci AD, Brandi G. Durvalumab: an investigational anti-PD-L1 antibody for the treatment of biliary tract cancer. Expert Opin Investig Drugs. 2021 Apr;30(4):343–350. Epub 2021 Mar 9. PMID: 33645367.
  • Baruch EN, Wang J, Wargo JA. Gut microbiota and antitumor immunity: potential mechanisms for clinical effect. Cancer Immunol Res. 2021 Apr 9;9(4):365–370. PMID: 34003768.
  • Kim E, Ahn H, Park H. A review on the role of gut microbiota in immune checkpoint blockade therapy for cancer. Mamm Genome. 2021 Mar 30;32(4):223–231. Epub ahead of print. PMID: 33783613.
  • Ogasawara S, Choo SP, Li JT, et al. Evolving treatment of advanced hepatocellular carcinoma in the Asia-Pacific region: a review and multidisciplinary expert opinion. Cancers (Basel). 2021 May 27;13(11):2626. PMID: 34071818; PMCID: PMC8197840.
  • Mohr R, Jost-Brinkmann F, Özdirik B, et al. Lessons from immune checkpoint inhibitor trials in hepatocellular carcinoma. Front Immunol. 2021 Mar 30;12:652172. PMID: 33859646; PMCID: PMC8042255.
  • Sangro B, Sarobe P, Hervás-Stubbs S, et al., Advances in immunotherapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2021 Apr 13:1–19. Epub ahead of print. PMID: 33850328; PMCID: PMC8042636. DOI:https://doi.org/10.1038/s41575-021-00438-0.

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