Hepatocellular Carcinoma Immunotherapy: Predictors of Response, Issues, and Challenges

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2024 Oct 26

PMID 39456872

Authors

Alessandro Rizzo

Oronzo Brunetti

Giovanni Brandi

Affiliations

Soon will be listed here.

Abstract

Immune checkpoint inhibitors (ICIs), such as durvalumab, tremelimumab, and atezolizumab, have emerged as a significant therapeutic option for the treatment of hepatocellular carcinoma (HCC). In fact, the efficacy of ICIs as single agents or as part of combination therapies has been demonstrated in practice-changing phase III clinical trials. However, ICIs confront several difficulties, including the lack of predictive biomarkers, primary and secondary drug resistance, and treatment-related side effects. Herein, we provide an overview of current issues and future challenges in this setting.

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References

Abbott M, Ustoyev Y . Cancer and the Immune System: The History and Background of Immunotherapy. Semin Oncol Nurs. 2019; 35(5):150923. DOI: 10.1016/j.soncn.2019.08.002. View

Rizzo A . Locoregional treatments plus immunotherapy in hepatocellular carcinoma: where do we stand?. Future Oncol. 2022; 18(14):1665-1668. DOI: 10.2217/fon-2021-1623. View

Lin Z, Qin L, Chen J . Biomarkers for response to immunotherapy in hepatobiliary malignancies. Hepatobiliary Pancreat Dis Int. 2022; 21(5):413-419. DOI: 10.1016/j.hbpd.2022.08.002. View

Szeto G, Finley S . Integrative Approaches to Cancer Immunotherapy. Trends Cancer. 2019; 5(7):400-410. PMC: 7467854. DOI: 10.1016/j.trecan.2019.05.010. View

Horn L, Spigel D, Vokes E, Holgado E, Ready N, Steins M . Nivolumab Versus Docetaxel in Previously Treated Patients With Advanced Non-Small-Cell Lung Cancer: Two-Year Outcomes From Two Randomized, Open-Label, Phase III Trials (CheckMate 017 and CheckMate 057). J Clin Oncol. 2017; 35(35):3924-3933. PMC: 6075826. DOI: 10.1200/JCO.2017.74.3062. View

Wang X, Wang Q . Alpha-Fetoprotein and Hepatocellular Carcinoma Immunity. Can J Gastroenterol Hepatol. 2018; 2018:9049252. PMC: 5899840. DOI: 10.1155/2018/9049252. View

Zheng Y, Wang T, Tu X, Huang Y, Zhang H, Tan D . Gut microbiome affects the response to anti-PD-1 immunotherapy in patients with hepatocellular carcinoma. J Immunother Cancer. 2019; 7(1):193. PMC: 6651993. DOI: 10.1186/s40425-019-0650-9. View

Li W, Deng Y, Chu Q, Zhang P . Gut microbiome and cancer immunotherapy. Cancer Lett. 2019; 447:41-47. DOI: 10.1016/j.canlet.2019.01.015. View

Santoni M, Buti S, Myint Z, Maruzzo M, Iacovelli R, Pichler M . Real-world Outcome of Patients with Advanced Renal Cell Carcinoma and Intermediate- or Poor-risk International Metastatic Renal Cell Carcinoma Database Consortium Criteria Treated by Immune-oncology Combinations: Differential Effectiveness by Risk.... Eur Urol Oncol. 2023; 7(1):102-111. DOI: 10.1016/j.euo.2023.07.003. View

10.

Fu C, Zhou L, Mi Q, Jiang A . Plasmacytoid Dendritic Cells and Cancer Immunotherapy. Cells. 2022; 11(2). PMC: 8773673. DOI: 10.3390/cells11020222. View

11.

Tan Z, Chiu M, Yang X, Yue M, Cheung T, Zhou D . Isoformic PD-1-mediated immunosuppression underlies resistance to PD-1 blockade in hepatocellular carcinoma patients. Gut. 2022; 72(8):1568-1580. DOI: 10.1136/gutjnl-2022-327133. View

12.

Rizzo A, Santoni M, Mollica V, Fiorentino M, Brandi G, Massari F . Microbiota and prostate cancer. Semin Cancer Biol. 2021; 86(Pt 3):1058-1065. DOI: 10.1016/j.semcancer.2021.09.007. View

13.

Paz-Ares L, Ciuleanu T, Cobo M, Schenker M, Zurawski B, Menezes J . First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021; 22(2):198-211. DOI: 10.1016/S1470-2045(20)30641-0. View

14.

de Castria T, Khalil D, Harding J, OReilly E, Abou-Alfa G . Tremelimumab and durvalumab in the treatment of unresectable, advanced hepatocellular carcinoma. Future Oncol. 2022; 18(33):3769-3782. DOI: 10.2217/fon-2022-0652. View

15.

Yang J, Shangguan J, Eresen A, Li Y, Wang J, Zhang Z . Dendritic cells in pancreatic cancer immunotherapy: Vaccines and combination immunotherapies. Pathol Res Pract. 2019; 215(12):152691. DOI: 10.1016/j.prp.2019.152691. View

16.

Rimassa L, Finn R, Sangro B . Combination immunotherapy for hepatocellular carcinoma. J Hepatol. 2023; 79(2):506-515. DOI: 10.1016/j.jhep.2023.03.003. View

17.

Rizzo A, Mollica V, Tateo V, Tassinari E, Marchetti A, Rosellini M . Hypertransaminasemia in cancer patients receiving immunotherapy and immune-based combinations: the MOUSEION-05 study. Cancer Immunol Immunother. 2023; 72(6):1381-1394. PMC: 10991194. DOI: 10.1007/s00262-023-03366-x. View

18.

Wang K, Wang C, Jiang H, Zhang Y, Lin W, Mo J . Combination of Ablation and Immunotherapy for Hepatocellular Carcinoma: Where We Are and Where to Go. Front Immunol. 2022; 12:792781. PMC: 8714655. DOI: 10.3389/fimmu.2021.792781. View

19.

Rizzo A, Ricci A, Brandi G . Atezolizumab in advanced hepatocellular carcinoma: good things come to those who wait. Immunotherapy. 2021; 13(8):637-644. DOI: 10.2217/imt-2021-0026. View

20.

Xing R, Gao J, Cui Q, Wang Q . Strategies to Improve the Antitumor Effect of Immunotherapy for Hepatocellular Carcinoma. Front Immunol. 2021; 12:783236. PMC: 8660685. DOI: 10.3389/fimmu.2021.783236. View