Advances in immunotherapy for hepatocellular carcinoma

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2021, Volume and Issue: 18(8), P. 525 - 543

Published: April 13, 2021

Hepatocellular carcinoma (HCC) is a prevalent disease with progression that modulated by the immune system. Systemic therapy used in advanced stage and until 2017 consisted only of antiangiogenic tyrosine kinase inhibitors (TKIs). Immunotherapy checkpoint has shown strong anti-tumour activity subset patients combination anti-PDL1 antibody atezolizumab VEGF-neutralizing bevacizumab or will soon become standard care as first-line for HCC, whereas anti-PD1 agents nivolumab pembrolizumab are after TKIs several regions. Other strategies such adoptive T-cell transfer, vaccination virotherapy have not yet demonstrated consistent clinical activity. Major unmet challenges HCC immunotherapy discovery validation predictive biomarkers, advancing treatment to earlier stages disease, applying liver dysfunction more effective combinatorial sequential approaches. Combinations other systemic local treatments perceived most promising opportunities some already under evaluation large-scale trials. This Review provides up-to-date information on best use currently available immunotherapies therapeutic development. Immunotherapeutic interventions might be tools hepatocellular carcinoma. carcinoma, mechanisms response resistance,

Language: Английский

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NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Nature, Journal Year: 2021, Volume and Issue: 592(7854), P. 450 - 456

Published: March 24, 2021

Abstract Hepatocellular carcinoma (HCC) can have viral or non-viral causes 1–5 . Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification patients optimal response to therapy unmet need 6,7 Here we report the progressive accumulation exhausted, unconventionally activated CD8 + PD1 T cells in NASH-affected livers. In preclinical models NASH-induced therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded within tumours did not lead tumour regression, which indicates that immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led increase incidence NASH–HCC and number size nodules, correlated with increased hepatic CXCR6 , TOX TNF cells. The HCC triggered by prevented depletion neutralization, suggesting help induce NASH–HCC, rather than invigorating executing surveillance. We found similar phenotypic functional profiles from humans NAFLD NASH. A meta-analysis three randomized phase III clinical trials tested inhibitors PDL1 (programmed death-ligand 1) more 1,600 advanced revealed improve survival two additional cohorts, NASH-driven who received anti-PDL1 showed reduced overall compared other aetiologies. Collectively, these data show particularly might be less responsive immunotherapy, probably owing NASH-related aberrant cell activation causing tissue damage leads impaired Our provide a rationale according underlying aetiology studies as primary adjuvant treatment.

Language: Английский

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Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma

NEJM Evidence, Journal Year: 2022, Volume and Issue: 1(8)

Published: June 6, 2022

BackgroundA single, high priming dose of tremelimumab (anti-cytotoxic T lymphocyte–associated antigen 4) plus durvalumab (anti–programmed cell death ligand-1), an infusion regimen termed STRIDE (Single Tremelimumab Regular Interval Durvalumab), showed encouraging clinical activity and safety in a phase 2 trial unresectable hepatocellular carcinoma.MethodsIn this global, open-label, 3 trial, the majority patients we enrolled with carcinoma no previous systemic treatment were randomly assigned to receive one three regimens: (300 mg, dose) (1500 mg every 4 weeks; STRIDE), weeks), or sorafenib (400 twice daily). The primary objective was overall survival for versus sorafenib. Noninferiority secondary objective.ResultsIn total, 1171 (n=393), (n=389), (n=389). median 16.43 months (95% confidence interval [CI], 14.16 19.58) STRIDE, 16.56 CI, 14.06 19.12) durvalumab, 13.77 12.25 16.13) Overall at 36 30.7%, 24.7%, 20.2%, respectively. hazard ratio 0.78 (96.02% 0.65 0.93; P=0.0035). monotherapy noninferior (hazard ratio, 0.86; 95.67% 0.73 1.03; noninferiority margin, 1.08). Median progression-free not significantly different among all groups. Grade 3/4 treatment-emergent adverse events occurred 50.5% 37.1% 52.4% sorafenib.ConclusionsSTRIDE improved Durvalumab carcinoma. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT03298451.)

Language: Английский

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Combination strategies with PD-1/PD-L1 blockade: current advances and future directions

Molecular Cancer, Journal Year: 2022, Volume and Issue: 21(1)

Published: Jan. 21, 2022

Antibodies targeting programmed cell death protein-1 (PD-1) or its ligand PD-L1 rescue T cells from exhausted status and revive immune response against cancer cells. Based on the immense success in clinical trials, ten α-PD-1 (nivolumab, pembrolizumab, cemiplimab, sintilimab, camrelizumab, toripalimab, tislelizumab, zimberelimab, prolgolimab, dostarlimab) three α-PD-L1 antibodies (atezolizumab, durvalumab, avelumab) have been approved for various types of cancers. Nevertheless, low rate α-PD-1/PD-L1 therapy remains to be resolved. For most patients, PD-1/PD-L1 pathway is not sole speed-limiting factor antitumor immunity, it insufficient motivate effective by blocking axis. It has validated that some combination therapies, including plus chemotherapy, radiotherapy, angiogenesis inhibitors, targeted therapy, other checkpoint agonists co-stimulatory molecule, stimulator interferon genes agonists, fecal microbiota transplantation, epigenetic modulators, metabolic superior efficacies higher rates. Moreover, bifunctional bispecific containing moiety also elicited more potent activity. These strategies simultaneously boost multiple processes cancer-immunity cycle, remove immunosuppressive brakes, orchestrate an immunosupportive tumor microenvironment. In this review, we summarized synergistic mechanisms with therapies. focused advances α-PD-1/PD-L1-based immunomodulatory studies. Given heterogeneity across patients types, individualized selection could improve effects relieve treatment resistance.

Language: Английский

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Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial

The Lancet Oncology, Journal Year: 2021, Volume and Issue: 23(1), P. 77 - 90

Published: Dec. 13, 2021

Language: Английский

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Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2–3 study

The Lancet Oncology, Journal Year: 2021, Volume and Issue: 22(7), P. 977 - 990

Published: June 15, 2021

Language: Английский

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Hepatobiliary Cancers, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology

Journal of the National Comprehensive Cancer Network, Journal Year: 2021, Volume and Issue: 19(5), P. 541 - 565

Published: May 1, 2021

The NCCN Guidelines for Hepatobiliary Cancers focus on the screening, diagnosis, staging, treatment, and management of hepatocellular carcinoma (HCC), gallbladder cancer, cancer bile ducts (intrahepatic extrahepatic cholangiocarcinoma). Due to multiple modalities that can be used treat disease complications arise from comorbid liver dysfunction, a multidisciplinary evaluation is essential determining an optimal treatment strategy. A team should include hepatologists, diagnostic radiologists, interventional surgeons, medical oncologists, pathologists with hepatobiliary expertise. In addition surgery, transplant, intra-arterial therapies, there have been great advances in systemic HCC. Until recently, sorafenib was only therapy option patients advanced 2020, combination atezolizumab bevacizumab became first regimen show superior survival sorafenib, gaining it FDA approval as new frontline standard unresectable or metastatic This article discusses recommendations

Language: Английский

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AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma

Hepatology, Journal Year: 2023, Volume and Issue: 78(6), P. 1922 - 1965

Published: May 18, 2023

Singal, Amit G.; Llovet, Josep M.; Yarchoan, Mark; Mehta, Neil; Heimbach, Julie K.; Dawson, Laura A.; Jou, Janice H.; Kulik, Agopian, Vatche Marrero, Jorge Mendiratta-Lala, Mishal; Brown, Daniel B.; Rilling, William S.; Goyal, Lipika; Wei, Alice C.; Taddei, Tamar H. Author Information

Language: Английский

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Targeting STAT3 in Cancer Immunotherapy

Molecular Cancer, Journal Year: 2020, Volume and Issue: 19(1)

Published: Sept. 24, 2020

Abstract As a point of convergence for numerous oncogenic signaling pathways, signal transducer and activator transcription 3 (STAT3) is central in regulating the anti-tumor immune response. STAT3 broadly hyperactivated both cancer non-cancerous cells within tumor ecosystem plays important roles inhibiting expression crucial activation regulators promoting production immunosuppressive factors. Therefore, targeting pathway has emerged as promising therapeutic strategy cancers. In this review, we outline importance tumorigenesis its regulation, highlight current status development STAT3-targeting approaches. We also summarize discuss recent advances STAT3-based combination immunotherapy detail. These endeavors provide new insights into translational application may contribute to promotion more effective treatments toward malignancies.

Language: Английский

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Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2021, Volume and Issue: 18(5), P. 293 - 313

Published: Jan. 28, 2021

Language: Английский

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