Dual Programmed Death Receptor‐1 and Vascular Endothelial Growth Factor Receptor‐2 Blockade Promotes Vascular Normalization and Enhances Antitumor Immune Responses in Hepatocellular Carcinoma

Hepatology, Journal Year: 2019, Volume and Issue: 71(4), P. 1247 - 1261

Published: Aug. 5, 2019

Background and Aims Activation of the antitumor immune response using programmed death receptor‐1 (PD‐1) blockade showed benefit only in a fraction patients with hepatocellular carcinoma (HCC). Combining PD‐1 antiangiogenesis has shown promise substantially increasing HCC who respond to treatment, but mechanism this interaction is unknown. Approach Results We recapitulated these clinical outcomes orthotopic—grafted or induced—murine models HCC. Specific vascular endothelial receptor 2 (VEGFR‐2) murine antibody significantly delayed primary tumor growth failed prolong survival, while anti‐PD‐1 treatment alone conferred minor survival advantage one model. However, dual anti‐PD‐1/VEGFR‐2 therapy inhibited doubled both models. Combination reprogrammed microenvironment by cluster differentiation 8–positive (CD8 + ) cytotoxic T cell infiltration activation, shifting M1/M2 ratio tumor‐associated macrophages reducing regulatory (Treg) chemokine (C‐C motif) 2–positive monocyte tissue. In models, VEGFR‐2 was selectively expressed cells. Using spheroid cultures tissue, we found that PD‐ligand 1 expression cells induced paracrine manner upon anti‐VEGFR‐2 part through interferon‐gamma expression. Moreover, increased tumor‐infiltrating CD4 also under therapy, promote normalized vessel formation face antiangiogenic antibody. Conclusions show durable fortification effect can overcome resistance either increase overall therapy–resistant therapy–responsive

Language: Английский

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Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma

Journal of Hepatology, Journal Year: 2020, Volume and Issue: 73(6), P. 1460 - 1469

Published: July 22, 2020

Nivolumab, a programmed death (PD)-1 (PD-1) inhibitor, led to durable responses, manageable safety, and increased survival in patients with advanced hepatocellular carcinoma (HCC). In our retrospective analysis, we studied the immunobiology potential associations between biomarkers outcomes nivolumab HCC.Fresh archival tumour samples from dose-escalation dose-expansion phases of CheckMate 040 trial were analysed by immunohistochemistry RNA sequencing assess several inflammatory gene expression signatures, including CD274 (PD-ligand 1 [PD-L1]), CD8A, LAG3, STAT1. Biomarkers assessed for association clinical (best overall response blinded independent central review per RECIST v1.1 [OS]).Complete or partial responses observed PD-L1-positive PD-L1-negative treated monotherapy. Median OS was 28.1 (95% CI 18.2-n.a.) vs. 16.6 months 14.2-20.2) PD-L1 ≥1% <1% (p = 0.03). Increased CD3 CD8 showed non-significant trend towards improved (both p 0.08), macrophage markers not associated OS. Tumour PD-1 0.05 0.03, respectively). An signature consisting 4 genes objective rate 0.05) 0.01).PD-1 expression, inflammation, signatures trended response. While further confirmation within larger phase III is needed evaluate predictive value these biomarkers, exploratory analyses suggest that anti-tumour immune may play role treatment benefit HCC.Certain tests be used provide picture how escaping system, allowing it continue grow create more tumours. Therapies such as are designed help system fight tumour. These determine effective therapies will liver cancer.NCT01658878.

Language: Английский

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Intra-tumoral tertiary lymphoid structures are associated with a low risk of early recurrence of hepatocellular carcinoma

Journal of Hepatology, Journal Year: 2018, Volume and Issue: 70(1), P. 58 - 65

Published: Sept. 11, 2018

Language: Английский

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The liver cancer immune microenvironment: Therapeutic implications for hepatocellular carcinoma

Hepatology, Journal Year: 2022, Volume and Issue: 77(5), P. 1773 - 1796

Published: Aug. 22, 2022

The liver is the sixth most common site of primary cancer in humans and fourth leading cause cancer‐related death world. Hepatocellular carcinoma (HCC) accounts for 90% cancers. HCC a prevalent disease with progression that modulated by immune system. Half patients receive systemic therapies, traditionally sorafenib or lenvatinib, as first‐line therapy. In last few years, immune‐checkpoint inhibitors (ICIs) have revolutionized therapy gained an increased interest treatment HCC. 2020, combination atezolizumab (anti‐programmed death‐ligand 1) bevacizumab (anti–vascular endothelial growth factor) improved overall survival over sorafenib, resulting Food Drug Administration (FDA) approval advanced Despite these major advances, better molecular cellular characterization tumor microenvironment still needed because it has crucial role development Inflamed (hot) noninflamed (cold) tumors genomic signatures been associated response to ICIs. However, there are no additional biomarkers guide clinical decision‐making. Other immune‐targeting strategies, such adoptive T‐cell transfer, vaccination, virotherapy, currently under development. This review provides overview on microenvironment, different players, current available immunotherapies, potential immunotherapy modalities.

Language: Английский

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Trial Design and Endpoints in Hepatocellular Carcinoma: AASLD Consensus Conference

Hepatology, Journal Year: 2020, Volume and Issue: 73(S1), P. 158 - 191

Published: May 20, 2020

Language: Английский

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