Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Current Progresses and Challenges

Liu, Hao-Tian; Jiang, Mengjie; Deng, Zeyi; Li, Le; Huang, Jian-Li; Liu, Zhen-Xiu; Li, Le‐Qun; Zhong, Jian‐Hong

doi:10.3389/fonc.2021.737497

Cited by 26 publications

(23 citation statements)

References 127 publications

(124 reference statements)

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“…Clinical practice has several treatment regimens for first- and second-line therapies [ 24 ]. A combination of immune checkpoint inhibitors and tyrosine kinase inhibitors could be a breakthrough treatment modality, but defects in interferon-γ or insufficient tumor antigen immunosuppressive cells in the tumor microenvironment develop resistance to immune checkpoint inhibitors [ 25 , 26 ]. Sorafenib and other TKIs have been used globally, and molecular biomarkers and genome changes in pathobiological issues have been emphasized [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Differential Response to Sorafenib Administration for Advanced Hepatocellular Carcinoma

et al. 2022

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Sorafenib has been used to treat advanced hepatocellular carcinoma (aHCC). However, there is no evidence for a response of different target lesions to sorafenib administration. Therefore, we aimed to evaluate the effect of sorafenib on various aHCC target lesions. The outcomes of sorafenib treatment on aHCC, i.e., treatment response for all Child A status patients receiving the drug, were analyzed. Of 377 aHCC patients, 73 (19.3%) had complete/partial response to sorafenib, while 134 (35.4%) and 171 (45.2) had a stable or progressive disease, respectively, in the first six months. Of the evaluated metastatic lesions, 149 (39.4%), 48 (12.7%), 123 (32.5%), 98 (25.9%), 83 (22.0%), and 45 (11.9%) were present in liver, bone, lung, portal/hepatic vein thrombus, lymph nodes, and peritoneum, respectively. The overall survival and duration of treatment were 16.9 ± 18.3 and 8.1 ± 10.5 months (with median times of 11.4 and 4.6, respectively). Our analysis showed poor outcomes in macroscopic venous thrombus and bone, higher AFP, and multiple target lesions. ALBI grade A had a better outcome. Sorafenib administration showed good treatment outcomes in selected situations. PD patients with thrombus or multiple metastases should be considered for sorafenib second-line treatment. The ALBI liver function test should be selected as a treatment criterion.

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Section: Discussionmentioning

confidence: 99%

Differential Response to Sorafenib Administration for Advanced Hepatocellular Carcinoma

et al. 2022

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“…In this study, we further showed that a combination of higher levels of PD-L1 expression and Tregs infiltration in tumor tissues was associated with a higher risk of HCC recurrence and poorer RFS than those of either biomarker alone in pre-S2 mutant-positive HCC patients after curative surgical resection. Considering that the therapeutics targeting PD-L1 and Tregs either alone or in combination show great promise in the treatment of many cancers including HCC [75][76][77][78][79][80], the results of this study may therefore not only suggest the levels of PD-L1 expression and Tregs infiltration in tumor tissues as valuable prognostic biomarkers but also support PD-L1-and Tregs-targeted therapies as potential therapeutic options for pre-S2 mutant-positive HCC patients after curative surgical resection although the efficacy remains to be validated.…”

Section: Discussionmentioning

confidence: 99%

Association of Increased Programmed Death Ligand 1 Expression and Regulatory T Cells Infiltration with Higher Hepatocellular Carcinoma Recurrence in Patients with Hepatitis B Virus Pre-S2 Mutant after Curative Surgical Resection

Jeng

Hsu

et al. 2022

Viruses

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Although surgical resection is available as a potentially curative therapy for hepatocellular carcinoma (HCC), high recurrence of HCC after surgery remains a serious obstacle for long-term patient survival. Therefore, the discovery of valuable prognostic biomarkers for HCC recurrence is urgently needed. Pre-S2 mutant is a mutant form of hepatitis B virus (HBV) large surface protein which is expressed from the HBV surface gene harboring deletion mutations spanning the pre-S2 gene segment. Pre-S2 mutant-positive HCC patients have been regarded as a high-risk population of HCC recurrence after resection surgery and display increased immune checkpoint programmed death ligand 1 (PD-L1) expression and pro-tumor regulatory T cells (Tregs) infiltration in tumor tissues. In this study, the association of higher levels of PD-L1 expression and Tregs infiltration in tumor tissues with post-operative HCC recurrence in pre-S2 mutant-positive HCC patients was evaluated. We found that patients with pre-S2 mutant in combination with higher levels of PD-L1 expression and Tregs infiltration in tumor tissues were independently associated with a higher risk of HCC recurrence (hazard ratio, 4.109; p value = 0.0011) and poorer recurrence-free survival (median, 8.2 versus 18.0 months; p value = 0.0004) than those of patients with either one or two of these three biomarkers. Furthermore, a combination of pre-S2 mutant, intra-tumoral PD-L1 expression, and tumor-infiltrating Tregs exhibited superior performance in identifying patients at a higher risk of HCC recurrence (area under the receiver operating characteristic curve, 0.8400). Collectively, this study suggests that higher levels of PD-L1 expression and Tregs infiltration in tumor tissues predicted a higher risk of HCC recurrence in pre-S2 mutant-positive HCC patients after curative surgical resection.

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“…Low expression of MHC-I (binding to cytotoxic CD8+ T cells) and high expression of MHC-II (binding to immunosuppressive CD4+ T cells) is the reason for immune escape in terms of the failure of antigen presentation related to HCC. The result is that a large number of immunosuppressive cells are recruited into the TME of HCC (40).…”

Section: Immunosuppressive Cells In the Tme Of Hccmentioning

confidence: 99%

Advances in Immune Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma

Chen

Yuan

et al. 2022

Front. Immunol.

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Hepatocellular carcinoma (HCC) is usually diagnosed in an advanced stage and has become the second deadliest type of cancer worldwide. The systemic treatment of advanced HCC has been a challenge, and for decades was limited to treatment with tyrosine kinase inhibitors (TKIs) until the application of immune checkpoint inhibitors (ICIs) became available. Due to drug resistance and unsatisfactory therapeutic effects of monotherapy with TKIs or ICIs, multi-ICIs, or the combination of ICIs with antiangiogenic drugs has become a novel strategy to treat advanced HCC. Antiangiogenic drugs mostly include TKIs (sorafenib, lenvatinib, regorafenib, cabozantinib and so on) and anti-vascular endothelial growth factor (VEGF), such as bevacizumab. Common ICIs include anti-programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1), including nivolumab, pembrolizumab, durvalumab, and atezolizumab, and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4), including tremelimumab and ipilimumab. Combination therapies involving antiangiogenic drugs and ICIs or two ICIs may have a synergistic action and have shown greater efficacy in advanced HCC. In this review, we present an overview of the current knowledge and recent clinical developments in ICI-based combination therapies for advanced HCC and we provide an outlook on future prospects.

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Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Current Progresses and Challenges

Cited by 26 publications

References 127 publications

Differential Response to Sorafenib Administration for Advanced Hepatocellular Carcinoma

Differential Response to Sorafenib Administration for Advanced Hepatocellular Carcinoma

Association of Increased Programmed Death Ligand 1 Expression and Regulatory T Cells Infiltration with Higher Hepatocellular Carcinoma Recurrence in Patients with Hepatitis B Virus Pre-S2 Mutant after Curative Surgical Resection

Advances in Immune Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma

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