Focus on clinical trials and randomised control trials and guidelines. <\/p>\n
Immunotherapy<\/span><\/span> <\/span><\/p>\n<\/div>\n There are many surgical treatment options for the treatment of HCC. However, resection or transplantation has limited effectiveness due to a low classification rate for surgery and a high 5-year recurrence rate ranging up to 70% after surgery. [30] This is related to the late diagnosis of HCC, which in most patients is at an advanced stage. Treatment is then based on a combination of targeted therapy, chemotherapy, or radiotherapy. Recently, immunotherapy has also been included in the treatment of HCC. <\/span><\/span> <\/span><\/p>\n<\/div>\n Continuous exposure of the liver to bacterial components and dietary antigens from the gastrointestinal tract led to the creation of an immune microenvironment consisting of Kupffer cells, hepatic stellate cells, sinusoidal hepatic endothelial cells, natural killer (NK) cells, gamma-delta T cells, and dendritic cells. [31] When the liver is damaged or infected, the protective response is <\/span>initiated<\/span> by cytokines, growth factors, chemokines, and interactions with the immune microenvironment of the liver, the incorrect regulation of which could result in the development of cancer. [32] Zhang et al. in their study found that hypoxia- and inflammation-related hypoxia-inducible factor 1<\/span><\/span>\u03b1<\/span><\/span> (HIF-1<\/span><\/span>\u03b1<\/span><\/span>) can stimulate the excessive expression of IL-1<\/span><\/span>\u03b2<\/span><\/span> in tumor-associated macrophages (TAMs), which, thanks to positive feedback, can induce the production of HIF-1<\/span><\/span>\u03b1<\/span><\/span> and <\/span>facilitates<\/span> the process of epithelial-mesenchymal transition (EMT) leading to metastatic progression. [33] Other important cytokines involved in the pathogenesis of HCC are IL-6, IL-11, and lncRNA activated by TGF-<\/span><\/span>\u03b2<\/span><\/span> (lncRNA-ATB). [32] Patients with HCC usually have an increased number of Tregs, which can inhibit the function of CD8 + T cells and thus the elimination of tumor cells. [34] Additionally, continuous antigen stimulation leads to the exhaustion of T cells and thus an increase in the expression of co-inhibitory signaling molecules such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and lymphocyte-activation gene 3 (LAG-3). [35]<\/span><\/span> <\/span><\/p>\n<\/div>\n The study of immune checkpoint inhibitors, i.e. monoclonal antibodies directed against extracellular ligands involved in suppressing the antitumor immune response, allowed the recognition on the basis of clinical trials of three categories of molecular targets, PD-1, CTLA-4, and LAG-3, which are intended to restore the antitumor capacity of lymphocytes T. [36] Compared to ICI (immune checkpoint inhibitor) monotherapy, combination therapy targeting several immune checkpoints is associated with better treatment outcomes, but the increased efficacy is associated with potential increase in immune-related adverse events. [32]<\/span><\/span> <\/span><\/p>\n<\/div>\n Nivolumab is a human anti-PD-1 IgG4 monoclonal antibody directed against PD-1. [37] It is used as a second-line therapy in the treatment of HCC after approval by the FDA in 2017. The <\/span>CheckMate<\/span> 040 (<\/span><\/span>NCT01658878<\/span><\/span><\/a>) study evaluated nivolumab in combination with ipilimumab in patients treated with sorafenib as a first-line therapy in the treatment of advanced HCC, while the <\/span>CheckMate<\/span> 459 study (<\/span><\/span>NCT02576509<\/span><\/span><\/a>) compared nivolumab with sorafenib. The results from the first study led to FDA approval in 2020 of this <\/span>regimen<\/span> for the treatment of patients with advanced HCC who were previously treated with sorafenib. The results of the second study showed that there was no significant difference in OS, but the use of immunotherapy showed a lower incidence of grade 3 to 4 adverse effects, and improvement in patients’ quality of life, so nivolumab may be an alternative treatment <\/span>option<\/span> for patients who cannot undergo therapy with tyrosine kinase inhibitors or antiangiogenic therapy. [38]. Currently, the monoclonal antibody atezolizumab is known, which binds to the PD-L1 protein (programmed death-ligand 1), blocking the binding site of PD-1. The IMbrave150 study (<\/span><\/span>NCT03434379<\/span><\/span><\/a>) compared atezolizumab therapy in combination with the antiangiogenic bevacizumab with a group of patients treated with sorafenib. This study showed statistically significantly better OS and PFS with monoclonal antibody immunotherapy compared to sorafenib. [39, 40] Another known monoclonal antibody is pembrolizumab. The phase II KEYNOTE-224 study (<\/span><\/span>NCT02702414<\/span><\/span><\/a>) tested the effectiveness of pembrolizumab monotherapy in patients with HCC previously treated with sorafenib (cohort 1) and with no prior systemic therapy (cohort 2), and the results in the study groups were better in terms of safety profile and OS. [41, 42] Similar effectiveness and safety were <\/span>demonstrated<\/span> by pembrolizumab in combination with the best supportive care (BCS) in the phase III KEYNOTE-394 study (<\/span><\/span>NCT03062358<\/span><\/span><\/a>), where the study group included Asian patients previously treated with sorafenib or oxaliplatin-based chemotherapy. Compared to the placebo plus BCS group, pembrolizumab showed statistically significant improvement in OS and PFS, as well as in the objective response rate (ORR). The findings of these studies <\/span>demonstrated<\/span> a consistent clinical benefit for pembrolizumab monotherapy in advanced HCC. The phase 3 KEYNOTE-937 study (<\/span><\/span>NCT03867084<\/span><\/span><\/a>), where pembrolizumab is being tested as adjuvant therapy is undergoing. [43]<\/span><\/span> <\/span><\/p>\n<\/div>\n The CTLA-4 protein, a CD28 homolog, prevents the binding of CD28 to CD80 and CD86, which is necessary for <\/span>optimal<\/span> T-cell activation. Moreover, it reduces the activity of helper T cells, increasing Treg activity, which leads to suppression of the immune response. A phase I\/II study (<\/span><\/span>NCT02519348<\/span><\/span><\/a>) compared <\/span>tremelimumab<\/span>, a monoclonal antibody against CTLA-4, in combination with durvalumab (T300+D) with <\/span>tremelimumab<\/span> or durvalumab monotherapy. The results showed that combination therapy was associated with overall treatment benefits and the most encouraging benefit-risk profile due to unique pharmacodynamic activity. [44] In the phase III HIMALAYA study (<\/span><\/span>NCT03298451<\/span><\/span><\/a>) the T300 + D regimen and durvalumab monotherapy were evaluated versus sorafenib. T300 + D, which a single dose is known as STRIDE (Single <\/span>Tremelimumab<\/span> Regular Interval Durvalumab) displayed efficacy and a favorable benefit-risk profile versus sorafenib. [45] The regimen of two ICIs that block CTLA-4 and PD-L1 is the first-line treatment for adults with advanced or <\/span>unresectable<\/span> HCC in the EU. [46]<\/span><\/span> <\/span><\/p>\n<\/div>\n LAG-3 present in CD8+ T cells <\/span>binds<\/span> to MHC class II molecules, and its increased expression correlates with dysfunction of T cells. [32] Zhou et al. showed that after using antibodies against PD-L1, TIM-3 (mucin domain containing-3), or LAG-3 (lymphocyte-activation gene 3), T lymphocytes respond to HCC antigens. [47] TIM-3 is present in TAM cells, and its increased expression correlates with poor prognosis of HCC patients. [48] The effectiveness of TIM-3-targeted therapies <\/span>remains<\/span> uncertain, but studies are currently underway using the anti-TIM-3 antibody, <\/span>Colbolimab<\/span>, LY3321367, or <\/span>sabatolimab<\/span>. [49] <\/span><\/span> <\/span><\/p>\n<\/div>\n Due to the role of TGF-\u03b2 in creating a tumor microenvironment conducive to growth and metastasis, as well as by hindering the infiltration of T lymphocytes into the tumor center, blocking the action of this cytokine has become another therapeutic target. [32] The discovery of the synergism of the effect of TGF-\u03b2 blockade and anti-PD-L1 antibodies allowed the consideration in a clinical trial (<\/span><\/span>NCT02423343<\/span><\/span><\/a>) of the combination of <\/span>galunisertib<\/span> with nivolumab in the treatment of recurrent or refractory non-small cell lung cancer (NSCLC) or hepatocellular carcinoma (HCC). The results showed that the combination is well tolerated. [50] The ongoing phase III <\/span>CheckMate<\/span> 9DX study (<\/span><\/span>NCT03383458<\/span><\/span><\/a>) is investigating if nivolumab will improve recurrence-free survival (RFS) compared to placebo in HCC patients who have undergone resection or local ablation but are at <\/span>high risk<\/span> of recurrence. A bifunctional inhibitor <\/span>bintrafusp<\/span> (M7824) targeting PD-L1 and the extracellular domain of TGF\u03b2R2 was also created, which have been tested in studies: <\/span><\/span>NCT02517398<\/span><\/span><\/a>, <\/span><\/span>NCT02699515<\/span><\/span><\/a>, <\/span><\/span>NCT03840915<\/span><\/span><\/a>, and <\/span><\/span>NCT04246489<\/span><\/span><\/a>. The recurring bleeding adverse events were reported, so the dose reduction was chosen. Further investigation is needed to evaluate the effectiveness of <\/span>bintrafusp<\/span>. [51]<\/span><\/span> <\/span><\/p>\n<\/div>\n ICIs can be combined not only with each other, but also with radiotherapy, FGFR inhibitors, tyrosine kinase inhibitors (TKI), SBRT, TACE, or chemotherapy. The combination of ICI + TKI in the <\/span>first-line<\/span> setting of metastatic disease is being investigated in several phase III trials, such as, the LEAP-002 trial (<\/span><\/span>NCT03713593<\/span><\/span><\/a>) evaluating <\/span>lenvatinib<\/span> plus pembrolizumab compared with placebo, and the trial <\/span><\/span>NCT03764293<\/span><\/span><\/a> with evaluation of <\/span>camrelizumab<\/span> (SHR-1210) plus <\/span>apatinib<\/span> vs. sorafenib. [32, 52] <\/span>The ORIENT<\/span>-32 trial (<\/span><\/span>NCT03794440<\/span><\/span><\/a>) evaluated the combination of <\/span>sintilimab<\/span> (a PD-1 inhibitor) plus IBI305, a bevacizumab biosimilar, versus sorafenib. The results showed that the combination has significantly greater OS and PFS than sorafenib which could <\/span>provide a novel treatment option for patients<\/span> with unresectable, HBV-associated HCC patients. [53]<\/span><\/span> <\/span><\/p>\n<\/div>\n In a phase II study (<\/span><\/span>NCT03092895<\/span><\/span><\/a>), previously untreated patients with advanced primary HCC received a combination of <\/span>camrelizumab<\/span> (anti-PD-1) plus FOLFOX4 (fluorouracil + calcium folinate + oxaliplatin) or GEMOX (gemcitabine and oxaliplatin). The results showed tolerability and preliminary antitumor activity. [54] The aim of the phase III study (<\/span><\/span>NCT03605706<\/span><\/span><\/a>