**6. Conclusions**

the ability to target tumor cells and can injure normal liver tissues. In a previous series of experiments, the cytotoxicity of NK cells against HCC cells was enhanced by first generating a new hepatoma cell line, K562-mb15-41BBL, which achieved a more efficient stimulation of NK cells in vitro [67]. Furthermore, HCC cells exposed to 5 μmol/L sorafenib for 48 h showed high sensitivity to NK cells. Finally, NKG2D, an engineered NK-cell-activating receptor, was tested in vitro and in mice. All of the outcomes were positive in increasing the cytotoxicity of

Chimeric antigen receptor redirected-T cells (CAR-T cells) are genetically modified T lymphocytes that specifically target tumor-associated antigens (TAAs) and kill cancer cells in an MHCindependent manner [68, 69]. CAR-T cells have achieved inspiring outcomes in patients with B cell malignancies with great therapeutic efficacy in leukemia and lymphoma therapy. CAR T therapy is being studied for solid tumors, such as HCC [70]. In some solid tumors with a tremendous phenotypic heterogeneity, CAR T cells could target the tumor antigen and cause antigen-positive cell death, while antigen-negative cancer cells may induce tumor relapse. However, Cart T cell structure engineering has been evolved significantly. Recently, CAR T cells with a transgenic "payload or TRUCK," also called the "fourth generation" CAR T cells, were designed [71]. This CAR T cells work by releasing inducible cytokines such as IL-12 which will augment T cell activation and further activate innate immune system to kill antigen negative cancer cells. Specific Tumor-associated antigens in HCC that recognized by cytotoxic T lymphocytes (CTLs) have been investigated. GPC3, which usually correlates with poor prognosis in HCC, has been demonstrated as a promising liver cancer-specific target in multiple studies, due to its overexpression in HCC and limited expression in normal tissues [72] GPC3-targeted CAR T cells could providing promising therapeutic intervention for GPC3-positive HCC. The ability of GPC3-targeted CAR T cells to eliminate GPC3-positive HCC cells was confirmed both in vivo and in vitro, and the survival of mice with HCC xenografts was prolonged with CAR T cell therapy in vivo [73]. In another study, T cells with two complementary CARs against GPC3 and asialoglycoprotein receptor 1 (ASGR1) decreased the risk of on-target, off tumor toxicities

NK cells, providing the possibility of further clinical trials in HCC.

and demonstrated potent antitumor immune responses targeting GPC3<sup>+</sup>

oncolytic viruses, small molecules and ablative therapies.

in vivo and in vitro [74]. However, to date, the related studies conducted have been predominantly basic, and more clinical trials are required to prove the efficacy of CAR T in HCC.

Combination therapies include combinations of different checkpoint inhibitors with TKIs,

Combining anti-PD-1 with sorafenib has been studied in an animal model in HCC. The results showed efficacy only with the concomitant targeting of the hypoxic and immunosuppressive microenvironment with agents such as CXCR4 inhibitors, and not when combined with sorafenib alone [75]. According to these results, a potential future approach could be by careful titration of VEGF inhibition with the aim to block the VEGF pathway and contemporarily

alleviate hypoxia by vascular normalization, enhancing immunotherapy efficacy [76].

ASGR1<sup>+</sup>

HCCs both

*4.3.1.4. CAR-T cell*

168 Liver Cancer

**4.4. Combination strategies**

Advanced HCC remains a deadly disease with limited systemic treatment options. The advent of sorafenib as first-line treatment ignited a plethora of trials testing various targeted and immunotherapeutic approaches. Currently, both regorafenib and nivolumab are FDA approved for second-line treatment among patients with advanced HCC who progressed


List of abbreviations: MOA: mechanism of action, Ref: references, DCR: disease control rate, FGFR: fibroblast growth factor receptor, McA: monoclonal antibody, MKI: multi-tyrosine kinase inhibitor, OS: overall survival, PFS: progression free survival, PDGFR: platelet-derived growth factor receptor, PD-1: programmed death-1, TKI: trosine kinase inhibitor, VEGFRs: vascular endothelial growth factor receptors.

**Table 1.** Most common systemic agents for advanced HCC.

on sorafenib. The list of available treatment options (**Table 1**) is expected to increase with the encouraging results of several ongoing early phase trials, which eventually will lead to improvement in patients survivals.

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