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Song et al. Hepatoma Res 2020;6:27 I http://dx.doi.org/10.20517/2394-5079.2020.05 Page 9 of 15

(PFS), compared with control groups [137] . Since medicines based on anti-PD-L1 monoclonal antibodies have
been validated to be effective for several cancer diseases, a phase Ib clinical trial of atezolizumab combined
with bevacizumab, the anti-PD-L1 antibody and VEGF blocking antibody respectively (ClinicalTrials.gov
NCT02715531), has announced an overall response rate of 32% among 73 patients with advanced HCC [138] .
Moreover, this combined therapy-based IMbrave150 phase III trial (ClinicalTrials.gov NCT03434379) is
currently implemented and significant improvements in OS and PFS compared with sorafenib have been
reported by the sponsor [139,140] [Figure 2].

CTLA-4 is another inhibitory molecule that attenuates activation and function of T cells. Upregulation of
+
CTLA-4 promote the apoptosis, secretion of anti-inflammatory cytokines and exhaustion of CD4 Th and
+
CD8 T cells in liver tissues from CHB and HCC patients [141-144] . Tremelimumab, which is the monoclonal
antibody blocking CTLA-4, was administered in HCV-related HCC patients and assessed to possess
antitumor and antiviral activity, along with good safety profile. The disease control rate was 76.4% and time
to progression was 6.48 months (95%CI: 3.95-9.14) [145] . The similar efficacy displayed in another cohort with
32 HCC patients enrolled. Combinational administration of Tremelimumab and tumor ablation results in
accumulation of intratumoral CD8 T cells and median OS of treated patients was 12.3 months (95%CI:
+
9.3 to 15.4 months), which is a potential new therapy for patients with advanced HCC [146] . Furthermore, a
preclinical study of durvalumab combined with tremelimumab was analyzed in patients with unresectable
+
+
HCC (11 HBV , 9 HCV , 20 uninfected). Among 40 patients, 60% (24/40) had discontinued treatment. The
uninfected patients after treatment showed predominantly clinical activity and no unexpected safety signals
were observed. The phase II portion of this study is still ongoing [147] [Figure 2].

Adoptive cells transfer
Chimeric antigen receptor (CAR) therapy is a promising strategy for cancer immunotherapy. Accumulating
evidence has demonstrated CAR-T cell therapy as effective strategy against lymphoid leukemia and multiple
myeloma [148-150] , whereas, efficacy and safety of CAR-T therapy for treatment of solid tumors remain elusive.
Glypican-3 (GPC3) is broadly expressed on liver cancer cells, but minority on normal hepatocytes. GPC3-
targeted CAR-T cells efficiently kill GPC3-positive hepatoma cells and the T cells expressing third-generation
CAR potentiate to suppress growth of xenografts with even low GPC3 expression level in mice [151] . Moreover,
GPC3-specific CAR-T therapy combination with sorafenib could effectively promote apoptosis of liver
cancer cells [152] [Figure 2].

However, side effects to CAR-T therapy contain high manufacturing and fatal toxicities, such as cytokine
release syndrome [153] . CAR-NK therapy is under investigation and probably provide better options. Similar to
CAR-T, FLT3- and CS1-targeted CAR-NK cells respectively suppress proliferation of cancer cells in myeloid
leukemia and multiple myeloma [154,155] . Furthermore, DAP12-targeted CAR-NK cells efficiently suppressed
tumor cells in ascites and proliferation of liver-metastatic tumors in colorectal cancer patients [156] . In vivo
studies have shown that injection of ErbB2-specific NK-92/5.28.z cells possess the ability to prolong survival
of glioblastoma-xenograft mice [157] [Figure 2].

CONCLUSION
Chronic HBV infection-induced progression of HCC mainly depends on direct intrusion of viral
components in hepatocytes, which disturbs its normal cellular metabolism and function. This subsequently
stimulates immune imbalance in liver. Frequently accompanied by systemic metabolic syndrome,
advancement of NALFD- associated HCC encompasses excessive lipid accumulation in hepatocytes
and immune cells, insulin resistance and inflammation induced malignant transformation. The hepatic
complexity of immune cells mediates tumorigenesis in situation of anergy of cytotoxic cells and enhancement
of immunosuppressive cells. Cytotoxic T cells are the major factor which eradicates HBV-infected cells or
malignant cells. The exhaustion mediated by MDSCs or Tregs leads to persistence of HBV and evasion of