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Ni et al. Hepatoma Res 2020;6:25 I http://dx.doi.org/10.20517/2394-5079.2020.14 Page 5 of 12

risk of tumor relapse in HCC patients who have undergone standard treatment.

ASPH was also utilized to make DC-based HCC vaccines. An adenovirus vector encoding the ASPH gene
(Ad-ASPH-IRES2-EGFP) was constructed and bone marrow-derived DCs were infected by Ad-AAH-
IRES2-EGFP to prepare ASPH-DC vaccines. After infection, DCs showed a mature phenotype with higher
expression of CD11c, CD80, and MHC-II. Co-culture of ASPH-DCs and T cells resulted in enhanced
killing capacity of T lymphocytes on the HepG2 HCC cell line. In addition, this ASPH-DC vaccine also
improved the killing function of cytotoxic T lymphocytes (CTLs) compared to controls in an animal
model. Therefore, this finding indicates that the ASPH-DC vaccine may be a potential candidate for DC-
[28]
based immunotherapy of HCC . However, for the ASPH-DC vaccine, only one molecule, ASPH, can be
targeted, which cannot account fully for HCC heterogeneity.

[29]
From these studies, Chen et al. conducted a systematic review and meta-analysis to evaluate the clinical
efficacy of DC-based vaccines in treating HCC. In total, there were 1276 cases from 19 clinical trials.
They found that DC-based vaccines not only improved tumor control and increased the survival rate of
HCC patients, its toxicity was also well-tolerated. These findings will provide new insight towards further
development of DC-based vaccines as an adjuvant treatment strategy. However, the sample size, publication
biases, varied study designs, pre-treatment and therapeutic processes of DCs have to be taken into
consideration when evaluating DC-based immunotherapy.

ADVANCEMENT OF ACT
Cellular immunotherapy appears to be a promising modality for the treatment of malignant tumors. The
mechanism of action in adoptive cell transfer is to treat cancer patients with their own naturally occurring
or genetically modified anti-tumor lymphocytes to control tumors. Several meta-analyses have confirmed
the evidence that adjuvant ACT for HCC patients after curative treatment reduces the risk of mortality and
tumor relapse [30,31] .

Chimeric antigen receptor T cells
Chimeric antigen receptor T cells (CAR-T cells) are T cells that have been engineered to express an artificial
T cell receptor. The FDA has approved CAR-T cells that target CD19 to treat myeloma, a hematological
malignancy derived from plasma cells . However, the use of CAR-T cells to treat solid tumors is limited
[32]
due to the scarcity of tumor-specific antigen targets and the poor infiltration of CAR-T cells into tumor
tissue. In the context of HCC, CAR-T cells are still under investigation. Currently, these targets include
GPC-3, CD133, NKG2D and CD147.

[33]
GPC3-targeted CAR-T cells could be a promising therapeutic option for HCC [33-35] . Gao et al. found
that GPC3-CAR-T cells could efficiently eliminate GPC3 positive HCC cells but not GPC3 negative cells
in vitro, and their cytotoxic activities might be positively associated with the expression levels of GPC3
on target cells. Moreover, third-generation GPC3-CAR-T cells could eliminate HCC xenografts with high
GPC3 expression and potently impair HCC xenograft growth with low expression levels of GPC3 in vivo.
Treatment with third-generation GPC3-targeted CAR-T cells also significantly prolonged the survival of
mice bearing established orthotopic Huh-7 xenografts. In addition, in order to reduce on-target, off-tumor
toxicity by GPC3-CAR-T cells, CAR-T cells targeting GPC3 and asialoglycoprotein receptor 1 (ASGR1) (a
liver tissue-specific protein) were prepared. Dual-targeted CAR-T cells carry anti-GPC3-CD3 ζ for primary
signal transduction and anti-ASGR1-28BB for co-stimulatory signal transduction. The results showed that
-
+
+
-
dual-targeted CAR-T cells had no cytotoxic effect on ASGR GPC3 tumor cells but killed GPC3 ASGR1
+
+
and GPC3 ASGR1 HCC cells in vitro. Moreover, the dual-targeted CAR-T cells potently suppressed the
+
+
growth of GPC3 ASGR1 HCC tumor xenografts while no obvious growth inhibition was seen with either
single or double antigen-negative tumor xenografts. Additionally, the dual-targeted T cells showed higher