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Qin et al. Hepatoma Res 2020;6:24 I http://dx.doi.org/10.20517/2394-5079.2020.04 Page 11 of 18

cannot promote T cells to attack tumor cells [127,128] . Existing studies suggest that it is only effective for some
patients, and a part of patients will get worse after this kind of treatment, so the treatment strategy for
advanced HCC also needs to be optimized.

Adoptive cell immunotherapy
Adoptive cell immunotherapy is a special therapy including active specific immunotherapy and passive
immunotherapy. In this type of therapy, cancer cells are killed by using patients’ own lymphocytes. Chimeric
antigen receptor T cell immunotherapy (CAR-T), NK cells, tumor-infiltrating lymphocytes (TILs) and
cytokine induced killer (CIK) cells constitute adoptive cell immunotherapy in HCC.

CAR-T
CAR-T cells are a special type of transgenic T lymphocytes that specifically recognize TAAs and improve
the targeting of effector T cells and break host immune tolerance [129] . A previous study confirmed that
an intracellular signaling domain, extracellular antigen-binding domain, and an extracellular hinge area
constitute the basic structure of CARs [130] . The intracellular signaling domain and extracellular antigen-
binding domain are connected by the extracellular hinge area. It is the hinge area that confers high activity
on the extracellular antigen-binding domain. Although CAR-T cell immunity has become a research hotspot
in the application of solid tumors, more studies on HCC are still in the basic research stage, and the key
point of technology lies in the selection of tumor-specific antigens. GPC3 is located on the cell surface and
is a member of the glypican family of heparan sulfate. A previous study reported that GPC3 is a TAA and
overexpressed in HCC compared with normal tissues. Gao et al. [131] found that GPC3-positive HCC cells
could be lysed by GPC3-targeted CAR-T cells and that the number of lysed tumor cells correlated with the
expression of GPC3. Liu et al. [132] recently stated, “The inducibly expressed IL-12-armored GPC3-CAR-T cells
could broaden the application of CAR-T-based immunotherapy to patients intolerant of lymphodepletion
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chemotherapy and might provide an alternative therapeutic strategy for patients with GPC3 cancers”.
Asialoglycoprotein receptor 1 (ASGR1) mediates the transport of targeted therapeutic molecules to the liver,
specifically expressed on liver parenchymal cells. GPC3 and ASGR1 make a suitable target combination
for dual-targeted CAR-T cells. Chen et al. [133] surveyed data and found that the risk of on-target, off-tumor
toxicity may be reduced when using T cells with two complementary CARs against GPC3 and ASGR1.
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Recently, 13 GPC3 HCC patients were enrolled a phase I trial, where all patients who received GPC3 CAR-T
treatment had no dose-limiting toxicity and tolerated the treatment well. The study results showed that GPC3
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CAR-T treatment was feasible and safe for Chinese patients with GPC3 HCC (NCT02395250) [134] . With
the application of CAR-T cells in the clinic, the safety of CAR-T cells has begun to attract people’s attention.
MacKay et al. [135] noted, “Immune-cell failure is a major challenge for CAR therapies, and its mechanism
remains to be investigated”. In addition, immune rejection and off-target effects of CAR-T cells also need to
be resolved [136] .

CIK cells
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CIK cells are a new type of non-MHC-restricted immunocompetent cells mainly including CD3 /CD56
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cells, CD3 /CD56 NK cells, CD3 /CD56 T cells, etc., among which CD3 /CD56 T cells are the main
effector cells [137,138] . Preclinical trials have shown that CIK cells have high activity against HCC cells in vitro.
In addition, Pan et al. [139] investigated the effect of CIK as adjuvant therapy on overall survival and relapse-
free survival of HCC patients who received surgical treatment. Survival analysis showed that compared
with hepatectomy alone, median overall survival and PFS were clearly prolonged in the hepatectomy/
CIK combination group (41, 16 months vs. 28, 12 months, respectively). The safety and efficacy of CIK cell
immunotherapy were investigated in a phase III clinical trial in which 230 HCC patients treated with RFA,
surgical resection or percutaneous ethanol injection were randomly injected with 6.4 × 10 autologous CIK
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cells (16 times during 60 weeks) or had no immunotherapy. The median time of recurrence-free survival in