Page 49 - Read Online

Qin et al. Hepatoma Res 2020;6:24 I http://dx.doi.org/10.20517/2394-5079.2020.04 Page 7 of 18

[82]
[82]
liver. Some clinical trials based on AFP have been initiated . Zhang et al. showed that cellular immune
responses may be responsible for the antitumor activity against AFP-positive tumor cells in the mouse HCC
model. Unfortunately, the AFP peptide vaccine also has certain limitations, where it only targets the AFP-
specific immune response.

[83]
Carcinoembryonic antigen glypican-3 (GPC3) is another important antigen that targets liver cancer . In
2012, a phase I clinical trial was been initiated. Thirty-three advanced HCC patients were injected with
GPC3 peptide, and nineteen HCC patients showed stable disease after 2 months treatment. The study results
showed that the GPC3-derived peptide vaccination not only has good immune tolerance, but also has a clear
[84]
immune response and antitumor efficacy .
Studies indicate that human telomerase reverse transcriptase (hTERT) is a catalytic enzyme necessary for
[87]
telomere extension [85,86] . Mizukoshi et al. showed that hTERT is an important target for T cell-based
immunotherapy in HCC. Another study found that 71.4% of liver cancer patients acquired TERT-specific
immunity and 57.1% of patients had no HCC recurrence after vaccination with hTERT461 peptide-specific T
[88]
cells . SSX-2, a cancer-testis antigen, has been shown to be overexpressed in HCC patients. Recent evidence
+
[89]
suggestw that a large number of SSX-2- and MAGE-A-specific CD8 T cells can be found in HCC .
DCs
DCs are the immune cells with the strongest antigen-presenting ability in the human immune system.
Some cytokines such as recombinant human interleukin 4 (rhIL-4) and recombinant human granulocyte
macrophage colony stimulating factor (rhGM-CSF) can activate the function of DCs, and DCs can be
sensitized via the lysis of liver cancer cells. Some research has shown that immature DCs do not cause
[90]
+
+
serious immune response but suppress CD8 T cell immunity . CD8 T cells and polarized CD4 T cells are
+
induced by mature DCs. Therefore, mature DCs should be selected as the tumor vaccine and their maturity
[91]
should be evaluated . In the body’s immune system, the CD4 T/CD8 T ratio is used to evaluate the
+
+
+
+
antitumor immunity. Encouragingly, the proportion of CD4 T/CD8 T has been shown to be significantly
increased after DC-based immunotherapy. In addition, the latest study demonstrated that the survival
rate and survival time of HCC patients were increased after DC-based immunotherapy when analyzing
[92]
1276 cases in 19 clinical trials . In addition, DC-derived exosomes are a novel class of vaccines for cancer
immunotherapy. AFP-rich derived exosomes can elicit a strong antigen-specific antitumor immune response,
[93]
providing a cell-free vaccine option for HCC immunotherapy .
However, there are many challenges in immunotherapy with DC vaccines. To resolve the problems better, some
[94]
researchers combine DC-based vaccines with checkpoint inhibitors to improve efficacy. Wilgenhof et al.
combined DC vaccines with an immune checkpoint cytotoxic T lymphocyte-associated antigen-4 (CTLA-4)
inhibitor for advanced melanoma in phase II clinical studies. The experimental results showed that the
combination of tumor vaccine and immune checkpoint inhibitor has significant advantages over single drug
treatment. Furthermore, a phase I/IIa clinical study achieved encouraging results showing that the adjuvant
[95]
DC vaccine for HCC was safe and well tolerated .

HCC cell vaccines
HCC cells or lysates that are physically or chemically disposed to eliminate pathogenicity could be used as
[96]
immunogens for tumor-specific immune responses. Nemunaitis et al. conducted a phase I trial of cellular
TM
immunotherapy using autologous whole-cell tumors (FANG ). They observed that FANG manufacturing
was successful in 7 of 8 attempts in this study. However, HCC vaccines are still in the early stage of clinical
research and more studies are needed to prove their efficacy.

Oncolytic virus vaccines
The basic principle of antitumor oncolytic viruses is to expand them inside cancer cells and lyse them,
eventually killing the cancer cells, and can selectively replicate and lyse in tumor cells without damaging