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TCR-T CELL THERAPY
TCR-T cell immunotherapy, as one of the novel and effective antitumor treatment means, has been widely
[68]
studied in oncotherapy. In 2011, Parkhurst et al. firstly reported that human carcinoembryonic antigen
[68]
(CEA)-targeted TCR-T cell therapy could induce objective regression of metastatic colorectal cancer . The
mechanisms of TCR-T cell therapies are similar to CAR-T immunotherapy. TCR-T therapy also modifies the
autologous T cells with TCR, and then retransfusion expands TCR-T cell back into the patient to recognize
and eliminate tumor cell, but the mechanisms for identifying antigens are quite different from CAR-T cell
[57]
therapies . The specific antigens recognized by CAR-T cell are all cell membrane antigens, while TCR-T
[69]
cell can identify intracellular and cell membrane antigen peptides presented by MHC molecules . In HBV-
related HCC, by performing the high-throughput TCR sequence of TILs in tumor and matched adjacent
[70]
normal tissues, Lin et al. found that the combination of TCR repertoire overlap and TNM stage showed a
[71]
better prognostic effect for HCC than TNM stage. Qasim et al. firstly reported an HBV-related end-stage
HCC case treated with HBV surface antigen as a target for HBV-specific TCR T cell therapy in 2015. In most
[72]
HBV-related HCC, HBV integrations have been observed and can result in the expression of HCC cells .
HCC cells comprise fragments of integrated HBV-DNA that encodes peptides, which can be identified by T
[73]
cells . Another trial was conducted in two advanced HCCs patients who underwent liver transplantation
[74]
with HCC relapses . During the one-year period of follow up, the volume of 5/6 pulmonary metastases was
[74]
decreased in one patient receiving HBV-specific TCR T cell therapy . Basic studies of TCR-T cells therapy
with specific targets, such as HCV, AFP, and GPC, may be a promising immunotherapy strategy for HCC
in the future [75-77] . With TCR-T immunotherapy, the efficacy and side effects seem to mainly depend on the
quality of the specific target and the TCR structure. The primary challenge is the discovery of new targets,
particularly in the promising field of neoantigens. However, it should be emphasized that neoantigens may
be expressed on a subset of tumor cells due to heterogeneity of tumor cell; otherwise, it may cause immune
escape.

DENDRITIC CELL VACCINE
DCs are powerful antigen-presenting cells that can stimulate T cells to induce antitumor activity. The
infiltration of DCs in tumor tissue was closely associated to the improved clinical prognosis in HCC
[80]
patients [78,79] . In 2002, Ladhams et al. firstly reported two patients with end-stage HCC treated with
autologous DCs vaccination co-cultured with autologous HCC antigens. The efficacy of DC vaccination
[81]
loaded with tumor antigens from different sources has been investigated in clinical studies. Lee et al.
reported a trial which enrolled 31 advanced HCC patients receiving DC vaccine pulsed with autologous
tumor lysates in 2005. They reported that rates of partial response and stable disease were 12.9% and 54.8%,
respectively. A Phase II clinical trial reported disease control rate was 28% for advanced HCC patients with
[83]
[82]
DC vaccination pulsed HepG2 lysate . In another study of note, El Ansary et al. , also using DC vaccine
pulsed with HepG2 lysate, showed that DC vaccination could partially improve survival outcome. DC
vaccination loaded with autologous tumor lysates or ex vivo HepG2 cell lysate were feasible and effective.

However, the efficacy of DCs vaccination pulsed with tumor cell lysate is not satisfactory, and thus the
[84]
use of specific antigen-modified DC vaccination has been attempted. Kakumu et al. suggested that the
depressed function of DCs is associated with pathogenesis of HCC with HBV or HCV infection. Several pre-
clinical studies indicated that DCs infected with AFP or HBV antigen or both were effective strategies to
enhance efficacy of DC-based vaccine [85-87] . GPC3-modified DCs were potent in inducing T cell proliferation
[88]
[89]
and interferon (IFN)-y production . Tada et al. reported a clinical effect was observed in one of the
five patients receiving DC vaccination pulsed with AFP, GPC3, and MAGE-1 fusion proteins in 2012.
Subsequently, a large sample study confirmed that the median time of progression of HCC patients with
DC vaccination pulsed with AFP, GPC3 and MAGE-1 fusion proteins was longer than the control group
[90]
(36.6 months vs. 11.8 months) .