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Lee et al. Hepatoma Res 2018;4:51 I http://dx.doi.org/10.20517/2394-5079.2018.78 Page 13 of 18

is a ligand of TIM-3, also induces Treg stimulation and T cell exhaustion . The TIM-3/galectin-9 signaling
[83]
pathway reportedly mediates T-cell dysfunction in HBV-associated HCC, which might explain the poor ORR
of HBV-associated HCC compared with that of non-HBV-associated HCC during the anti-PD-1 antibody
administration [78,83,87] .

Galectin-3 interacts with lymphocyte activation gene-3 (LAG-3) and inhibits CD8+ T cell and NK cell
functions . LAG-3 expression on TILs, along with PD-L1 on tumor cells, is also reported in HCC . As in
[88]
[83]
the PD-1/PD-L1 in HCC tumor, the galectin-3/LAG-3 expression is also associated with a poor prognosis in
HCC patients . Another report also showed up-regulated LAG-3 expression and impaired effector function
[89]
of CD8+ CTLs in HBV-positive HCC patients . Taken together, TIM-3, LAG-3, and PD-1 act synergistically
[90]
and facilitate the HCC immune evasion resulting in worse prognosis . According to these findings, TIM-
[88]
3 and LAG-3, checkpoint molecules expressed on the effector T cell, could mediate resistance to the PD-1/
PD-L1 blockade [86,88] . Given the fact that there are multiple players in the establishment of immune escape
in HCC, anti-PD-1/PD-L1 therapy is being paired with agents targeting TIM-3 (NCT03099109) and LAG-3
[83]
(NCT01968109), respectively .

HCC IMMUNOTHERAPIES IN COMBINATION WITH OTHER CANCER TREATMENTS
While the present adoptive immunotherapy has been restricted to the patients with small tumor burdens
so far, treatments using these engineered immune cells have generated some remarkable responses in
patients with advanced cancer by combinational immunotherapy . Ongoing investigations of adoptive
[91]
immunotherapy combined with traditional HCC treatments, including surgery, locoregional interventions,
and systemic chemotherapy, may achieve the best objective responses in various stages of HCCs [92,93] . In
2013, a retrospective study was conducted in 174 HCC patients from January 1999 to April 2012. Among
them, 85 patients were given CIK cell infusion after treatment with TACE and RFA alone. The results
demonstrated that CIK cell infusion significantly prolonged the PFS in patients compared to TACE or
RFA monotherapy . A different approach is pretreatment of HCC with TACE, RFA, or RT to induce
[94]
inflammation of cancer cells, thereby creating conditions that favor tumor neoantigen generation prior to
the initiation of immunotherapy .
[84]
Although the efficacy of immune checkpoint inhibitors in HCC is promising, the majority of the patients
remain refractory, due to the immunosuppressive mechanisms of HCC comprising multiple humoral
mediators and suppressive checkpoint molecules [82,83] . To enhance the anti-tumor activity, several studies
on combined immune checkpoint blockades are being conducted [Table 3]. The most relevant combination
is a CTLA-4 and PD-1/PD-L1 blockade . The rationale of this strategy is based on the idea that if CD8+
[28]
CTL do not exist in cancer tissue, blockade of the PD-1/PD-L1 pathway cannot be expected to be efficacious.
Therefore, blocking CTLA-4 may be an effective strategy to increase the number of activated effector T cells
[20]
that infiltrate the tumor tissue . Durvalumab, a monoclonal antibody to PD-L1, is currently evaluated
in combination with an anti-CTLA-4 antibody (tremelimumab) for sorafenib-experienced HCC patients
[83]
in a phase II trial (NCT02519348) . Another anti-CTLA-4 antibody, ipilimumab, is also being analyzed
in combination with the anti-PD-1 antibody, nivolumab, for evaluation of the safety and efficacy in HCC
[20]
patients (NCT01658878, NCT03222076) .
Given the fact that molecular target agents could collectively block the signaling from various growth
factors and affect immune effectors and the vasculature, the combination of TKIs and immune checkpoint
inhibitors could reactivate the immune response to HCC [28,84] . Several early phase studies are currently
underway to explore the safety and tolerability of TKIs such as sorafenib (NCT03211416, NCT01658878,
NCT02988440), lenvatinib (NCT03418922, NCT03006926), cabozantinib (NCT03299946, NCT01658878),
axitinib (NCT03289533), and capmatinib (NCT02795429) in combination with immune checkpoint