Page 77 - Read Online

Page 12 of 18 Lee et al. Hepatoma Res 2018;4:51 I http://dx.doi.org/10.20517/2394-5079.2018.78

investigating pembrolizumab monotherapy in patients with advanced HCC who were previously treated
with sorafenib, were presented at the 2018 Gastrointestinal Cancers Symposium. Results showed the ORR
of 16.3% (95% CI, 9.8%-24.9%; n = 17/104) with CR of 1% (95% CI, 0.0%-5.2%) and PR of 15.4% (95% CI, 9.1%-
23.8%). The DCR was 61.5% (95% CI, 51.5%-70.9%; n = 64/104) and median PFS time was 4.8 months (95% CI,
3.4-6.6 months), with a 6-month PFS rate of 43% and 6-month OS rate of 78%.

Furthermore, a clinical trial of monotherapy agents targeting PD-L1, such as avelumab, has also been
conducted in advanced HCC patients (NCT03389126) .
[28]

The CTLA-4 pathway
Tremelimumab is an IgG2 type anti-CTLA-4 antibody that was evaluated in a phase II clinical trial
(NCT01008358) investigating the tremelimumab monotherapy in 21 patients with HCV-related HCC .
[80]
This study with tremelimumab in HCV infected HCC patients has shown a good safety profile along with
a promising PR rate of 17.6% and a time-to-progression (TTP) of 6.5 months . In this CTLA-4 trial, a
[80]
transient complete virologic response or decrease in HCV viral load was also observed in most patients with
the DCR of 76.4% [28,80] . The trial demonstrated efficacy of tremelimumab monotherapy in HCC patients and
the anti-tumoral and antiviral effects that warrant further investigation.

Notably, the feasibility of combined locoregional therapies and tremelimumab administration was
investigated in patients with liver cirrhosis and HCC . The use of tremelimumab plus RFA, cryoablation, or
[81]
TACE in patients with BCLC B or C HCC was associated with ORR of 26.3% in areas outside of the ablation
zone, and median TTP was 7.4 months. The combination of tremelimumab with local tumor ablation is
a smart synergistic mechanism, because, in patients responding to local ablative therapy, prolonged TTP
gives time for immunotherapy to unfold . In addition, local tumor ablation releases TAA from apoptotic
[72]
or necrotic HCC tissue, which in turn accelerates tumor specific APCs and CTLs activation, resulting in
immunological synergy evolving from the combination of both treatment modalities [Figure 1]. Also, in this
study, 12 of 14 patients with quantifiable HCV experienced a marked reduction in viral load, especially in the
patients with PR. Studies have shown that tremelimumab in combination with tumor ablation is a potential
[81]
new treatment for patients with advanced HCC . Particularly, the positive antiviral immune responses may
act as a surrogate for disease control in HCC immunotherapy .
[72]

In summary, immune checkpoint blockade therapy (anti-PD-1 and anti-CTLA-4) had a favorable safety
profile in patients with HCC . It can be used safely in patients with HBV and HCV infection, and its high
[20]
ORR was a great achievement compared to the rates achievable with other types of immunotherapy .
[28]
Other immune checkpoint pathways
Although anti-PD-1/PD-L1 antibody is a promising agent for the treatment of HCC, a considerable percentage
of HCC patients could not attain satisfactory tumor control, likely due to the immune suppressive cellular
components, humoral mediators, and diverse inhibitory checkpoint molecules [28,82] . Their crosstalk becomes
more complex during tumor progression. Also, the continuous production of cytokines and chemokines in
the inflamed liver and solid immunosuppressive stroma of HCC could induce the production of many types
of suppressive checkpoint molecules [83,84] .

Cellular components including MDSCs, TAMs, Tregs and type 2 helper T cells might facilitate the immune
evasion of HCC tumor cells [20,83] . MDSCs also produce transforming growth factor (TGF)-β and IL-10 that
lead to the suppression of CD56+ NK cell and CD8+ CTL activities . TGF-β from MDSCs induces the
[85]
expression of T-cell immunoglobulin and mucin-containing protein-3 (TIM-3) on TAMs, which is associated
with galectin-9 and further facilitates the M2 polarization of macrophages in tumors . Galectin-9, which
[86]