Page 63 - Read Online

Ni et al. Hepatoma Res 2020;6:25 I http://dx.doi.org/10.20517/2394-5079.2020.14 Page 3 of 12
[7]
can be used to treat advanced HCC in patients previously on sorafenib as second line treatment . HCC
however, shows relatively low responsiveness to PD-1/PD-L1 inhibitor antibodies with an objective
[14]
response rate of only around 20% .
Factors regulating and predictive of the response to anti-PD-1/PD-L1 immunotherapy in HCC are still
largely unknown. To test whether PD-L1 expression on tumor cells can serve as a biomarker for PD-1
[15]
blockade therapy, Ou et al. used a mouse liver cancer cell line BNL-MEA transfected with a PD-L1
plasmid to establish an orthotopic HCC model. Wild-type (WT) and PD-L1-expressing tumor-bearing
mice were then treated with PD-1 inhibitor antibodies. PD-L1-expressing tumors showed better response
+
to anti-PD-1 therapy than WT tumors. In addition, depletion of CD8 T cells abolished the anti-tumor
responses. Thus, PD-L1 expression in HCC cells may contribute to tumor immune evasion by suppressing
T cell function. In turn, PD-L1 expression on tumor cells can be a biomarker for PD-1 ICB in this rodent
model of HCC. However, the use of PD-L1 expression on human HCC cells as a biomarker needs to
be investigated further. In a study of HCC patients treated with anti-PD-1 antibodies, the responders’
(responding to PD-1 ICB) fecal samples exhibited higher taxa richness and more gene counts compared
to those from non-responders. During PD-1 inhibitor immunotherapy, dynamic analysis showed that
the dissimilarity of beta diversity displayed was obvious between patients from as early as Week 6.
Proteobacteria increased from week 3 and became predominant at week 12 in non-responders. The
dynamic variation in characteristics of the gut microbiome may predict immunotherapy outcomes in HCC,
which is important for disease-monitoring and treatment decision-making .
[16]
Due to the low response rate to anti-PD-1 monotherapy, combining immunotherapy has become a new
direction for future exploration in HCC treatment. Combination therapy of PD-1 ICB with targeted
therapy, CTLA-4 ICB, oncolytic immunotherapy, epigenetic modulation and radiotherapy are all worthy of
attention.

Recently, anti-PD-L1 therapy in combination with anti-VEGF antibodies demonstrated success based
on the Phase III IMbrave150 trial in 501 patients with unresectable HCC who had not received previous
systemic therapy. Participants were split 2:1 to receive the combination of anti-PD-L1 and anti-VEGF
antibody versus sorafenib. Both anti-PD-L1 and anti-VEGF were administered intravenously whereas
sorafenib is an oral medication. Patients in both arms received treatment until unacceptable toxicity
developed or when there was no longer any clinical benefit. The trial met its co-primary endpoints,
showing statistically significant and clinically meaningful improvements in overall survival (OS) and
progression-free survival compared to the standard-of-care, sorafenib. Safety were consistent with those
known for both anti-PD-L1 and anti-VEGF antibodies (ClinicalTrials.gov Identifier: NCT03434379). These
findings indicate that the PD-L1/VEGF inhibitor combination can improve the efficacy of ICB.

The combined immunotherapy of anti-PD-1 with anti-CTLA-4 is now in a phase II trial on treating
patients with resectable HCC (ClinicalTrials.gov Identifier: NCT03222076). Recently a case that achieved
complete response with such combined therapy was reported. There was correlation of clinical response
+
with increased CD8 T cell infiltration, as well as increased effector T cell clusters. The study is ongoing and
final results may contribute to a paradigm shift in the perioperative treatment of HCC .
[17]
Enhancer of Zeste Homolog 2 (EZH2) and DNA Methyltransferase 1 (DNMT1) are two components
of epigenetic modulation. In a mouse HCC model, combining anti-PD-L1 therapy with either DZNep
(EZH2 inhibitor) or 5-Azacytidine (DNMT1 inhibitor) resulted in significantly increased tumor regression
compared to epigenetic therapy or immunotherapy alone, which suggests that epigenetic modulation
[18]
might be a potential, novel strategy to enhance immunotherapy for HCC . Mechanistically, epigenetic
modulators can activate transcriptionally repressed chemokine genes and stimulate T cell trafficking into