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Monge Bonilla et al. Hepatoma Res 2020;6:68 I http://dx.doi.org/10.20517/2394-5079.2020.58 Page 9 of 14

Both RNA and peptide-based vaccines are under investigation. A phase I/II trial for advanced solid
tumours including HCC treated with NCI-4650, an mRNA-based vaccine, was terminated due to slow
accrual (NCT03480152). Peptide-based vaccines for HCC utilize shared TAAs. A phase I trial evaluated the
anti-tumour efficacy of an AFP-derived peptide vaccine subcutaneously injected in 15 patients with HCC;
10 HCV and 2 HBV infected patients. The study showed that the vaccine was well tolerated and 33% of the
patients had an AFP-specific cytotoxic CD8+ T cell response. One patient had a CR for over 2 years and 8
[104]
patients had stable disease . GPC3 is another antigen that is highly expressed in HCC. In a phase I trial
of 33 patients (8 HBV and 15 HCV infected), the GPC3 peptide vaccine was well tolerated and induced
a GPC3-specific T cell response. There was one PR (HCV infected) and 19 showing SD. GPC3-specific T
[105]
cell frequency correlated with OS while higher GPC3-specific T cell frequency showed longer OS . The
additional PD-1 blockade seemed to augment the efficacy of the GPC3 vaccine by increasing the number
of vaccine-induced cytotoxic T lymphocytes [106] . A phase II trial of a TERT-derived peptide vaccine in
combination with low dose cyclophosphamide showed no effective antitumor response in 40 advanced
HCC patients [107] . A study utilizing IMA970A with CV8102 vaccines has completed but the results have
not yet been published (NCT03203005). Current vaccine trials include the hepcortespenlisimut-L vaccine
(NCT02256514, NCT02232490), pneumonia vaccine (NCT03942328), heat shock protein-peptide complex
vaccine (NCT04206254), Quilt-2.025 NANT neoepitope yeast vaccine (NCT03552718), DNAJB1-PRKACA
fusion kinase peptide vaccine (NCT04248569), personalize DC vaccine (NCT03674073, NCT04147078)
and multiple signals loaded DC vaccine (NCT04317248). The results of these trials will be instructive for
the next generation of vaccine trial design.

ONCOLYTIC VIRUSES
Oncolytic viruses have attracted lots of attention with the hope of tumour eradication through selective
[108]
direct viral replication within tumour cells and activation of cell‐mediated, tumour‐specific immunity .
For example, JX‐594 (Pexa‐Vec, pexastimogene devacirepvec), derived from a strain of vaccinia, has been
studied in HCC [109,110] . In a randomized phase 2 study with 20% HCV infected and 40% HBV infected
patients among the 40 enrolled participants, JX-594 resulted in one CR and three PR [109] . Nevertheless, it
also showed high-dose JX‐594 doubled OS to 14.7 months from 6.7 months in the low-dose treatment
group. All patients in the study experienced minimal TRAEs. In contrast, a phase 2b trial in 129 HCC
patients in the second line setting, including 51.1% HBV- and 14.0% HCV-infected, did not show an OS
benefit among 129 patients, compared to those treated with best supportive care . Patients are presently
[111]
being recruited for a clinical trial to test JX-594 with nivolumab (NCT03071094) and with sorafenib
(NCT02562755), for treatment of advanced HCC as a first-line treatment.

FUTURE DIRECTIONS
HCC is a heterogenic disease in terms of aetiology. HBV or HCV infection add to the complexity of the
immune response in HCC. There are emerging data to illuminate the immune landscape, pathway, and
mutation profiles of HCC that may provide aetiology-directed study design to obtain the best combination
with immunotherapy in the future. Information about the specific immune and genetic landscape of HCV-
related HCC is limited, however. In addition, the availability of reported response outcome from patients
with different aetiologies in completed clinical trials would provide important data. The ultimate goal is to
create aetiology-specific or even personalized therapies for HCC patients.

Furthermore, the schedule and sequence of this combination approach needs further evaluation to
determine the optimal timing in order to obtain maximal tumour-directed immunological cell killing,
whilst avoiding off-target effects. With more evidence available from other cancer types, especially
haematological malignancies, utilizing a maintenance strategy versus moving to a first line or neoadjuvant
approach for curative therapy in early HCC is also an interesting topic. In addition, along with the