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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
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