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Page 4 of 13 da Fonseca et al. Hepatoma Res 2019;5:37 I http://dx.doi.org/10.20517/2394-5079.2019.012

CANCER VACCINES
The number of vaccine trials in HCC is limited and the results showed only a modest efficacy. The aim of
cancer vaccines is to stimulate the immune cells to recognize and attack tumor cells by managing tumor
antigens and maturated dendritic cells, which makes the connection between innate and adaptative
[31]
immune system .
In HCC, a restricted number of tumor-associated antigens has been identified. Research in HCC vaccines
[32]
mainly focus on alpha-fetoprotein (AFP) because this is usually expressed in this malignancy . Initially,
a study was conducted based on an AFP-derived peptide and was able to produce T-cell responses. In
another study, dendritic cells pulsed with a lysate of HepG2 cell line showed safety and evidence of activity
[33]
[34]
in patients with advanced HCC . El Ansary et al. also observed modest clinical responses, increasing
in CD8+ lymphocytes count and in serum interferon concentration using an autologous dendritic cell
vaccine .
[34]
The “Cancer Vaccine development for Hepatocellular Carcinoma” - HEPAVAC project has the goal of
developing strategies for a therapeutic peptide-based vaccine for HCC including both “off-the-shelf”
and personalized antigens. A multi-epitope vaccine (IMA970A) is currently under evaluation in early/
intermediate HCC patients in a phase I/II European multicenter clinical trial (NCT03203005). The actual
study start date was September-2017 and the completion date is expected to be on January-2020.

Combination of dendritic cell infusion following trans-catheter hepatic arterial embolization was shown to
be safe and to enhance tumor-specific responses more effectively than embolization alone, but recurrence
[35]
was not completely prevented .

The PHOCUS trial, aimed to compare an oncolytic vaccine virus armed with granulocyte-macrophage
colony stimulating factor gene (JX-594) to sorafenib halted patient enrollment following a planned interim
futility analysis that conclude that the trial was unlike to meet its primary endpoint of overall survival in
[36]
the final analysis . This oncolytic vaccine virus is also in a phase I/II trial in combination with nivolumab
in first-line treatment of advanced HCC (NCT03071094).

Up to now, no HCC vaccine is approved for clinical use. Further research on development and applicability
of this strategy, together with the completion of the active trials is warranted.

CELL-BASED IMMUNOTHERAPY
Several approaches involving cell-based treatments are being evaluated in HCC. Briefly, this modality
consists of the use of autologous effector cells that are manipulated, expanded and sensitized ex vivo before
being delivered to the patient . Different types of lymphocytes, engineered T cell receptor (TCR) and
[37]
chimeric antigen receptor (CAR) composes the mainstay of cell-based immunotherapy.

[38]
In the late 1980s, Onishi et al. innovatively reported clinical responses in HCC patients treated with
a combination of IL-2 and lymphokine-activated killer (LAK) cells showing a favorable safety profile .
[38]
[39]
However, further studies with LAK cells showed conflicting results in terms of efficacy .
The post-operative use of isolated and expanded tumor-infiltrating lymphocytes is a promising strategy in
HCC. In a study with 12 patients submitted to surgery, this therapy was associated with decreased recurrence
[40]
rates at 6 and 12 months after resection comparing to a control group . Cytokine-induced killer (CIK) cells,
which comprises a mixture of T lymphocytes (CD3+/CD56+ cells, CD3-/CD56+ NK cells and CD3+/CD56-
cytotoxic T cells) provided longer progression-free survival (PFS) after HCC resection in a randomized trial