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da Fonseca et al. Hepatoma Res 2019;5:37 I http://dx.doi.org/10.20517/2394-5079.2019.012 Page 5 of 13
[41]
involving 150 patients, with an acceptable toxicity profile . In another randomized trial, adjuvant CIK cells
[41]
provided longer time to recurrence, but with no impact in overall survival (OS) . An open-label phase III
trial tested the efficacy of CIK cells as an adjuvant therapy after resection or percutaneous treatment. The
study included 230 patients with HCC to receive CIK cells or no adjuvant treatment. The study met its
primary endpoint, with a significant improvement in recurrence-free survival and OS with activated CIK
[42]
cells .
NK cells are also being studied in the HCC field. An ongoing phase II trial (NCT02008929) is focused on
safety and efficacy of ex vivo expanded allogeneic NK cells in patients with high risk of recurrence after
surgical resection and a second phase II trial (NCT02854839) is evaluating the role of NK adoptive cells
after trans-arterial chemoembolization (TACE).

One of the most promising cellular therapies consists in the use of CAR T cells, which combines adoptive
cellular immunotherapy with targeted therapy throughout receptor proteins that have been engineered to
give T cells ability to recognize a specific protein independent of MHC. This approach has shown positive
[43]
results when targeting CD19 via CAR for B-cell malignancies . Currently, there are active clinical trials
with CAR T cells in HCC with different target proteins, such as Glypican 3 (NCT02905188; NCT03146234
and NCT02723942). Nevertheless, a phase I/II trial with CAR-T anti-VEGFR2 (NCT01218867) in metastatic
tumors (with HCC patients allowed to be enrolled) failed to show a significant clinical activity in
preliminary results.

Antigens from hepatitis virus B (HBV) can be potentially used as a target in adoptive cellular therapy,
since HBV antigens can be found in both primary tumor and HCC metastasis. In a case report, HCC
tumor cells were recognized in vivo by lymphocytes engineered to express an HBV-specific TCR. Therefore,
[44]
this strategy has a potential to control HBV-associated HCC . An AFP directed therapy is also being
investigated in a phase I trial with autologous T cells with AFP-specific TCR in advanced HCC patients
(NCT03132792).

Considering this scenario, adoptive cellular therapies for HCC showed an acceptable safety profile and
seems to be an encouraging strategy in the adjuvant setting. However, confirmatory studies are required
and there is no sufficient evidence to support its use in clinical practice outside clinical trials.

IMMUNE CHECKPOINT INHIBITORS
A major boost in the field of immunotherapy for cancer treatment came with the advent of immune
checkpoint inhibitors (ICI). This class of drugs provided crucial improvements in the management of
[46]
[45]
several tumors, such as lung cancer , melanoma and others. The ICIs currently approved for clinical
use target either CTLA-4 or PD/PD-L1 pathways. Tremelimumab, which is an anti-CTLA4 monoclonal
antibody, was the first ICI evaluated in a clinical trial involving HCC patients. In a phase II study, 21
patients with chronic hepatitis C virus (HCV) infection not eligible for surgery received tremelimumab
15 mg/kg every 90 days for a maximum of 4 doses. A disease control rate of 76.4% was achieved, with
45% of these responses lasting more than 6 months. Few patients presented grade 3/4 adverse events and
tremelimumab was considered well tolerated. Besides, a significant drop in HCV viral load was observed
[47]
among patients enrolled in this trial .

Tremelimumab was also tested in a trial combining tumor ablation or TACE considering the hypothesis
that tumor destruction by local therapies could enhance antigenic release and stimulate a systemic immune
response. Thirty-two patients received tremelimumab every 4 weeks at two dosages (3.5 and 10 mg/kg) for a
total of 6 infusions, followed by an infusion every 3 months. The local therapy consisted of TACE in patients