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Page 8 of 14 Monge Bonilla et al. Hepatoma Res 2020;6:68 I http://dx.doi.org/10.20517/2394-5079.2020.58

CELL-BASED IMMUNOTHERAPY
There are several cell-based immunotherapies being studied in patients with advanced HCC, including
chimeric antigen receptor T (CAR-T) cells, cytokine-induced killer cells (CIKs) and T cell receptor (TCR)-
engineered T cells.

Proteins found in HCC currently being investigated as targets in CAR-T cell research in early stage studies
include GPC3 (NCT02905188, NCT03084380, NCT03130712, NCT03198546, and NCT03302403), AFP
(NCT03349255), EpCAM (NCT03013712), c-Met/PD-L1 (NCT03672305), MUC-1 (NCT03198546), and
DR5, c-Met or EGFRvIII (NCT03638206). The earliest study in CEA positive liver metastases treated with
CAR-T cells was reported in a phase I trial. Anti-CEA CAR-T administered through hepatic artery infusion
[94]
with or without systemic IL-2 treatment resulted in one case of stable disease (SD) . HCC patients were
not included, however. A phase I trial with anti-GPC3 CAR-T cells for relapsed or refractory GPC3-
positive HCC showed one PR and three SD observed among 6 patients, respectively. No dose-limiting
[95]
toxicity was identified and only one grade 3 fever was reported .
Cytokine-induced killer cells (CIKs) are a mixture of heterogeneous immune cells generated by the ex vivo
expansion of peripheral blood mononuclear cells with the support of IL-2, IFNg, and anti-CD3 monoclonal
antibodies. A randomized phase II trial in treatment-naïve patients with HCC (over 50% patients had
[96]
HBV infection) demonstrated that CIK therapy prolonged OS and PFS, compared to standard of care .
A multicentre open-label randomized phase III trial in patients with HCC after curative treatment
demonstrated that CIK therapy prolonged recurrence-free survival and OS, though a significant proportion
of patients with CIK infusion developed adverse events. In this trial, CIK infusion seemed to benefit
the HBV-infected population (over 80% of the patient population) more than the HCV-infected or the
[97]
uninfected group. No information of hepatitis flares or conversion was reported .
TCR-engineered T cells are generated by integrating a cloned tumour antigen-specific TCR into T cells.
Phase I trials are currently evaluating genetically modified T cells expressing AFP-specific TCRs in patients
with advanced HCC (NCT03132792) and an autologous TCR-engineered T cell therapy targeting MAGEA1
in solid tumours including HCC (NCT03441100). Since HBV-DNA integration is often seen in HBV-
related HCC, cell based therapy studies in HCC have looked into the possibility of using the HBV antigens
expressed in HCC cells as a target for autologous TCR redirected therapy [98,99] . Vector-mediated gene
transfer may be a means to introduce HLA-A2-restricted, HBV-specific TCRs into T cells of chronic HBV-
and HBV-related HCC patients. Through TCR gene transfer, it has been demonstrated that TCR transduced
T cells have the capacity of recognizing HCC cell lines expressing HBV antigens. This data showed that
HBV-specific T cell clones cause apoptosis of HCC tumour cells that express the HBV X protein, proving
that HBV proteins are identified by the immune system as non-self-tumour antigens [100] . Nevertheless,
HBV antigens were expressed in HCC metastases and there is published evidence of the recognition of
tumour cells by lymphocytes engineered to express HBV-specific receptor TCR with HCC autologous T
cells genetically modified to express and HBV-specific TCR and treat chemo-resistant metastatic HCC .
[101]
These findings suggest that autologous TCR therapy redirected against HBV-associated HCC may have
therapeutic potential in the future.

VACCINES
Vaccines against HBV and HCV reduce the likelihood of developing HCC. Vaccine therapy in HCC is an
area of important on-going research with the goal of improving the immune response against malignant
cells through tumour specific antigens and subsequent T cell activation [102] . Clinical study protocols
including different stages of HCC have been conducted by the Cancer Vaccine development for the HCC
Consortium (HEPAVAC) [103] .