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Page 6 of 15 Missale et al. Hepatoma Res 2018;4:22 I http://dx.doi.org/10.20517/2394-5079.2018.72

Adoptive cell transfer
Adoptive transfer of autologous cytokine activated killer cells (CIK) has been one of the first immunothera-
peutic approaches [122] . Anti-CD3 antibodies in the presence of IL-2, IL-1 and IFN-γ expand and activate ex
vivo NKT-cells that are reinfused in the patient. This approach has been performed as adjuvant treatment in
patients undergoing liver resection for HCC or percutaneous ablative treatments like percutaneous ethanol
injection (PEI) or transarterial chemo-embolization (TACE). A systematic review of phase II and III stud-
ies conducted in patients undergoing CIK infusion either alone or associated with resection, PEI or TACE,
showed a significant effect on overall and progression free survival [123] . More recently a randomized con-
trolled trial of adjuvant CIK was conducted in patients undergoing curative liver resection showing a signifi-
cant effect on TTR but no effect on DFS and OS [124] . Another randomized phase 3 study from Korea could
demonstrate that patients receiving CIK post-resection, PEI or radiofrequency thermal ablation (RFA) had
a significantly increased recurrence-free and overall survival [125] . Several other studies with similar method-
ological approach are ongoing in patients with HCC and other solid tumors.

Cancer vaccines
More than 15 years ago, discovery of TAAs raised enthusiasm on their possible use for vaccination strate-
gies. Several different approaches have been employed from tumor lysates to individual epitopes associated
with different adjuvants by parenteral route (subcutaneous, intradermal or intravenous), or intratumoral in-
jection. Alternatively DCs pulsed with synthetic peptides or transfected with RNA vectors have been used to
expand tumor-specific T-cell response. Target antigens for HCC have been cancer testis TAAs like MAGE,
synovial sarcoma X breakpoint 2 (SSX-2) and NY-ESO-1, beside GPC-3, human telomerase reverse tran-
scriptase (TERT), carcinoembryonic antigen (CEA) and AFP. Clinical trials have been conducted in patients
with advanced or non-resectable HCC or as an adjuvant treatment in patients undergoing resection or RFA
or TACE. Efficacy in these studies has been limited. Phase II studies with antigen-pulsed DCs [126] , intrader-
mal GPC-3 peptide [127] , or intravenous tumor (HepG2 cell line) lysate-pulsed DCs [128] have been conducted
showing partial response associated with antigen-specific T-cells responses in PBMCs in some patients. In
particular, antigen-pulsed DCs vaccination [126] showed no tumor recurrence up to 24 weeks in 9 out of 12
treated patients. Phase I GPC-3 studies achieved their aims: safety, immunogenicity and dose finding, how-
ever phase II studies with GPC-3 aimed at relapse prevention after curative treatments (surgery or RFA)
failed to achieve clinically relevant results [129,130] . Infusion of autologous DCs pulsed with lysate of HepG2 cell
line was performed in a phase II trial in patients with advanced HCC. Clinical response (either stable disease
or partial response) was shown in 28% of patients performing at least three infusions. Treatment was safe
and antigen-specific immune response could be demonstrated in some patients [128] .

A particular vaccination strategy has been conducted with an oncolytic, genetically modified vaccinia virus
(JX-594) that has been injected in the tumor lesions of advanced HCC patients. The rational of this approach
is the release of tumor antigens from oncolytic tumor cells destruction associated with local expression of
granulocyte-macrophage colony stimulating factor (GM-CSF), an inserted gene of the genetically modi-
fied vaccinia. JX-594 has been tested in a dose finding study showing improved overall survival in patients
receiving a higher infectious dose compared to lower dose [131] . A phase II trial failed to achieve survival ad-
vantage. In this trial however HCC patients were very advanced having progressed to sorafenib treatment.
A phase III randomized clinical trial (NCT02562755) is now ongoing, comparing patients on sorafenib to
patients undergoing three vaccination rounds followed by sorafenib treatment.

Table 1 represents a summary of completed clinical trials based on adoptive cell transfer and vaccines.

Cell therapy
More efficient adoptive cell transfer immunotherapeutic approaches, are represented by the CAR T-cell ther-
apy which until now has been primarily used in hematologic malignancies. T cells are genetically engineered
to express chimeric antigen receptors (CARs). Autologous engineered T cells are expanded ex vivo into the