**4.3. Direct immunological strategy**

#### *4.3.1. Adoptive cell therapy*

triggering key signals through oncolysis to dendritic cells (DCs) and other antigen-presenting cells (APCs) [44]. OVs have some advantages over other treatment modalities, those include: the low probability of generating resistance as OVs often target multiple oncogenic pathways; OVs replicate in a tumor-selective fashion with minimal systemic toxicities; and virus dose in the tumor increases over time due to in situ virus amplification, as opposed to classical drug pharmacokinetics that decreases with time [45]. The efficacy of an evolutionary cancerfavoring engineered vaccinia virus (CVV) was investigated in an animal model of metastatic HCC. In this animal study, the subjects were randomized into sorafenib, CVV, or sorafenib with CVV. Metastatic regions were interestingly rare in the CVV-treated groups (i.e., CVV or sorafenib with CVV) whereas metastatic regions existed in the sorafenib-treated group [46].

JX-594 is a thymidine kinase gene-inactivated oncolytic vaccinia virus engineered for the expression of transgenes encoding human granulocyte-macrophage-colony-stimulating factor (GM-CSF) and β-galactosidase, which increases antitumor immune responses [39, 47–49]

Oncolytic viruses have produced enough therapeutic efficacy with great optimism in the future trials. Although the initial concerns of clinical investigators were for safety like a risk of viral infection or introduce oncogenic mutation, these have proven not to be a significant

Cancer vaccination is performed by utilizing antigenic substances to stimulate tumor-specific immune responses that can remove cancer cells and prevent recurrences. HCC vaccines

Peptide-based tumor-associated antigens (TAAs), such as alpha-fetoprotein (AFP), GPC3, SSX-2, NY-ESO-1, human telomerase reverse transcriptase (hTERT), HCA587, and melanoma antigen gene-A (MAGE-A), are excellent vaccine targets for the treatment of HCC [50].

AFP which normally originates from embryonic liver cells, can be overexpressed on HCC cell surfaces. However, immune responses to AFP are limited due to acquired immune tolerance during the development of the immune system. To overcome this tolerance, a research group investigated the use of a recombinant rat AFP to induce cross-reactions between xenografts and endogenous molecules in animals and observed modest cellular and humoral immune responses [51]. In a phase II trial of GPC3-derived peptide vaccine for HCC, 25 patients received 10 vaccinations over 1 year after surgery. The recurrence rate in patients who underwent both surgery and vaccination was significantly lower than the rate in 21 patients who underwent surgery only (24% vs. 48 and 52.4% vs. 61.9% at 1 and 2 years, *p* = 0 047 and 0.387,

DCs, were found to be the most powerful APCs in the body's immune system, and capable of stimulating naïve T cells and driving primary immune responses. A phase I/IIa comparative

respectively), demonstrating the efficacy of the GPC3-derived vaccine [52].

This virus is safe in humans and extremely toxic to cancer cells.

include cancer cells, antigen peptides, DCs, and DNA-based.

issue in these trials.

166 Liver Cancer

*4.2.3. HCC vaccines*

*4.2.3.1. Antigen peptide vaccines*

*4.2.3.2. Dendritic cell (DC) vaccines*

Adoptive cell therapy (ACT) is an immunotherapeutic approach that attacks cancer cells using genetically engineered patients' lymphocytes. It functions by stimulating or loading autologous lymphocytes with cytokines or tumor antigens, cultivating them ex vivo and then re-infusing them into the patient [55–57]. Adoptive immunotherapy for HCC includes cytokine-induced killer (CIK) cells, tumor-infiltrating lymphocytes (TILs), natural killer (NK) cells, and chimeric antigen receptor (CAR) T cells. The effectiveness and safety of ACT in patients with HCC have been studied in many experiments, which paved the road for its clinical implication.
