**4.1. Introduction**

Immune-based approaches that focus on vaccination strategies, cytokines or non-specific T cell activation have been tested for many years in HCC without promising result. However, the recent advancement in immune-oncology with the FDA approval of many immune checkpoint inhibitors, sparked a great interest in the immune-based treatment approaches for patients with HCC. The strategy of adopting an immunocentric approach to HCC treatment may be potentially more efficacious and less toxic. Interestingly, what makes the immunotherapy appealing in liver cancer is that HCC is a high immunogenic cancer, due to high blood flow with unique vast tumor antigen repertoire because of mutations and aberrant expression profiles [24]. On the other hand, there is an inherently immunosuppressive microenvironment of the liver; "Tolerogenic Liver"; that helps evade the immune response. The liver's pathway to immune tolerance is multifactorial. T-cells are stimulated through a dual signaling pathway that requires the interaction of T cell receptors (TCR) with major histocompatibility complex (MHC)/peptide complexes on antigen presenting cells (APCs) and expression of co-stimulatory molecules on T cells and APCs. Down-regulation of MHC class I molecules on tumor cells induces impairment of tumor antigen processing and presentation [25]. In addition, a reduced expression of co-stimulatory molecules, such as B7-1 and B7-2, in HCC leads to T cell anergy [26]. Programmed cell death protein-1 (PD-1) overexpression in tumors promotes immune evasion and tumor growth by suppressing T-cell response [27]. PD-L1 is not the only immunosuppressive factor in the tumor microenvironment. HCC immune evasion can also be achieved through overexpression of MHC class II molecules in tumor cells, which leads to CD4<sup>+</sup> T cell anergy in the absence of co-stimulatory molecules (CMs) on T cells and APCs. A better understanding of the antigenic profile of HCC and tumor microenvironment has helped to develop a refined immunotherapeutic strategies in treatment of HCC [28].

no HCC cirrhotic patients [34]. Moreover, there is frequent and early disease progression in patients with HCC with higher numbers of tumor-infiltrating and circulating PD-1 + CD8<sup>+</sup> T cells post hepatic resection [35]. Therefore, a supporting great rationale exists for using PD-1 and PD-L-1 blocking antibodies against HCC. Some PD-1 inhibitors, such as nivolumab,

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The CheckMate-040 phase I/II trial studied the safety and antitumor effect of nivolumab in 48 patients with advanced HCC [36]. The target population included patients with intermediate or advanced HCC and preserved liver function (Child-Turcotte-Pugh-A cirrhosis) who were candidates for systemic therapy and had progressed or were intolerant to sorafenib. In the escalation and expansion cohorts, objective tumor responses occurred in 15 and 20% of patients, respectively. There were durable responses that lasted for a median of 17 months. An additional 45% of patients had a stable disease associated with durability, lasting 6 months at minimum. Those responses were consistent across the different HCC risks, and both in

Overall, frequencies of grade 3/4 treatment-related AEs were 20%. Only 3% of patients discontinued nivolumab because of treatment-related adverse events, while no treatment-related deaths occurred. Elevated transaminases was the most frequent laboratory alteration (20%). However, only 5% of the patients had grade 3 or higher. Immune-related hepatitis requiring steroid therapy. CheckMate-040 showed that nivolumab might be effective with acceptable toxicity in HCC, regardless of hepatitis status. On September 22, 2017, and based on the outcome of CheckMate-040 study, the FDA granted accelerated approval to nivolumab for the treatment of hepatocellular carcinoma (HCC) as second-line therapy in patients who have

CheckMate-459 is an ongoing phase III study, (NCT02576509) that randomizes patients with

The efficacy and safety of pembrolizumab in HCC has been investigated. The phase I/II study KEYNOTE-224 tested pembrolizumab in 104 patients with advanced HCC who progressed on sorafenib. The overall response rate was 16.3%. Durable response was seen with 94% of responders were estimated to have a response duration of 6 months or longer. The median PFS was 4.8 months, and the median OS was not been reached. The safety profile was generally comparable to that established for pembrolizumab monotherapy in other indications,

Targeting tumor vasculature by oncolytic viruses (OVs) is an attractive strategy that offers several advantages. Oncolytic viruses are wild-type or engineered viruses that selectively target and replicate in cancer cells and cause lysis without harming normal tissues [39]. The underlying mechanism of the antitumor activity for oncolytic viruses involves direct killing of tumor cells by expanding in the cells and causing cell lysis. Different from normal cell, viruses can expand in cancer cells considerably due to the impairment of the tumor's defense mechanisms against viral infection. [40–43]. In addition,, OVs can initiate antitumor immune response by

advanced HCC to either nivolumab or sorafenib in the first-line setting [37].

pembrolizumab, and pidilizumab, have been investigated for cancer treatment.

sorafenib-naïve and sorafenib-exposed patients.

been previously treated with sorafenib.

and no viral flares were seen [38].

*4.2.2. Oncolytic immunotherapy*
