The unmet needs in the treating HCC are present at various stages (early, intermediate, and advanced stages) and in various settings, such as neoadjuvant and/or adjuvant settings before and after resection [31,32] or ablation [33,34], adjuvant settings after transcatheter arterial chemoembolization [35,36], and first- or second-line treatment for advanced HCC

The unmet needs in the treating HCC are present at various stages (early, intermediate, and advanced stages) and in various settings, such as neoadjuvant and/or adjuvant settings before and after resection [31,32] or ablation [33,34], adjuvant settings after transcatheter arterial chemoembolization [35,36], and first- or second-line treatment for advanced HCC. six (13%) had vascular invasion. Thirty-two (68%) patients had previously been treated with sorafenib, indicating that these patients had relatively advanced liver cancers. The results of an interim analysis performed on March 12, 2015, after the treatment with the anti-PD-1 antibody, showed that 17 patients remained on the study treatment, while 30 patients terminated or discontinued the treatment because of disease progression (n=26), complete response (CR) (n=2), or adverse events (AE) (n=2, for elevated bilirubin or events unrelated to the study drug). According to the Common Terminology Criteria for Adverse Events (CTCAE) grading, the only grade 4 AE was an elevated lipase level, whereas grade 3 AEs included elevated liver enzymes [aspartate aminotransferase (AST) (11%, n=5) and alanine aminotransferase (ALT) (9%, n=4)]. None of the patients developed serious liver dysfunction or autoimmune disease. The overall objective response rate was 19% (n=8), including the two GPR40 Activator 1 patients GLUR3 who achieved CR (5%). Disease control rates were 67% (n=28) for stable disease (SD) or better and 33% (n=14) for progressive disease (PD), indicating an extremely favorable study outcome (table ?(table11). Table 1 Best overall responses in 2013, described the results of a clinical trial involving patients with HCC, which showed that the incidence of side effects was slightly higher with the anti-CTLA-4 antibody than with the anti-PD-1 antibody [8,9] (table ?(table22). Table 2 Clinical trials of immune checkpoint inhibitors in HCC thead th align=”left” rowspan=”1″ colspan=”1″ Drug /th th align=”left” rowspan=”1″ colspan=”1″ HBV/HCV eligibility (patient no.) /th th align=”left” rowspan=”1″ colspan=”1″ Dosage /th th align=”left” rowspan=”1″ colspan=”1″ Results /th th align=”left” rowspan=”1″ colspan=”1″ Treatment-related grade 3C4 AE (%) /th /thead Tremelimumab (anti-CTLA-4)HCV + only (21)15 mg/kg every 90 days 4PR 17.6% (3/17) DCR 76.4% child B (42.9%) prior therapy (57.4%)AST/ALT (45), syncope (10), diarrhea (5), neutropenia (5), rash (5) hr / Nivolumab (anti-PD-1)Non-infected (24) HCV (12) HBV (11)0.1 C 10 mg/kg every 2 monthsRR 19% (2 CR, 6 PR/42) child B (2%) prior systemic therapy (100%)AST/ALT (11/9), lipase (8) anemia (2) fatigue (2) Open in a separate window DCR=disease control rate; RR=response rate. Modified with permission from El-Khoueiry AB, et al. [1) and Sangro B, et al. [8). When cancer cells develop, the tumor-associated antigens are recognized and presented by antigen presenting cells such as dendritic cells, leading to the activation of immature T-cells that become CD8-positive T-cells (cytotoxic T-cells) in the lymph nodes (priming phase). These T-cells circulate in the blood and attack cancer cells by releasing molecules such as perforin and granzymes at the tumor site (effector phase). However, T-cell receptor recognition of tumor-associated antigens leading to the attack of cancer cells by CD8-positive T-cells is associated with the binding of cytokines, particularly interferon- (IFN-) secreted by cytotoxic T-lymphocytes (CTL), to the IFN- receptor on the tumor surface. Subsequently, IFN- induces the expression of PD-L1 or PD-L2 molecules on the cancer surface, both of which bind PD-1, to escape from the CTL attack. Therefore, an IFN- signal is sent to the CTL to downregulate the antitumor GPR40 Activator 1 immune response, allowing the tumor to escape from the attack of CTLs (immune escape or immune tolerance) (fig. ?(fig.11). Open in a separate window Fig. 1 The immune checkpoint molecule PD-1 is expressed on the cytotoxic T-cell. PD1 ligands (PD-L1 and PD-L2) are expressed on the tumor surface because cytokines such as IFN- produced by CTLs bind to the IFN- receptor, which promotes the expression of the PD-1 ligands, PD-L1 and PD-L2. Interaction of PD-1 and its ligands results in immune escape by the tumor. MHC=major histocompatibility complex; TCR=T cell receptor; CD28=cluster of differentiation 28; IFNR=interferon gamma. The anti-PD-1 antibody blocks the binding of PD-1 on activated T-cells to PD-L1 or PD-L2 on the antigen presenting GPR40 Activator 1 cells or tumor cells, thus releasing the immune escape status and resulting in the recovery of the T-cell attack on tumor cells (fig. ?(fig.2).2). Unlike cytotoxic chemotherapy or molecular targeted therapy, the anti-PD-1 antibody restores the human immune system, an intrinsic powerful and precise weapon, allowing it to regain its original strength to attack and kill cancer cells [10,11,12,13,14,15,16,17,18,19,20,21]. Open in a separate GPR40 Activator 1 window Fig. 2 Immune checkpoint blockade: the anti-PD-1 antibody restores the capacity for an effective attack on the cancer cells. Another immune checkpoint inhibitor, the anti-PD-L1 antibody, functions in a similar manner [22]. In addition, PD-L1 and tumor infiltrating lymphocytes may be predictive bio-markers for the efficacy of the anti-PD-1 antibody [23]. A study suggested that the Kupffer phase of Sonazoid?-enhanced contrast ultrasonography [24] could.