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Feun et al.                                                                                                                                                               Immunotherapy for hepatocellular carcinoma

                                                              functional vector represents a novel immunotherapy
                                                              approach to treat HCC.

                                                              PD-1/PD-L1 pathway has been associated with T-cell
                                                              exhaustion in chronic hepatitis virus infection. [25]
                                                              Inhibition of T-cell activation is due to PD-1 ligation,
                                                              which causes recruitment of SHP-2 phosphatase. This
                                                              in turn inhibits PI3K activity and downstream activation
                                                              of AKt, with dampening of T-cell receptor signaling.
                                                              PD-1/PD-L-1 involvement in chronic viral infection-
                                                              associated T-cell exhaustion was first shown in a
                                                              murine lymphocytic choriomeningitis model. [26]  PD-1/
                                                              PD-L-1 blockade can produce functional recovery of
                                                              T-cells, cytokine secretion, cytotoxic capability and
                                                              decreased viral load.

                                                              IMMUNOTHERAPY TRIALS IN HCC
           Figure 1: Selected known mechanisms of immune tolerance in   Interferons
           HCC. HCC: hepatocellular carcinoma; IL-10: interleukin-10; TGF-β:
           transforming growth factor beta; PD: programmed death; CTLA:   Immunotherapy has been used for HCC in the past
           cytotoxic T-lymphocyte antigen                     with limited success. Interferon alpha was combined
                                                              with systemic chemotherapy and modest activity was
           complex and involves a balance of multiple factors   observed. In one study, 26 patients with advanced
           [Figure 1]. The factors which are involved in tumor   HCC received intravenous cisplatin, doxorubicin,
           progression include hepatic tolerance to various   and  5-fluorouracil  combined  with  subcutaneous
           antigens, chronic inflammation which predisposes   administered human recombinant α-interferon-2a
           to immunosuppression and liver cancer dependent    (PIAF regimen). [27]  The disease control rate was 50%
           immune tolerance. Poorly counter-balancing this    (4 partial responses and 9 stable disease). The 1-year
           involves antitumor immune response.                survival rate was 24.3% and median survival time
                                                              was 6.0 months. A modified PIAF showed superior
           RATIONALE FOR IMMUNOTHERAPY FOR HCC                response rate and survival compared to standard dose

           NK cells have been divided into two major groups,   PIAF. [28]  A randomized trial of PIAF versus standard
           one mainly cytotoxic and the other mainly involved   dose doxorubicin showed that PIAF had more activity
                                                                                                            [29]
           in cytokine secretion. In HCV-related hepatocellular   and greater toxicity, particularly myelosuppression.
           carcinoma a prevalent cytotoxic NK phenotype was   Since myelosuppression was greater than single
           found in HCC patients with longer time to tumor    agent doxorubicin, this treatment regimen is best for
           recurrence and overall survival. [23]  This suggests a   younger patients with good performance status and
           role for NK cells in the immune response against   adequate bone marrow reserve.
           HCC and a rationale for immunotherapy using NK
           enhancing therapy.                                 Checkpoint inhibitors
                                                              Checkpoint inhibitors have demonstrated activity in a
           Pim kinases are downstream effector molecules      number of cancers including HCC. CTLA-4 blockade
           of certain oncogenes. Pim-3 expression occurs in   has been evaluated using Tremelimumab. [30]  In this
           certain solid tumors and is highly expressed in HCC   study the drug was given at 15 mg/kg intravenously
           tissues and cell lines. In HCC Pim-3 is associated with   every 90 days. Twenty patients were treated and 17
           acceleration of HCC development and has been found   patients were assessable for response. In these 17
           to inhibit apoptosis by phosphorylating the proapoptotic   patients, the overall response rate was 17.6% and
           BH3-only protein BAD. A dual-function vector with   disease control rate was 76.4%. The median time
           both immunostimulatory and Pim-3-silencing effects   to tumor progression was 6.48 months. Toxicity was
           inhibited Hepa1-6 cell growth by regulating expression   mainly hepatic. There were > grade 3 AST and ALT
           of apoptosis-related proteins and inducing secretion   elevation in 45% patients and 25%, respectively.
           of type I interferons. [24]  NK cells, CD4+ T and CD8+   Serum bilirubin elevated occurred in 10%. Skin rash
           T-cells and macrophages were required for effective   occurred in 5%. An antiviral effect was noted. FoxP3+
           tumor inhibition and CD4+ T-cells were demonstrated   natural T reg expanded and viral hepatitis C load
           to play helper role in NK cell activation. This novel bi-  decreased.
                           Hepatoma Research ¦ Volume 3 ¦ March 22, 2017                                   45
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