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Feun et al.                                                                                                                                                               Immunotherapy for hepatocellular carcinoma

           side effects from lymphodepleting chemotherapy,    surface. This molecule is overexpressed in 80% of
           cytokine release syndrome, and possible autoimmune   HCC and when present, carries a poor prognosis. [48,49]
           toxicities. Car-T-cell treatment has been successful   Not only is it a prognostic factor and important for cell
           to treat various hematologic malignancies including   proliferation by stimulating Wnt signaling, but it is a
           lymphoid leukemia and acute myeloid leukemia.      tumor specific and becomes an attractive target as a
                                                              tumor antigen. [50]  Clinical trials have started with both
           Adding checkpoint inhibitor to sorafenib therapy is also   peptide-based vaccine [51]  or anti-GPC3 antibodies. [52,53]
           reasonable. Sorafenib reduces hepatic infiltrated T regs   The phase I trial of peptide-based vaccine showed the
           by suppressing TGF-β signal. [42]  However, sorafenib   treatment was well tolerated and one partial response
                                                                                                            [51]
           has other effects which may inhibit the immune system.   and several stable disease responses were observed.
           For example, sorafenib but not sunitinib, appears to   There was a correlation between overall survival and
           have a detrimental effect on dendritic cell phenotype   GPC-3 specific CTL response. Two recent phase I
           and can inhibit cytokine secretion, migration ability   studies of antibody therapy against glypican-3 were
           and T-cell stimulatory capacity, while not affecting the   reported recently. [52,53]  In the first study, a recombinant,
           function and phenotype of T-cells.  Sorafenib has been   humanized monoclonal antibody against GPC3 was
                                        [43]
           shown to inhibit JAK-STAT signal transduction in human   performed in advanced HCC. [52]  There were no dose-
           immune cells. [44]  The immune effects of sorafenib   limiting toxicities (DLT) noted. The most common
           were dose dependent. At pharmacologic doses of     side effects include transfusion reactions (35%),
           sorafenib, the drug decreased T effector cell activation   fatigue and pyrexia and diarrhea. Stable disease
           by down regulating CD25 surface expression. At low   was seen in several patients. A phase I study of
           doses, sorafenib produced T effector cell activation,   this antibody in Japanese patients with advanced
           with significant increase in T effector cell proliferation,   HCC was performed. [53]  The most common toxicity
           IL2 secretion and up regulation of CD25 cell surface   was lymphocytopenia, natural killer cell decrease,
           expression  and  could  reduce T  regulatory  cell   C-reactive protein increase and pyrexia. Infusion
           suppression. Thus, the dose of sorafenib used may be   reactions were observed in 62% patients. No DLT or
           critical for the desired immune effects. Other actions of   maximum tolerated dose (MTD) was noted. There
           sorafenib on the immune system include: (1) inhibit NK   were no partial or complete responses but stable
           function; (2) increase MDSC; and (3) upregulate PD-L1   disease was noted in several patients. A phase I trial
           expression. In mice bearing orthotopic HCC, sorafenib   of combination of anti GC33 antibody with sorafenib
           upregulated tumor-specific T effector cell function,   in 40 patients was reported. [54]  There were 3 DLTs
           while the proportion of PD-1 expressing CD8+ T-cells   seen (grade 3 hyponatremia, grade 3 hyponatremia
           and regulatory T-cells were reduced. [45]  In addition,   and hypoglycemia and grade 3 ALT increase). One
           the function of T regulatory cells was inhibited. In   partial response and 6 stable diseases were reported.
           another study mouse and human HCC tumor samples    No MTD was obtained with combining the antibody
           expressing low pERK showed intense inflammatory    to GC33 with sorafenib at a dose of 400 mg bid daily.
           infiltrating cells and significant enrichment of CD8+ that   A phase I trial of T-cell redirecting bispecific antibody
           expressed PD-1. [46]  Patients with pERK PD-1 positive   against glypican-3 is another approach. [55]
           tumors had worse prognosis than pERK PD-1 negative
           tumors. PD-1 immunotherapy could complement        Another clinical trial for HCC starting at University
           sorafenib by targeting tumor cells resistant to sorafenib.   of Miami is the study of a bifunctional fusion protein
                                                              that will combine PD-L-1 antibody with the soluble
           Recently, PD-L1 expression in HCC was shown        extracellular domain of TGF-β receptor type II as a
           to be significantly associated with markers of     TGF-β neutralizing “trap”. This compound (developed
           tumor aggressiveness including high AFP serum      by  Merck)  will  target  two  major  mechanisms  of
           levels, satellite nodules, macrovascular invasion,   immunosuppression, PD-1/PD-L-1 axis as described
           microvascular invasion, poor histologic differentiation   previously  and TGF-β. TGF-β  is  known  to  have
           progenitor subtype (cytokeratin 19 expression). [47]   growth inhibitory effects on normal epithelial cells and
           High PD-L1 expression in immune cells in the tumor   can act as tumor suppressor in early stage cancer
           microenvironment also correlated with high serum AFP   development. Later as the tumor advances, TGF-β
           levels, macrovascular invasion, poor differentiation,   loses its ability to suppress cancer and various
           high PD-1 expression and lymphoepithelioma subtype.  cancers can actually produce this molecule which acts
                                                              as a stimulatory molecule for cell growth and division.
           Targeting glypican-3 (GPC3) immunologically is a   Then, TGF-β can downregulate the effector function of
           novel approach. GPC3 is a member of the glypican   T cytotoxic cells and natural killer cells, while inducing
           family of heparin sulfate proteoglycans on the cell   differentiation of CD4+ T-cells to T reg cells. In mice,
            48                                                                                                      Hepatoma Research ¦ Volume 3 ¦ March 22, 2017
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