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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