Page 105 - Read Online

Page 4 of 12 Zhang et al. Hepatoma Res 2020;6:40 I http://dx.doi.org/10.20517/2394-5079.2020.20

clinical data suggest that both CTLA-4 and PD-1/PD-L1 blockade a portion of HCC patients. Compared to
CTLA-4 blockade, PD-1 and PD-L1 blockade showed relatively higher ORR, which could reach 10%-20%
in advanced HCC patients. PD-1/PD-L1 blockade agents were more tolerable and less hepatoxic. Further
studies for combined PD-1/PD-L1 and CTLA-4 blockades in HCC treatment are still expected, which
may help to mitigate the adverse effects of the treatment. Immune checkpoint blockade in advanced HCC
combined with other conventional ablative treatments, such as radiofrequency ablation (RFA) or microwave,
TACE, chemotherapy, targeted medicine, or surgery would be the most promising approach for HCC
patients. However, for unresectable advanced HCC, it is more appropriate to search for other combination
strategies, such as the combination with multi-kinase inhibitors, vaccines, and oncolytic viruses, as well as
dual inhibition of two immune checkpoint molecules.

Based on current evidence, combination therapies with CTLA-4 are now an expected direction for the
immunotherapy of advanced HCC patients in the future. A Phase III study (NCT03298451) of durvalumab
with or without tremelimumab vs. sorafenib in patients of advanced HCC enrolled about 1,350 patients
and explored two treatment schedules. Given the limited data to date, further testing of this combination is
ongoing in a Phase II expansion. Most ongoing clinical trials have been designed to assess the efficiency of
the combination strategies.

CAR-T CELL THERAPY
CD19 targeted CAR-T immunotherapy is an expecting therapeutic option that has shown high efficacy in
[55]
treating hematologic malignancies . Moreover, a great number of CAR-T cell products in solid tumors
[56]
has also been investigated in preclinical and clinical studies. In 2008, Wilkie et al. reported for the
[56]
first time that MUC1 targeted CAR-T could significant delay tumor growth in solid tumor . The basic
principle of CAR-T cell therapy is the modification of T cells with CARs, so that they can identify tumor
cells, and then the retransfusion of these CAR-T cells into the human body to fight against the target
cells [57,58] . Several studies have found that GPC3-targeted CAR-T cell therapy can eliminate HCC cells in
preclinical research [59-61] . GPC3 is a 70-kDa heparan oncofetal proteoglycans that is located on the tumor cell
[62]
membrane . It has been demonstrated that GPC3 is detected in HCC tissues with higher expression but not
[63]
in normal tissues . A Phase I trial (NCT02395250) of 13 Chinese GPC3-positive HCC patients illustrated
[64]
the safety and preliminary efficacy of GPC3 CAR-T cells in 2017 . According to the patient’s tolerance, the
preliminary analysis showed that GPC3 targeted CAR-T combined with the lymphodepleting conditioning
[64]
had a certain efficacy . The pre-clinical studies for dual-targeted CAR-T cells co-expressing GPC3 CARs
and GPC3-specific CAR-modified T cells fusing a soluble PD1-CH3 fusion protein showed promising
results [60,61] .

α-fetoprotein (AFP) has been used not only as a biomarker for surveillance and diagnosis of HCC, but
[65]
also as a target for immunotherapy . In a clinical trial of 15 HCC patients who were given a subcutaneous
injection of AFP-derived peptides, 1 patient had a complete response and the disease stabilized in 8
[66]
patients . AFP, an intracellular/secreted protein, can generate AFP peptide-major histocompatibility
[67]
complex (MHC) complexes as targets for CAR T-cell therapy for solid tumors. Liu et al. detected that AFP-
targeted CAR-T cells showed significant antitumor capacity in a mouse model Additionally, AFP-derived
vaccines can augment the activity of ICIs, leading to deterioration of HCC.

The experience from successful clinical studies of hematologic malignancies provides us with the
understanding that, although selection of the specific antigen to avoid off-target or on-target/off-tumor
toxicity is a primary task to be tackled, for HCC, the challenge of CAR-T is the need to ascertain a
specific neoantigen and overcome the TME, gut microbiome, and HCC genomic features. Furthermore,
the activation, proliferation, and persistence of CAR-T are more important for therapy. In addition,
standardization in the production of CAR-T and achieving individualized treatment should be considered.