Page 28 - Read Online

Feng et al. Hepatoma Res 2021;7:3 I http://dx.doi.org/10.20517/2394-5079.2020.107 Page 9 of 15

CHIMERIC ANTIGEN RECEPTOR T CELL THERAPY
In addition to immune checkpoint inhibitors, oncolytic viruses and vaccines, adoptive therapy using
genetically modified T cells have also become one of the potential immunotherapy options for HCC. T cells
can be engineered to express a chimeric antigen receptor (CAR), which is composed of a T cell receptor
CD3ζ chain and co-stimulatory receptors (e.g., CD28 and TNFRSF9) to form an antigen recognition
[90]
domain . The antigen recognition domain endows CAR-T cells with specificity for tumor-associated
antigens, which shows promise in the treatment of HCC. Besides, CAR-T cells have a strong adaptive
immunity and can recognize antigens that are not present in MHC molecules. CAR-T cell therapy has
been used in the preclinical treatment of a variety of solid tumors, but there are few clinical studies on
HCC, and more are still in the preclinical research stage. Like the HCC vaccine, the technical difficulty lies
[91]
in the choice of tumor-specific antigens . CD133 is expressed by cancer stem cells derived from various
epithelial cells and is an attractive cancer treatment target. CAR-T cells targeting CD133 have shown the
[92]
feasibility of treating advanced HCC, with controllable toxicity and effective activity . Glypican-3 (GPC3)
is a member of the heparan sulfate glycoprotein family and belongs to a transmembrane glycoprotein. It
plays an important role in cell proliferation, differentiation and metastasis. CAR-T cells targeting glypican-3
[95]
can inhibit the growth of HCC [93,94] . Besides, there are HCC recognition antigens such as NKG2D
[96]
and CD147 for CAR-T cell transformation. In addition, the CAR of CAR-T cells can be inserted into
the expression of a variety of cytokine genes to overcome the immunosuppressive effects of the HCC
microenvironment [97,98] . The clinical trials of CAR-T cell therapy for liver cancer are summarized in Table 5.

THE CURRENT COMBINATION OF THERAPEUTIC STRATEGIES FOR HCC
Currently, there are many immunotherapy and other target therapy drugs approved by the Food
and Drug Administration (FDA) of The United States of America (USA) for liver cancer treatment,
including Atezolizumab, Avastin (Bevacizumab), Bevacizumab, Cabometyx (Cabozantinib-S-Malate),
Cyramza (Ramucirumab), Keytruda (Pembrolizumab), Lenvatinib Mesylate, Lenvima (Lenvatinib
Mesylate), Nexavar (Sorafenib Tosylate), Nivolumab, Opdivo (Nivolumab), Pemazyre (Pemigatinib),
Pembrolizumab, Pemigatinib, Ramucirumab, Regorafenib, Sorafenib Tosylate, Stivarga (Regorafenib),
Tecentriq (Atezolizumab). Single agent therapy has historically shown poor results in HCC, leading to
trials of combination therapy for a more efficacious outcome. For example, the FDA has approved Opdivo
(nivolumab) + Yervoy (ipilimumab) based on the CheckMate 040 trial, atezolizumab + bevacizumab
for patients with advanced HCC based on the IMbrave150 (NCT03434379) study. The CheckMate 040
is a multicentered, open-labelled, multicohort, phase 1/2 study. The result showed that nivolumab +
ipilimumab had manageable safety, promising objective response rate, and durable responses. The arm A
regimen (4 doses nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks then nivolumab 240 mg every
[99]
2 weeks) received accelerated approval in the US based on this study . The IMbrave150a study is a global,
open-labelled, phase 3 trial for patients with unresectable HCC who had not previously received systemic
treatment. The study included 336 patients in the atezolizumab + bevacizumab group and 165 patients in
the sorafenib group. The result showed that atezolizumab + bevacizumab resulted in better overall (overall
survival at 12 months was 67.2% vs. 54.6%) and progression-free survival (6.8 months vs. 4.3 months)
outcomes than sorafenib [100] . There are many different combinations of immune checkpoint inhibitors
with other different therapeutic strategies under investigation. Some of the combination clinical trials are
concluded in the Table 1.

CONCLUSION AND PROSPECT
Immunotherapy is a revolution in HCC treatment. Significant responses have been observed in various
tumor types with immunotherapy, especially immune checkpoint inhibitors and CAR-T cells. However,
it is clear that not all HCC patients are sensitive to current immunotherapy, and even in those who
do respond, the effect is difficult to last. Lots of data indicate that most HCCs are immunosuppressive