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Table 3. Selective clinical trials of combination immunotherapy agents in HCC
Antibody features Antibody name Enrollment NCT number Status
CTLA-4 and PD1 Nivolumab, ipilimumab 45 NCT03222076 Recruiting
50 NCT03203304 Recruiting
CTLA-4 + chemoembolization Tremelimumab, TACE 61 NCT01853618 Completed
CTLA-4 + PD-L1 Durvalumab, remelimumab 433 NCT02519348 Ongoing
CTLA-4 + PD-1 + anti-OX40 CTLA-4, PD-1, INCAGN01949 52 NCT03241173 Completed
CTLA-4 + PD1 + ablative Durvalumab, tremelimumab, ablative 90 NCT02821754 Recruiting
PD-1 + TIL TIL, PD-1 332 NCT01174121 Recruiting
PD-1 + neoadjuvant Nivolumab, cabozantinib 15 NCT03299946 Ongoing
Pembrolizumab, sorafenib 27 NCT03211416 Recruiting
PD-1 + oncolytic Nivolumab, Pexa Vec 30 NCT03071094 Ongoing
PD-1 + radiation Nivolumab, SIRT 40 NCT03380130 Ongoing
PD-1 + TGF-β receptor I kinase inhibitor Nivolumab, galunisertib 75 NCT02423343 Ongoing
PD-1 + TKI Nivolumab, lenvatinib 30 NCT03418922 Ongoing
Pembrolizumab, lenvatinib 104 NCT03006926 Ongoing
Nivolumab, cabozantinib 15 NCT03299946 Ongoing
Pembrolizumab, regorafenib 57 NCT03347292 Recruiting
PD-1 + radioembolization Nivolumab, yttrium-90 35 NCT02837029 Recruiting
Yttrium-90, nivolumab 40 NCT03380130 Ongoing
40 NCT03033446 Recruiting
Pembrolizumab, SBRT 30 NCT03316872 Recruiting
Pembrolizumab, yttrium-90 30 NCT03099564 Recruiting
PD-1 + chemotherapy Nivolumab, sorafenib 40 NCT03439891 Recruiting
PD-1 + immunomodulator Nivolumab, CC-122 (avadomide) 21 NCT02859324 Ongoing
PD-1 + transarterial chemoembolization Nivolumab, Ddeb-TACE 14 NCT03143270 Recruiting
PD-1 + anti-CCR4 antibody Nivolumab, mogamulizumab 114 NCT02705105 Completed
PD-1 + anti-VEGF Nivolumab, bevacizumab 1 NCT03382886 Terminated
PD-1 + curative resection Toripalimab, surgery 402 NCT03859128 Recruiting
PD-1 + curative resection or ablation Pembrolizumab 950 NCT03867084 Recruiting
PD-L1 + small molecule DNA Durvalumab, guadecitabine (SGI-110) 90 NCT03257761 Recruiting
PD-L1 + anti-VEGFR2 Durvalumab, ramucirumab (LY3009806) 114 NCT02572687 Ongoing
PD-L1 + anti-VEGF Atezolizumab, bevacizumab 430 NCT02715531 Ongoing
PD-L1 + TKI Avelumab, regorafenib 362 NCT03475953 Recruiting
Avelumab, axitinib 22 NCT03289533 Completed

HCC: hepatocellular carcinoma; SIRT: selective internal radiation therapy; VEGF: vascular endothelial growth factor; VEGFR: VEGF
receptors; SBRT: stereotactic body radiation therapy; CTLA-4: cytotoxic T lymphocyte-associated antigen-4; TIL: tumor infiltrating
lymphocytes; OX40: tumor necrosis factor receptor superfamily member 4; TGF: transforming growth factor; TKI: tyrosine kinase
inhibitor; PD-L1: programmed cell death-ligand 1; PD-1: pro-grammed cell death-1; CCR4: CC-chemokine receptor 4; TACE: transcatheter
arterial chemoembolization

+
combined use of CTLA4 and PD-L1 inhibitors can reverse the instability of CD8 T cells and enhance
intrahepatic HCV-specific CD8 and CD4 T cell cytokine response. Moreover, in the acute hepatitis C
+
phase, the combination of PD-1/CTLA-4 inhibitors can reverse HCV-specific CD8 T cell dysfunction [124] .
+
Interestingly, after the clearance of HCV, CD8 T cell proliferative ability can be restored preferentially
under the action of immune checkpoint inhibitors [125] . In addition, Stein et al. [126] combined the PD-L1
monoclonal antibody atezolizumab and bevacizumab to treat patients with advanced HCC (NCT02715531).
Moreover, the efficacy of immune checkpoint inhibitors (ipilimumab and nivolumab) combined with liver
[98]
resection is being evaluated (NCT03682276, NCT03510871) . As new adjuvant therapies, the curative
effect of checkpoint inhibitors is also being evaluated in HCC patients undergoing surgical resection (e.g.,
[98]
NCT03859128 and NCT03847428) .
Although many studies have reported that immune checkpoint inhibitors are showing encouraging results
in the treatment of HCC, there are still potentially serious adverse reactions. PD-1 inhibitors block the
interaction between PD-1 and PD-L1 and also inhibit T cells and APCs. PD-1/PD-L1 monoclonal antibodies