Prospects for immunotherapy as a novel therapeutic strategy against hepatocellular carcinoma

Table 1 Review of clinical trials of immune checkpoint inhibitor therapy and glypican-3-based immunotherapy in patients with hepatocellular carcinoma

Immunotherapy			Title	Trial no.	Phase	n	Primary endpoint	Result	Status	Ref.
GPC3-based immunotherapy
	GPC3 peptide vaccination
		HLA-A 24:02–restricted GPC3298–306 peptide vaccine, and HLA-A 02:01–restricted GPC3144-152 peptide vaccine	Phase I trial of a glypican-3-derived peptide vaccine for advanced HCC	UMIN000001395	I	33	The safety and immune ; response to GPC3 vaccination	Well-tolerated. The GPC3 vaccine induced a GPC3-specific CTL response in 90.1% patients (30/33)	Completed	[29]
		HLA-A 24:02–restricted GPC3298–306 peptide vaccine, and HLA-A 02:01–restricted GPC3144-152 peptide vaccine	Immunological efficacy of glypican-3 peptide vaccine in patients with advanced HCC	UMIN000005093	I	11	The frequency of peptide-specific ; CD8+ T-cells in PBMCs and infiltration into the tumor after vaccination	The number of peptide-specific CD8+ T-cells in PBMCs increased in 9 out of 11 cases. In 3 cases, they infiltrated into the tumor after the vaccination	Completed	[78]
		HLA-A 24:02–restricted GPC3298–306 peptide vaccine, and HLA-A 02:01–restricted GPC3144-152 peptide vaccine	Phase II study of the GPC3-derived peptide vaccine as an adjuvant therapy for HCC patients	UMIN000002614	II	35	The 1- and 2-y recurrence rate	The 1- and 2-yr recurrence rates were 24.4% and 53.7%, respectively	Completed	[80]
	Anti GPC3 antibody
		GC33	First-in-man Phase I study of GC33, a novel recombinant; humanized antibody against GPC3, in patients with advanced HCC	NCT00746317	I	20	Tolerability and tumor response	Well-tolerated. The median TTP was 26.0 wk in patients with GPC3-high HCC	Completed	[73]
		GC33	Japanese phase I study of GC33, a humanized antibody against GPC3 for advanced HCC	Japic CTI-101255	I	13	Determined maximum tolerated dose of GC13	Well-tolerated for GC33 dose of 20 mg/kg in Japanese patients with HCC	Completed	[74]
		GC33	-	NCT01507168	II	185			Ongoing	-
		Anti-GPC3 CAR-T based GC33	-	NCT02395250	I	13			Ongoing	-
Immune checkpoint inhibitor therapy
	Anti-PD-1 antibody
		Nivolumab	Nivolumab in patients with advanced HCC: an open-label, noncomparative, phase 1/2 dose escalation and expansion trial	NCT01658878	I /II	262	Safety, tolerability, and clinical efficacy, including ORR, DCR, DOR, and PFS	ORR was 20%. DCR was 64% (CR and PR; 3 and 39 cases). The median DOR and PFS was 9.9 and 4.0 mo, respectively	Completed	[94]
		Nivolumab	-	NCT02576509	III	726			Ongoing	-
		Pembrolizumab	Pembrolizumab in patients with advanced HCC previously treated with sorafenib: non-randomised, open-label phase 2 trial	NCT02702414	II	104	Clinical efficacy, including ORR, DCR, DOR, and PFS	ORR was 16.3%. DCR was 61.5% (CR and PR; 1 and 16 cases). The median DOR and PFS were 2.1 and 4.8 mo, respectively	Completed	[96]
		Pembrolizumab	-	NCT02702401	III	408			Ongoing	-
		Pembrolizumab (with Lenvatinib)	-	NCT03006926	I	104			Ongoing	-
	Anti-CTLA-4 antibody
		Tremelimumab	A clinical trial of CTLA-4 blockade with tremelimumab in patients with HCC and chronic hepatitis C	NCT01008358	II	21	Clinical efficacy, including ORR, TTP, and OS	PR (n = 3) and SD (n = 10) rate were 17.6% and 58.8, respectively. The median TTP and OS were 6.48 and 8.2 mo, respectively	Completed	[97]
		Tremelimumab (with RFA or TAE)	Tremelimumab in combination with ablation in patients with advanced HCC	NCT01853618	II	32	Clinical efficacy as adjuvant therapy after RFA or TAE	PR rate was 26%. The median TTP and OS were 7.4 and 12.3 mo, respectively	Completed	[101]
		Tremelimumab (with Durvalumab)	-	NCT02519348	II	144			Ongoing	-

GPC3: Glypican-3; CAR-T: Chimeric antigen receptor modified T cells; PD-1: Programmed cell death-1; CTLA-4: Cytotoxic T-lymphocyte-associated protein-4; RFA: Ragiofrequency ablation; TAE: Transcatheter arterial emboliazation; HCC: Hepatocellular carcinoma; ORR: Objective response rate; DCR: Disease control rate; DOR: Duration of response; PFS: Progression free survival; TTP: Time to progression; OS: Overall survival; PBMC: Peripheral blood mononuclear cell; CR: Complete response; PR: Partial response; SD: Stable disease; CTL: Cytotoxic T lymphocyte.