Immunotherapy for hepatocellular carcinoma: Current status and future perspectives

Table 1 Immunotherapy with immune checkpoint inhibitor in hepatocellular carcinoma (clinical trial with reported results)

Treatment	Patients, n	ORR%	OS in mo	Ref.
Atezolizumab	59	17 (5)	NA	[44]
Nivolumab	371	15(4)	16.4	[21]
Camrelizumab	217	15 (0)	13.8	[165]
Pembrolizumab	278	18 (2)	13.9	[36]
Durvalumab	104	11 (0)	13.6	[46]
Tremelimumab	69	7 (0)	15.1	[46]
Durvalumab and tremelimumab	159	9.5-24.0 (1-2)	11.3-18.7	[46]
Pembrolizumab and levantinib	100	36 (1)	22	[20]
Nivolumab and ipilimumab	148	31-32 (0-8)	12.5-22.8	[42]
Atezolizumab and bevacizumab	336	27 (6)	NE	[20]
Nivolumab and cabozantinib	36	14 (3)	21.5	[42]
Nivolumab, ipilimumab and cabozantinib	35	31 (6)	NE	[42]

NA: Not available; NE: Not evaluable; ORR: Overall response rate; OS: Overall survival.

Table 2 Advantages and disadvantages of vaccination strategies used in hepatocellular carcinoma

Vaccine type	Advantages	Disadvantages
Peptides	Easy to prepare; known target Ag	Adjuvants are needed; restricted Ag repertoire; restriction to human leukocyte Ag
Dendritic cells	Adjuvants are not needed	Individualized production
Peptide pulsed	Known target Ag	Restriction to human leukocyte Ag; restricted Ag repertoire
Protein pulsed	No restriction to human leukocyte Ag; known target Ag	Protein synthesis is more interesting; restricted Ag repertoire
Tumor lysate pulsed	Not human leukocyte Ag restricted full Ag repertoire; available	Tumor samples not always available; the predominance of self-Ags that may eclipse tumor Ags
Cell line pulsed	Not human leukocyte Ag restricted; unlimited Ag source	Responses against cell line-specific Ag

Ag: Antigen.

Table 3 Vaccination clinical trials in hepatocellular carcinoma with reported results

Vaccine	Patient inclusion criteria	Patients, n	Immune response, %	Observations	Ref.
AFP HLA-A*02 restricted peptides + IFA	AFP + tumors from (stage IV patients)	6	66	Increased CTL response	[134]
DCs pulsed with autologous tumor lysate	Unresectable HCC	8	62	Immune response generation	[152]
DCs pulsed with autologous tumor lysate	Advanced HCC	31	0	Improved survival	[138]
DCs pulsed with AFP HLA-A*02 restricted peptides	Stage IV patients with surgery chemotherapy	10	60	No clinical responses	[135]
DCs pulsed with hepatoma cell-line (HEP-G2) lysate	No other therapeutic option	35	11.4	Evidence of antitumor efficacy	[139]
Gv1001 peptide + GM-CSF + cyclophosphamide	Advanced-stage HCC with no previous antitumor treatment	37	0	The immunological response is not detected	[137]
GPC3 HLA-A*24:02 and HLA-A*02-restricted peptides + IFA	Metastatic HCC or advanced HCC	33	91	Antitumor efficacy	[148]
DCs pulsed with fused recombinant proteins (AFP, MAGE-1 and GPC-3)	Surgical resection and locoregional therapy	12	92	Improved survival	[65]
GPC3 HLA-A*24:02 and HLA-A*02-restricted peptides + IFA	Vaccines as adjuvant therapy	41	85	Improved recurrence rate	[136]
AFP HLA-A*24:02 restricted peptides + IFA	Stage B/C tumors	15	33	Increased CTL response	[154]

Clinical trials with no published results have been excluded from the review. Incomplete Freund’s Adjuvant, *immunologic response measurement was not appropriate. AFP: Alpha-fetoprotein; CTL: Cytotoxic T lymphocyte; DC: Dendritic cell; HCC: Hepatocellular carcinoma; GPC-3: Glypican-3; IFA: Incomplete Freund’s Adjuvant; MAGE: Melanoma-associated antigen.