Potentiality of immunotherapy against hepatocellular carcinoma

Table 1 Immunotherapeutic clinical trials in hepatocellular carcinoma since 2000

	Author	Country	Year	Indication	Immunotherapy	n	Clinical result	Ref.
Cytokine therapy	Llovet et al	Spain	2000	Advanced HCC	RCT: IFN-α2b vs no treatment	30 and 28	RR: 2/30 (7%), DCR: NANo significant difference in RR or survival	[91]
	Ikeda et al	Japan	2000	Adjuvant(resection or ethanol injection)	RCT: IFN-βvs no treatment	10 and 10	Significantly longer recurrence-free survival after IFN-β therapy (P = 0.0004	[92]
	Sakon et al	Japan	2002	Advanced HCC	5-FU + IFN-α	11	RR: 8/11 (73%), DCR: 9/11 (82%)MST: NA	[93]
	Kubo et a	Japan	2001	Adjuvant (resection)	RCT: IFN-α vs. no treatment	15 and 15	Significantly longer recurrence-free survival after IFN-α therapy (P = 0.037)	[94]
	Ladhams et al	Australia	2002	Advanced HCC	Dendritic cell pulsed with autologous tumor	2	Slowing in the rate of tumor growth in one of two patients	[95]
	Palmieri et al	Italy	2002	Advanced HCC	Low dose IL-2	18	RR: 3/18 (17%), DCR: 16/18 (89%)MST: 24.5 mo	[96]
	Reinisch et al	Austria	2002	Advanced HCC	GM-CSF + IFN-γ	15	RR: 1/15 (7%), DCR: 10/15 (67%)MST: 5.5 mo	[97]
	Feun et al	United States	2003	Advanced HCC	Doxorubicin + 5-FU + IFN-α2b	30	RR: 2/30 (7%), DCR: 3/30 (10%)MST: 3 mo	[99]
	Shiratori et al	Japan	2003	adjuvant (ethanol injection)	RCT: IFN-αvs no treatment	49 and 25	Longer recurrence-free and overall survival after IFN-α therapy (P-value not reported	[100]
	Patt et al	United States	2003	Advanced HCC	5-FU + IFN-α2b	43	RR: 9/36 (25%), DCR 22/36 (61%)MST: 19.5 mo	[49]
	Komorizono et al	Japan	2003	Advanced HCC	Cisplatin + 5-FU + IFN-α	6	RR: 2/6 (33%), DCR 3/6 (50%)MST: NA	[50]
	Sangro et al	Spain	2004	Advanced HCC	Intratumoral adenovirus encoding IL-12 genes	21 (8 HCC)	RR: 1/8 (13%), DCR 7/8 (88%)MST: NA	[102]
	Yin et al	China	2005	Advanced HCC	Cisplatin + doxorubicin + 5-FU + IFN-2α	26	RR: 4/26 (15%), DCR 13/26 (50%)MST: 6 mo	[105]
	Vitale et al	Italy	2007	Advanced HCC	5-FU + IFN-α2b	9	RR: 3/9 (33%), DCR 4/9 (44%)MST: 11.5 mo	[108]
TAA targeted therapy	Butterfield et al	United States	2003	Advanced HCC	AFP peptide vaccination	6	RR: 0/6 (0%), DCR 0/6 (0%)MST: 8 mo	[56]
	Kuang et al	China	2004	Adjuvant	RCT: autologous formalin-fixed tumor vaccine vs no treatment	18 and 21	Significantly longer recurrence-free survival after vaccination (P = 0.003)	[8]
	Greten et al	Germany	2010	Advanced HCC	a telomerase peptide vaccine in combination with a low dose cyclophosphamide	40	RR: 0/40 (0%), DCR 17/37 (45.9%)MST: 9.8 mo	[114]
	Sawada et al	Japan	2012	Advanced HCC	GPC3-derived peptide vaccine	33	RR: 1/33 (3%), DCR 20/33 (60.6%)MST: 9.0 moOS was significantly longer in patients with high GPC3-specific CTL frequencies	[60]
	Zhu et al	United States	2013	Advanced HCC	GPC3 monoclonal antibody	20	RR: 0/20 (0%), DCR 4/20 (60.6%)MST in GPC3 high was likely to be longer than that in GPC3 low or no expression group [49.4 wk vs 13.0 wk]	[61]
Immune checkpoint inhibitors	Sangro et al	Spain	2013	Advanced HCC	anti-CTLA-4 antibody	21	RR: 3/21 (17.6%), DCR 13/21 (76.4%)MST: 8.2 mo	[69]
Cell transfer immunotherapy	Takayama et al	Japan	2000	Adjuvant (resection)	RCT: activated autologous lymphocyte vs no treatment	76 and 74	Significantly longer recurrence-free survival after transfer of activated lymphocytes (P = 0.008)	[10]
	Stift et al	Austria	2003	Advanced HCC	Dendritic cell pulsed with autologous tumor	20 (2 HCC)	RR: NA, DCR: NAMST: 10.5 moPersistent AFP over a period of 6 mo in one of two patients	[98]
	Iwashita et al	Japan	2003	Advanced HCC	Dendritic cell pulsed with autologous tumor	10 (8 HCC)	RR: 0/8 (0%), DCR 6/8 (75%)MST: NA	[101]
	Shi et al	China	2004	Advanced and early HCC	Cytokine induced killer cell	13	RR: NA, DCR: NAMST: NA	[78]
	Mazzolini et al	Spain	2005	Advanced HCC	Dendritic cell transfected with adenovirus encoding IL-12 gene	17 (8 HCC)	RR: 0/0 (0%), DCR: 2/8 (25%)MST: NA	[103]
	Chi	Taiwan	2005	Advanced HCC	Local radiation + intratumoral DC injection	14	RR: 2/14 (14%), DCR 9/14 (64%)MST: 5.6 mo	[104]
	Lee et al	Taiwan	2005	Advanced HCC	Dendritic cell pulsed with autologous tumor	31	RR: 4/31 (13%), DCR 21/31 (68%)MST: NA	[79]
	Kumagi et al	Japan	2005	Advanced HCC	Intratumoral dendritic cell injection after ethanol injection	4	Feasibility study	[106]
	Butterfield et al	United States	2006	Advanced HCC	Dendritic cell pulsed with AFP peptide	10	RR: 0/10 (0%), DCR 0/10 (0%)MST: 7.5 mo	[55]
	Nakamoto et al	Japan	2007	Advanced and early HCC	Non-RCT: TACE + dendritic cell vs TACE alone	10 and 11	No significant difference in survival	[107]
	Weng et al	China	2008	Adjuvant (TACE and RFA)	RCT: cytokine induced killer cell vs no treatment	45 and 40	Significantly longer recurrence-free survival after immunotherapy (P = 0.01)	[109]
	Hui et al	China	2009	Adjuvant (resection)	RCT: cytokine induced killer cell 3 courses vs 6 courses vs no treatment	41, 43 and 43	Significantly longer recurrence-free survival after immunotherapy (P = 0.001 and 0.004)	[110]
	Palmer et al	United Kingdom	2009	Advanced HCC	Dendritic cell pulsed with liver tumor cell line lysate (HepG2)	35	RR: 1/25 (4%), DCR 7/25 (28%)MST: 5.6 mo	[111]
	Olioso et al	Italy	2009	Advanced HCC	Cytokine induced killer cell + IFN-α	12 (1 HCC)	Complete responseSurvival time: 33 mo (alive)	[112]
	Hao et al	China	2010	Advanced HCC	Non-RCT: TACE + cytokine induced killer cell vs TACE alone	72 and 74	Significantly longer survival after combination therapy (P < 0.001)	[113]
	Ma et al	China	2010	Adjuvant (RFA)	RFA and autologous RetroNectin activated killer cells	7	During a 7-mo follow-up, no severe adverse events, recurrences, or deaths	[115]
	Nakamoto et al	Japan	2011	Adjuvant (TACE)	TACE + OK432-stimulated DCs vs TACE alone	13 and 22	Significantly longer recurrence-free survival after immunotherapy (P = 0.046)	[80]
	Zhou et al	China	2011	HCC with hepatitis B (PMWA)	Immature DCs, CIK, CTL and tumor lysate-pulsed DC	10	This Phase I study revealed this therapy was safe and increased the percentage of effector cells	[116]
	Qiu et al	China	2011	Adjuvant (resection)	RCT: TAA-pulsed DC and CIK vs no treatment	9 vs 9	Significantly longer recurrence-free survival after immunotherapy (P = 0.00121)	[117]
	Tada et al	Japan	2012	Advanced HCC	TACE + multiple TAA-pulsed DC	5	This Phase I/II study revealed this therapy was safe and increased the percentage of effector cells	[118]
	Cui et al	China	2014	Adjuvant (RFA)	RFA + NK cells, γδT cells and CIK cells vs RFA alone	30 and 32	Significantly longer recurrence-free survival after immunotherapy	[76]

CIK: Cytokine-induced killer cells; CTL: Cytotoxic T lymphocyte; DCR: Disease control rate; GM-CSF: Granulocyte macrophage colony-stimulating factor; HCC: Hepatocellular carcinoma; IFN: Interferon; IL: Interleukin; LAK: Lymphokine-activated killer cell; MST: Median survival time; NA: Not assessed; NK: Natural killer; PMWA: Percutaneous microwave ablation; RCT: Randomized control trial; RFA: Radiofrequency ablation therapy; RR: Response rate; TAA: Tumor-associated antigen; TACE: Transcatheter arterial chemoembolization; TIL: Tumor-infiltrating lymphocyte.

Table 2 Criteria for immunotherapy

Criteria	Author	Year	Journal
RECIST	Therasse et al[119]	2000	J Natl Cancer Ins
irRC	Wolchok et al[120]	2009	Clin Cancer Res
mRECIST	Lencioni et al[121]	2010	Semin Liver Dis
irRECIST	Wolchok et al[120]	2014	Ann Oncol: conference minutes

RECIST: Response Evaluation Criteria in Solid Tumors; irRC: Immune-related response criteria; mRECIST: Modified RECIST; irRECIST: Immune-related response RECIST.