Immunotherapy for hepatocellular carcinoma: From basic research to clinical use

Table 1 Information of clinical trials of checkpoint blockade on hepatocellular carcinoma after 2008

Interventions	Design	Start year	Main inclusion criteria	Primary outcomes	Registered No.	Status
CP-675,206: anti-CTLA-4 antibody	Phase II	2008	Unresectable disease not amenable to loco regional treatment, HCV chronic infection	Tumor response	NCT01008358	Completed
CT-011 (Pidilizumab): anti-PD-1 antibody	Phase I/II	2009	HCC not eligible for surgery, TACE, or other systematic treatments	Safety and tolerability	NCT00966251	Terminated because of slow accrual
Nivolumab: anti-PD-1 antibody	Phase I	2012	Advanced HCC, failed in previous one line therapy	Adverse events	NCT01658878	Recruiting
Tremelimumab: anti-CTLA-4 antibody, combined with TACE or RFA	Phase I	2013	Not amenable to curative resection, transplantation or ablation	Safety and feasibility	NCT01853618	Recruiting

HCV: Hepatitis C virus; RFA: Radiofrequency ablation; TACE: Transarterial chemoembolization; HCC: Hepatocellular carcinoma; PD-1: Programmed death 1.

Table 2 Information of clinical trials of tumor vaccine on hepatocellular carcinoma after 2008

Interventions	Design	Start year	Main inclusion criteria	Primary outcomes	Registered No.	Status
AFP + GM-CSF plasmid prime and AFP adenoviral vector boost	Phase I/II	2008	Locoregionally treated HCC	Dose, toxicity, and immunological response rate	NCT00669136	Terminated because of poor accrual
DC loaded with autologous tumor	Phase II	2008	Metastatic HCC, available of tumor tissue	2-mo response rate	NCT00610389	Unknown
DC loaded with specific peptides of AFP	Phase I/II	2009	Patients with previous treatment, AFP ≥ 40 ng/mL, HLA A 0201 group	Adverse events	NCT01128803	Terminated
DEC-205-NY-ESO-1 fusion protein vaccine	Phase I	2012	After resection and TACE for HCC	Adverse events	NCT01522820	Recruiting
COMBIG-DC: allogeneic DC cancer vaccine	Phase I	2013	Not eligible for curative treatment or TACE, BCLC stage B and C	Adverse events	NCT01974661	Recruiting
In-situ therapeutic cancer vaccine	Phase I	2013	Refractory HCC, not eligible for or failed any treatment, AFP > 30	Safety	NCT01923233	Recruiting
V5 therapeutic vaccine	Phase III	2014	Advanced HCC	Changes in plasma AFP	NCT02232490	Not yet recruiting

AFP: α-fetoprotein; DC: Dendritic cell; GM-CSF: Granulocyte macrophage colony-stimulating factor; HCC: Hepatocellular carcinoma; HLA: Human leukocyte antigen; TACE: Transarterial chemoembolization; BCLC: Barcelona clinic liver cancer classification.

Table 3 Information of clinical trials of adoptive therapy on hepatocellular carcinoma after 2008

Interventions	Design	Start year	Main inclusion criteria	Primary outcomes	Registered No.	Status
Immuncell-LC: activated T lymphocyte	Phase III	2008	Stage I and II, complete resection within 12 wk	Efficacy and safety	NCT00699816	Completed
CIK	Phase III	2008	After radical resection of HCC, no prior anti-cancer therapy	Time to recurrence	NCT01749865	Recruiting
CIK	Phase III	2008	After radical resection, no prior anti-cancer treatment	Time to recurrence	NCT00769106	Recruiting
Ex vivo expanded autologous immune killer cell, combined with TACE	Phase II/III	2009	Never receive TACE treatment, BCLC stage B and C	2-yr reduction of tumor cells	NCT01024530	Unknown
NK cells, combined with liver transplantation	Phase I	2010	After liver transplantation for HCC	Side effect	NCT01147380	Ongoing, but not recruiting
Young TIL	Phase II	2010	Metastatic HCC with at least one lesion resectable	Tumor regression rate	NCT01174121	Recruiting
Autologous tumor infiltrating lymphocytes, combined with IL-2	Phase I	2011	Metastatic HCC	Safety and tolerability	NCT01462903	Unknown
CIK, combined with Licartin	Phase IV	2012	Postoperative patients	1-yr PFS	NCT01758679	Recruiting
Dendritic and cytokine-induced killer cells	Phase II	2013	After complete resection or TACE	PFS	NCT01821482	Not yet recruiting
CTL induced by DC loaded with multiple antigens	Phase I	2013	Complete tumor resection within 8 wk	2-yr PFS and adverse events	NCT02026362	Recruiting
DC incubated with irradiated autologous tumor stem cells + GM-CSF	Phase I	2013	Candidates for HCC resection	Vital signs, physical examinations and adverse events	NCT01828762	Completed
Cord blood-derived CIK	Phase I	2013	After radical resection	Adverse events	NCT01914263	Not yet recruiting
Autologous NKT cells	Phase I	2013	Advanced HCC, refractory to standard treatments	Adverse events	NCT01801852	Recruiting
Immuncell-LC, combined with Nexavar	Phase II	2013	Stage III and IV, receiving or ready for Nexavar treatment	2-yr PFS	NCT01897610	Recruiting
MG4101: ex vivo expanded allogeneic NK cell	Phase II	2013	Stage III, after curative resection	1-yr DFS	NCT02008929	Recruiting

CIK: Cytokine-induced killer; CTL: Cytolytic T lymphocyte; DC: Dendritic cell; DFS: Disease-free survival; NK: Natural killer; NKT: Natural killer T; PFS: Progression-free survival; TACE: Transarterial chemoembolization; TIL: Tumor infiltrating lymphocyte; HCC: Hepatocellular carcinoma; GM-CSF: Granulocyte macrophage colony-stimulating factor; IL-2: Interleukin 2; BCLC: Barcelona clinic liver cancer classification.