Efficacy of cytokine-induced killer cell infusion as an adjuvant immunotherapy for hepatocellular carcinoma: a systematic review and meta-analysis

Figures & data

Figure 1 Quality assessment. (A) Risk of bias summary; (B) Risk of bias graph.

Table 1 Summary of basic characteristics of studies selected for meta-analysis

Study (year published)	Study design	Treatment	Number of patients	Mean age, years	Male gender	Follow-up time, months	Child–Pugh class, number (%)	Cancer stage, no (%)	Type of viral hepatitis, number (%)
Lee et al,^Citation18 2015	RCT	Surgery/RFA/PEI + CIK	114	55.4	83.3%	NR	NR	AJCC I: 98 (86.0%) II: 16 (14.0%)	HBV only: 96 (84.2%) HCV only: 9 (7.9%) HBV + HCV: 2 (1.8%) Others: 7 (6.1%)
		Surgery/RFA/PEI	112	56.4	81.3%			AJCC I: 94 (83.9%) II: 18 (16.1%)	HBV only: 90 (80.4%) HCV only: 10 (8.9%) HBV + HCV: 2 (1.8%) Others: 10 (8.9%)
Guo et al,^Citation33 2014	Retrospective	TACE + CIK	30	≤60: 43.3% >60: 56.7%	90.0%	Range: 2–43	A: 24 (80%) B: 6 (20%)	BCLC A: 5 (16.7%) B: 15 (50%) C: 10 (33.3%)	HBsAg+: 28 (93.3%)
		TACE only	38	≤60: 34.2% >60: 65.8%	89.5%		A: 31 (81.6%) B: 7 (18.4%)	BCLC A: 5 (13.1%) B: 21 (55.3%) C: 12 (31.6%)	HBsAg+: 36 (94.7%)
Yu et al^Citation23 2014	RCT	Standard treatment + CIK	66	<60: 56.1% ≥60: 43.9%	87.9%	Median: 18.6	A: 62 B: 4	BCLC A: 8 B: 31 C: 27	Hepatitis B: 35
		Standard treatment	66	<60: 65.2% ≥60: 34.8%	87.9%		A: 62 B: 4	BCLC A: 8 B: 31 C: 27	Hepatitis B: 37
Pan et al,^Citation17 2013	Retrospective	Surgery alone	206	50.03	86.9%	Median: 60	NR	Pathology I: 17 II: 92 III: 97	HBsAg+: 176 HBeAg+: 182
		Surgery + CIK	204	49.16	87.3%			Pathology I: 18 II: 102 III: 84	HBsAg+: 47 HBeAg+: 43
Huang et al,^Citation16 2013	Retrospective	TACE + RFA + CIK	85	50a	90.6%	Median (range): 78 (5–173)	A: 76 B: 9	BCLC A: 36 B: 29 C: 20	HBV: 66
		TACE + RFA	89	53a	88.8%		A: 74 B: 15	BCLC A: 37 B: 34 C: 18	HBV: 69
Tong et al,^Citation28 2013	Prospective	TACE + CIK TACE only	20 18	56	NR	NR	NR	NR	NR
Deng et al,^Citation24 2013	RCT	TACE + RFA	21	≥50: 81.0% <50: 19.0%	52.4%	NR	A: 19 B: 2	NR	HBsAg+: 20
		TACE + RFA + CIK	20	≥50: 65.0% <50: 35.0%	90.0%		A: 18 B: 2		HBsAg+: 17
He et al,^Citation25 2012	RCT	TACE only	58	52.1	86.2%	Mean: 40	A: 49 B: 9	NR	NR
		TACE + CIK	60	56.3	93.3%		A: 54 B: 6
Wang et al,^Citation30 2012	Prospective	TACE + RFA + CIK	38	53	89.5%	Mean: 44	A: 27 B: 11	NR	HBV: 31
		TACE + RFA	38	55	86.8%		A: 25 B: 13		HBV: 32
Hao et al,^Citation15 2010	Prospective	TACE + CIK	72	53a	90.3%	NR	A: 65 B: 7	BCLC A: 7 B: 6 C: 59	HBsAg+: 68
		TACE only	74	51a	86.5%		A: 66 B: 8	BCLC A: 5 B: 4 C: 65	HBsAg+: 68
Dong et al,^Citation14 2009	RCT	Surgery + CIK-I	41	≥50: 65.9% <50: 34.1%	75.6%	NR	A: 34 B: 7	NR	HBsAg+: 32
		Surgery + CIK-II	43	≥50: 60.5% <50: 39.5%	74.4%		A: 34 B: 9		HBsAg+: 33
		Surgery only	43	≥50: 65.1% <50: 34.9%	79.1%		A: 34 B: 9		HBsAg+: 31
Yu et al,^Citation32 2009	Prospective	Surgery + TACE + CIK	25	49	88.0%	Range: 3–34	A: 24 B: 1	Clinical I: 0 II: 8 III: 15 IV: 2	NR
		Surgery + supportive therapy	25	52	92.0%		A: 20 B: 5	Clinical I: 1 II: 9 III: 14 IV: 1
Weng et al,^Citation13 2008	RCT	TACE + RFA + CIK	45	43a	68.9%	Max: 18	A: 36 (80%) B: 9 (20%)	NR	NR
		TACE + RFA	40	45a	72.5%		A: 33 (82.5%) B: 7 (17.5%)
Huang et al,^Citation26 2007	RCT	TACE + RFA + CIK TACE + RFA	55 30	46.2 47.1	67.3% 70.0%	NR	NR	NR	NR
Shi et al,^Citation31 2007	Prospective	TACE + CIK	38	NR	NR	NR	NR	Okuda I: 8 II: 13 III: 7	NR
		TACE	134					Okuda I: 2 II: 106 III: 26
Hao et al,^Citation29 2006	Prospective	TACE + CIK	21	50.90	81.0%	NR	A: 15 B: 4 C: 2	Clinical I: 2 II: 16 III: 3	HBV infection: 21
		TACE only	46	49.83	97.8%		A: 34 B: 9 C: 3	Clinical I: 4 II: 39 III: 3	HBV infection: 44
Zhang et al,^Citation27 2006	RCT	TACE only TACE + CIK TACE + PEI TACE + PEI + CIK	30 16 62 36	45.5	75.0%	NR	NR	NR	NR

Note:

a Data for age are presented as the median.

Abbreviations: AJCC, American Joint Committee on Cancer; BCLC, Barcelona Clinic Liver Cancer; CIK, cytokine-induced killer cells; HBsAg, surface antigen of the hepatitis B virus; HBV, hepatitis B virus; HCV, hepatitis C virus; NR, not recorded; PEI, percutaneous ethanol injection; RFA, radiofrequency ablation; TACE, transcatheter arterial chemoembolization.

Figure 2 PRISMA flow diagram.

Abbreviations: CIK, cytokine-induced killer; PRISMA, Preferred Reporting Items for Systematic review and Meta-Analysis.

Table 2 Summary of outcomes of included studies

Study	Number of patients	Mean age (yr)	Inclusion criteria	Treatment	OS (HR)	PFS (HR)	DFS (HR)
Lee et al,^Citation18 2015	114	55.4	1. Patients with HCC clinical stage I or II according to AJCC 2. Child–Pugh class A	Surgery/RFA/PEI + CIK	0.21 (0.06–0.75)	NR	(Adjusted) 0.66 (0.44–0.98)
	112	56.4	3. ECOG score 0 or 1 4. Age between 20 and 80 years	Surgery/RFA/PEI
Guo et al,^Citation33 2014	30	≤60: 43.3% >60: 56.7%	1. Age >18 years 2. Child–Pugh A or B 3. KPS ≥70 4. Without ascites or distant metastatic disease	TACE + CIK	0.75 (0.43–1.31)	0.46 (0.25–0.86)	NR
	38	≤60: 34.2% >60: 65.8%	5. Life expectancy >6 months 6. Without severe infection or pregnancy	TACE only
Yu et al,^Citation23 2014	66	<60: 56.1% ≥60: 43.9%	1. Age between 18 and 80 years 2. Child–Pugh score A or B 3. BCLC stage A, B or C 4. Life expectancy >3 months	Standard treatment + CIK	0.62 (0.37–1.06)	0.7 (0.45–1.08)	NR
	66	<60: 65.2% ≥60: 34.8%	5. Without severe cardiovascular disease or pregnancy	Standard treatment
Pan et al,^Citation17 2013	206	50.03	1. HCC without previous treatment 2. Child–Pugh class A or no Cirrhosis	Surgery alone	(adjusted) 0.495 (0.699–0.35)	NR	NR
	204	49.16	3. Solitary HCC 4. Adequate liver functional reserve to survive the operation	Surgery + CIK
Huang et al,^Citation16 2013	85 89	50a 53a	1. Diagnosis meeting the AASLD and the EASL criteria for HCC 2. ECOG score 0 or 1 3. Child–Pugh class A or B, good liver function 4. No previous surgery, chemotherapy or radiotherapy for HCC 5. No portal vein thrombosis	TACE + RFA + CIK TACE + RFA	0.56 (0.40–0.77)	0.67 (0.53–0.85)	NR
Tong et al,^Citation28 2013	20 18	56	Inoperable HCC, diagnosed according to AASLD 2010	TACE + CIK TACE only	0.4 (0.19–0.84)	0.55 (0.33–0.93)	NR
Deng et al,^Citation24 2013	21	≥50: 81.0% <50: 19.0%	1. Diagnosed according to AASLD 2. Normal liver function, and AFP >25 ng/mL	TACE + RFA	0.76 (0.51–1.11)	NR	0.47 (0.25–0.88)
	20	≥50: 65.0% <50: 35.0%	3. Solitary HCC, tumor ≤3; no tumor thrombosis or distant metastasis 4. No residual tumor after 8-weeks treatment with TACE and RFA; AFP <37.5 ng/mL for >2 weeks	TACE + RFA + CIK
He et al,^Citation25 2012	58 60	52.1 56.3	1. Age >18 years 2. Diagnosis according to Chinese anticancer association professional committee of liver cancer	TACE only TACE + CIK	0.52 (0.38–0.70)	NR	NR
Wang et al,^Citation30 2012	38	53	1. Diagnosed primary HCC according to AASLD 2. Tumor diameter >3 cm; tumor diameter ≤3 cm combined portal vein hypertension; or hyperbilirubinemia	TACE + RFA + CIK	(adjusted) 0.830 (0.551–1.250)	NR	0.579 (0.381–0.880)
	38	55	3. Multiple tumors 4. ECOG score >1 5. Child–Pugh class A or B	TACE + RFA
Hao et al,^Citation15 2010	72 74	53a 51a	1. Age >18 years 2. Patients had unresectable HCC or refused resection 3. Total bilirubin <3× upper limit or normal 4. Child–Pugh class A or B 5. No extrahepatic metastasis 6. Newly diagnosed or postoperative recurrence	TACE + CIK TACE only	0.448 (0.244–0.822)	0.564 (0.361–0.883)	NR
Dong et al,^Citation14 2009	41	≥50: 65.9% <50: 34.1%	1. Solitary tumor 2. No postoperative transfusion	Surgery + CIK-I	0.98 (0.67–1.44)	NR	0.67 (0.50–0.89)
	43	≥50: 60.5% <50: 39.5%	3. HCC confirmed by pathology 4. Resection margin >1 cm	Surgery + CIK-II
	43	≥50: 65.1% <50: 34.9%	5. No tumor fracture or hemorrhage 6. No tumor distant metastases	Surgery only
Yu et al,^Citation32 2009	25	49	Primary HCC postsurgical resection, with pathological diagnosis of HCC	Surgery + TACE + CIK	0.92 (0.34–2.51)	NR	NR
	25	52		Surgery + supportive therapy
Weng et al,^Citation13 2008	45 40	43a 45a	1. Histologically and clinically confirmed nodular or massive HCC 2. Tumor diameters ranged from 2 to 13 cm 3. No tumor embolus in portal vein or remote metastasis 4. Child–Pugh class A or B KPS >90	TACE + RFA + CIK TACE + RFA	NR	NR	0.59 (0.28–1.27)
Huang et al,^Citation26 2007	55 30	46.2 47.1	1. Histologically and clinically confirmed nodular or massive HCC 2. Patients had TACE + RFA for 2–3 times, without residual tumor or distant metastasis	TACE + RFA + CIK TACE + RFA	0.36 (0.15–0.89)	NR	NR
Shi et al,^Citation31 2007	38 134	NR	Primary HCC	TACE + CIK TACE	0.21 (0.10–0.44)	NR	NR
Hao et al,^Citation29 2006	21 46	50.90 49.83	Patients diagnosed HCC according to Chinese anticancer association professional committee of liver cancer	TACE + CIK TACE only	0.6 (0.3–1.2)	NR	NR
Zhang et al,^Citation27 2006	30 16 36	45.5	Primary HCC	TACE only TACE + CIK TACE + PEI + CIK	0.7 (0.53–0.93)	NR	NR

Note:

a Median age was presented.

Abbreviations: AASLD, American Association for the study of liver diseases; AFP, α-fetoprotein; AJCC, American Joint Committee on Cancer; BCLC, Barcelona Clinic Liver Cancer; CIK, cytokine-induced killer; DFS, disease-free survival; EASL, European Association for the Study of the Liver; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; HCC, hepatocellular carcinoma; KPS, Karnofsky Performance Score; NR, not recorded; OS, overall survival; PEI, percutaneous ethanol injection; PFS, progression-free survival; RFA, radiofrequency ablation; TACE, transcatheter arterial chemoembolization.

Figure 3 Meta-analysis for treatment effect on (A) OS, (B) PFS, and (C) DFS/RFS.

Abbreviations: CI, confidence interval; CIK, cytokine-induced killer; DFS, disease-free survival; HR, hazard ratio; OS, overall survival; RFS, recurrence-free survival; RCT, randomized controlled trial.

Figure 4 Sensitivity-analysis for treatment effect on (A) OS, (B) PFS, and (C) DFS/RFS.

Abbreviations: CI, confidence interval; CIK, cytokine-induced killer; DFS, disease-free survival; HR, hazard ratio; OS, overall survival; RFS, recurrence-free survival; RCT, randomized controlled trial.

LeeJHLeeJHLimYSAdjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinomaGastroenterology20151487 1383 1391.e625747273

 PubMed Web of Science ®Google Scholar

GuoWLiuLWuDDendritic cell-cytokine induced killer cell immunotherapy combined with transcatheter arterial chemoembolization for hepatocellular carcinoma: safety and efficacyNan Fang Yi Ke Da Xue Xue Bao2014345 674 67824849434

 PubMedGoogle Scholar

YuXZhaoHLiuLA randomized phase II study of autologous cytokine-induced killer cells in treatment of hepatocellular carcinomaJ Clin Immunol2014342 194 20324337625

 PubMed Web of Science ®Google Scholar

PanKLiYQWangWThe efficacy of cytokine-induced killer cell infusion as an adjuvant therapy for postoperative hepatocellular carcinoma patientsAnn Surg Oncol20132013 4305 431123892527

 PubMed Web of Science ®Google Scholar

HuangZMLiWLiSCytokine-induced killer cells in combination with transcatheter arterial chemoembolization and radiofrequency ablation for hepatocellular carcinoma patientsJ Immunother2013365 287 29323719239

 PubMed Web of Science ®Google Scholar

TongLQZhaoHFYouLGTransarterial chemoembolization combined with autologouscytokine-induced killer cells therapy for primary liver cancerZhong Guo Pu Tong Wai Ke Za Zhi201322 9

 Google Scholar

DengWJ CJLuoYJXiangGYEfficacy and safety of min-imally invasive treatment combined with autologous CIK cellsinfusionLing Nan Xian Dai Ling Chuang Wai Ke201313 29 31

 Google Scholar

HeXBWangJHuJHCIK cells combined with TACE treatmentof primary liver cancer randomized controlled studySi ChuanXi Xue201233 1696 1697

 Google Scholar

WangJPLiWHuangZLValue of CIK in the treatment of TACE combined with RFA for HCC in long-term survival and prognostic analysisZhonghua Yi Xue Za Zhi20129243 3062 306623328379

 PubMedGoogle Scholar

HaoMZLinHLChenQYeYBChenQZChenMSEfficacy of transcatheter arterial chemoembolization combined with cytokine-induced killer cell therapy on hepatocellular carcinoma: a comparative studyChin J Cancer2010292 172 17720109346

 PubMedGoogle Scholar

DongHLiQWangJZhangTKongDLA randomized, controlled trial of postoperative adjuvant cytokine-induced killer cells immunotherapy after radical resection of hepatocellular carcinomaDig Liver Dis2009411 36 4118818130

 PubMedGoogle Scholar

YUWYEYZhouDEffect of postoperative transcatheter arterial chemoembolization combined with cytokine-induced killer immunotherapy on recurrence and survival rate of hepatocellular carcinoma patientsJ Min Invasive Med200945 459 461

 Google Scholar

WengDSZhouJZhouQMMinimally invasive treatment combined with cytokine-induced killer cells therapy lower the short-term recurrence rates of hepatocellular carcinomasJ Immunother2008311 63 7118157013

 PubMed Web of Science ®Google Scholar

HuangLXZhouQMXiaJCMinimally invasive treatmentcombined with autologous CIK cell therapy for primary hep-atocellular carcinoma: safety and efficacyGuang Dong Yi Xue200728 1466 1468

 Google Scholar

ShiYGaoCJChenFXXuYMDongSLCytokine-induced killer cell for interventional chemotherapy of hepatocellular carcinomaJ Interv Radiol2007164 235 239

 Google Scholar

HaoMZChenQYeYBTranscatheter arterial chemoembolization combined with cytokine-induced killers in treatment of hepatocellular car-cinomaZhong Guo Zhong Liu Sheng Wu Zhi Liao Za Zhi200613 303 305

 Google Scholar

ZhangZNXuYMChenFXClinical study on the treatment of advanced hepatocellular car-cinoma by CIK cellDong Nan Guo Fang Yi Yao20068 84 87

 Google Scholar