Clinical applications of dendritic cells–cytokine-induced killer cells mediated immunotherapy for pancreatic cancer: an up-to-date meta-analysis

Figures & data

Figure 1 Flow diagram of the selection process.

Table 1 Clinical information from the eligible trials in the meta-analysis

Included studies	Nation	Tumor stage	Patients, exp/con	Age (years)		Parameter types
				Exp	Con
Ge and Ge (2016)^Citation24	China	I–IV	50/50	57.7±4.6 (mean)	57.5±4.7 (mean)	OS, LYM subsets
Kang and Zhang (2016)^Citation25	China	Kps >60	22/22	65.1±6.3 (mean)	66.1±6.3 (mean)	ORR, DCR, QoL
Li (2016)^Citation26	China	Kps ≥70	27/27	ND	ND	OS, ORR, DCR, QoL, AE
Liu (2012)^Citation27	China	I–IV	25/25	ND	ND	LYM subsets, cytokines
Mu et al (2016)^Citation28	China	III–IV	90/90	56.5±8.3 (mean)	57.8±7.3 (mean)	ORR, DCR, LYM subsets, AE
Shen et al (2015)^Citation29	China	III–IV	38/36	62 (median)	66 (median)	ORR, DCR
Wang (2015)^Citation30	China	I–IV	10/30	64.3±3.1 (mean)	63.8±3.4 (mean)	ORR, DCR
Wang et al (2013)^Citation16	China	Ps ≤2	28/30	ND	ND	ORR, DCR, AE
Wang et al (2016)^Citation17	China	Ps <3	25/5	<65 (14)	<65 (38)	OS, ORR, DCR, AE
Wen et al (2013)^Citation31	China	ND	30/30	63.5±13.2 (mean)	65.3±12.8 (mean)	OS, ORR, DCR
Zhang et al (2013)^Citation32	China	Kps >60	58/68	63 (median)	65 (median)	ORR, DCR, QoL
Zhang (2014)^Citation33	China	I–IV	30/30	ND	ND	OS, LYM subsets, cytokines
Zhang et al (2016)^Citation34	China	ND	40/40	55.9±8.7 (mean)	56.8±8.2 (mean)	OS
Zheng et al (2016)^Citation35	China	I–IV	40/40	39–82	35–83	OS, LYM subsets

Notes: Con, control group (chemotherapy alone group); Exp, experimental group (chemotherapy with DC–CIK immunotherapy).

Abbreviations: AE, adverse reaction; DC–CIK, dendritic cells–cytokine-induced killer; DCR, disease control rate; Kps, Karnofsky Performance Score; LYM, lymphocyte; ND, not determined; OS, overall survival; ORR, overall response rate; Ps, performance status score; QoL, quality of life.

Table 2 Information of DC–CIK immunotherapy

Included studies	Therapeutic regimen		Administration route	Culture conditions	Cell dose (cycles)
	Experimental group	Control group
Ge and Ge (2016)^Citation24	Con Reg + DC–CIK	Gemcitabine + oxaliplatin +5-Fu	Intravenous infusion	ND	6×10^9 (2 cycles)
Kang and Zhang (2016)^Citation25	Con Reg + DC–CIK	Gemcitabine	ND	ND	ND
Li (2016)^Citation26	Con Reg + CIK	Gemcitabine + cisplatin + RT	Intravenous infusion	ND	>1×10^10 (≥2 cycles)
Liu (2012)^Citation27	Con Reg + DC–CIK	ND	Intravenous infusion	IFN-γ, IL-2, CD3, GM-CSF, IL-4	6×10^9 (2 cycles)
Mu et al (2016)^Citation28	Con Reg + DC–CIK	Gemcitabine + nab-paclitaxel	Intravenous infusion	ND	ND (4 cycles)
Shen et al (2015)^Citation29	Con Reg + CIK	Gemcitabine	Intravenous infusion	IFN-γ, IL-2, CD3	ND
Wang (2015)^Citation30	Con Reg + CIK	Gemcitabine	Intravenous infusion	ND	ND (2 cycles)
Wang et al (2013)^Citation16	Con Reg + CIK	S-1	Intravenous infusion	IFN-γ, IL-1α, IL-2, CD3	ND (≥1 cycle)
Wang et al (2016)^Citation17	Con Reg + CIK	(gemcitabine + S-1)/other	Intravenous infusion	IFN-γ, IL-2, CD3	5×10^9 (2 cycles)
Wen et al (2013)^Citation31	Con Reg + DC–CIK	Mitomycin + adriamycin + Fu	Intravenous infusion	ND	ND
Zhang et al (2013)^Citation32	Con Reg + CIK	Gemcitabine	Intravenous infusion	ND	ND
Zhang (2014)^Citation33	Con Reg + DC–CIK	Gemcitabine + oxaliplatin +5-Fu	Intravenous infusion	GM-CSF, IL-4	ND
Zhang et al (2016)^Citation34	Con Reg + DC–CIK	Gemcitabine + oxaliplatin +5-Fu	Intravenous infusion	ND	>1×10^9 (ND)
Zheng et al (2016)^Citation35	Con Reg + DC–CIK	Gemcitabine + oxaliplatin +5-Fu	Intravenous infusion	ND	6×10^9 (2 cycles)

Notes: Con, control group (chemotherapy alone group); exp, experimental group (chemotherapy with DC–CIK immunotherapy); RT, three-dimensional conformal radiotherapy.

Abbreviations: Con Reg, control group regimen; DC–CIK, dendritic cells–cytokine-induced killer; ND, not determined; 5-Fu, 5-fluorouracil; GM-CSF, granulocyte-macrophage colony-stimulating factor.

Figure 2 Risk of bias summary: review of authors’ judgments about each risk of bias item for included studies.

Note: Each color represents a different level of bias: red for high-risk, green for low-risk, and yellow for unclear-risk of bias.

Figure 3 Forest plots of the comparison of ORR (A) and DCR (B) between the experimental and control groups.

Notes: Control group, chemotherapy alone group; experimental group, chemotherapy with DC–CIK immunotherapy. The fixed-effects meta-analysis model (M–H method) was used.
Abbreviations: CI, confidence interval; DC–CIK, dendritic cells–cytokine-induced killer; DCR, disease control rate; M–H, Mantel–Haenszel; ORR, overall response rate.

Table 3 Comparison of CR, PR, SD, PD, ORR, and DCR between the experimental and control groups

Parameter	Number of patients (n)		Analysis method	Heterogeneity		OR	95% CI	P-value
	Experimental group	Control group		I^2 (%)	P-value
CR	328	390	Fixed	0	0.84	1.97	0.85–4.54	0.11
PR	328	390	Fixed	0	0.96	1.49	1.06–2.10	0.02
SD	328	390	Fixed	35	0.14	1.31	0.95–1.80	0.10
PD	328	390	Fixed	0	0.74	0.43	0.30–0.61	<0.00001
ORR	328	390	Fixed	0	0.96	1.69	1.20–2.38	0.003
DCR	328	390	Fixed	0	0.70	2.33	1.63–3.33	<0.00001

Abbreviations: CI, confidence interval; CR, complete response; DCR, disease control rate; OR, odds ratio; ORR, overall response rate; PR, partial response; PD, progressive disease; SD, stable disease.

Figure 4 Forest plot of the comparison of OS between the experimental and control groups.

Notes: Control group, chemotherapy alone group; experimental group, chemotherapy with DC–CIK immunotherapy. The fixed-effects meta-analysis model (M–H method) was used.
Abbreviations: CI, confidence interval; DC–CIK, dendritic cells–cytokine-induced killer; M–H, Mantel–Haenszel; OS, overall survival.

Figure 5 Forest plots of the comparison of QoL between the experimental and control groups.

Notes: (A) QoL improvement; (B) Kps. Control group, chemotherapy alone group; experimental group, chemotherapy with DC–CIK immunotherapy. The fixed-effects meta-analysis model was used.
Abbreviations: CI, confidence interval; DC–CIK, dendritic cells–cytokine-induced killer; Kps, Karnofsky Performance Score; M–H, Mantel–Haenszel; QoL, quality of life.

Figure 6 Forest plot of the comparison of immunophenotype in pre- and posttherapies.

Note: The random effects meta-analysis model (IV method) was used.
Abbreviations: CI, confidence interval; IV, inverse variance.

Figure 7 Forest plot of the comparison of IFN-γ and IL-4 in pre- and posttherapies.

Note: The fixed-effects meta-analysis model (IV method) was used.
Abbreviations: CI, confidence interval; IV, inverse variance; IFN-γ, interferon-γ; IL-4, interleukin-4.

Table 4 Comparison of adverse events between the experimental and control groups

Adverse events	Number of patients (n)		Analysis method	Heterogeneity		OR	95% CI	P-value
	Experimental group	Control group		I^2 (%)	P-value
Fever	170	204	Random	67	0.03	2.39	0.70–8.23	0.17
Fever I + II	55	57	Random	57	0.13	4.34	1.35–13.89	0.01
Fever III + IV	55	57	Random			3.11	0.12–79.87	0.49
Skin rash	145	147	Random	0	0.46	1.32	0.54–3.19	0.54
Skin rash I + II	55	57	Random	0	0.66	2.21	0.52–9.36	0.28
Skin rash III + IV	55	57	Random			3.33	0.13–85.11	0.47
Leukopenia	55	57	Random	0	0.33	0.56	0.22–1.47	0.24
Leukopenia I + II	55	57	Random	0	0.92	0.86	0.36–2.06	0.73
Leukopenia III + IV	55	57	Random	0	0.62	0.32	0.06–1.64	0.17
Thrombocytopenia	55	57	Random	0	0.38	0.54	0.18–1.64	0.27
Thrombocytopenia I + II	55	57	Random	0	0.70	0.61	0.22–1.73	0.36
Thrombocytopenia III + IV	55	57	Random			0.32	0.01–8.24	0.49
Diarrhea	55	57	Random	0	0.48	1.52	0.57–4.03	0.40
Diarrhea I + II	55	57	Random	0	0.49	1.58	0.58–4.32	0.37
Diarrhea III + IV	55	57	Random			1.08	0.14–8.21	0.94
Nausea, vomiting	55	57	Random	0	0.42	0.83	0.30–2.28	0.72
Nausea, vomiting I + II	55	57	Random	0	0.49	0.95	0.35–2.60	0.92
Nausea, vomiting III + IV	55	57	Random			0.35	0.01–8.83	0.52
Gastrointestinal AE	52	84	Random	0	0.32	0.65	0.23–1.90	0.43
Fatigue	53	87	Random	72	0.06	0.66	0.08–5.80	0.71
Neutropenia	28	30	Random			1.09	0.28–4.25	0.90
Myelosuppression	25	57	Random			0.48	0.19–1.26	0.14

Abbreviations: AE, adverse reaction; CI, confidence interval; OR, odds ratio.

Table 5 Meta-analysis of 1-year OS, ORR, and DCR in CIK and DC–CIK subgroups

Immunotherapy type (subgroup)	Parameters	Number of patients (n)		Analysis method	Heterogeneity		OR	95% CI	P-value
		Experimental group	Control group		I^2 (%)	P-value
CIK	ORR	186	248	Fixed	0	0.96	1.80	1.12–2.90	0.01
	DCR	186	248	Fixed	0	0.44	2.25	1.47–3.44	0.0002
	1-Year OS	52	84	Random	86	0.007	3.58	0.41–30.95	0.25
DC–CIK	ORR	142	142	Fixed	0	0.50	1.57	0.95–2.58	0.08
	DCR	142	142	Fixed	0	0.73	2.53	1.32–4.85	0.005
	1-Year OS	190	190	Random	0	0.95	3.62	2.25–5.84	<0.00001

Abbreviations: DC–CIK, dendritic cells–cytokine-induced killer; DCR, disease control rate; OR, odds ratio; ORR, overall response rate; OS, overall survival.

Figure 8 Funnel plot of each meta-analysis.

Notes: 1-Year OS (A); 3-year OS (B); ORR (C); and DCR (D).
Abbreviations: DCR, disease control rate; ORR, overall response rate; OS, overall survival; SE, standard error; OR, odds ratio.

Figure S1 Forest plots of the comparison of PR (A), PD (B), CR (C), and SD (D) rates between the experimental and control groups.

Notes: Control group, chemotherapy alone group; experimental group, chemotherapy with DC–CIK immunotherapy. The fixed-effects meta-analysis model (M–H method) was used.

Abbreviations: CI, confidence interval; CR, complete response; CIK, cytokine-induced killer; DC–CIK, dendritic cells–CIK; M–H, Mantel–Haenszel; PD, progressive disease; PR, partial response; SD, stable disease.

Figure S2 Forest plot of the comparison of adverse effects between the experimental and control groups.

Notes: Control group, chemotherapy alone group; experimental group, chemotherapy with DC–CIK immunotherapy. The random effects meta-analysis model (M–H method) was used.

Abbreviations: CI, confidence interval; DC–CIK, dendritic cells–cytokine-induced killer; M–H, Mantel–Haenszel.

Figure S3 Forest plots of the comparison of all-grade adverse effects including fever (A), skin rash (B), leukopenia (C), thrombocytopenia (D), diarrhea (E), and nausea and vomiting (F).

Notes: Control group, chemotherapy alone group; experimental group, chemotherapy with DC–CIK immunotherapy. The fixed-effects meta-analysis model (M–H method) was used.

Abbreviations: CI, confidence interval; DC–CIK, dendritic cells–cytokine-induced killer; M–H, Mantel–Haenszel.

Figure S4 Forest plots of the comparison of ORR (A) and DCR (B) in CIK and DC–CIK subgroups.

Notes: Control group, chemotherapy alone group; experimental group, chemotherapy with DC–CIK immunotherapy. The fixed-effects meta-analysis model (M–H method) was used.

Abbreviations: CI, confidence interval; CIK, cytokine-induced killer; DC–CIK, dendritic cells–CIK; DCR, disease control rate; M–H, Mantel–Haenszel; ORR, overall response rate.

Figure S5 Forest plot of the comparison of 1-year OS in CIK and DC–CIK subgroups.

Notes: Control group, chemotherapy alone group; experimental group, chemotherapy with DC–CIK immunotherapy. The random effects meta-analysis model (M–H method) was used.

Abbreviations: CI, confidence interval; CIK, cytokine-induced killer; DC–CIK, dendritic cells–CIK; M–H, Mantel–Haenszel; OS, overall survival.

GeJNGeCLEffect of DC–CIK cells on immune function in patients with pancreatic cancer after chemotherapyJ Community Med201614172627

 Google Scholar

KangJZhangHYClinical analysis of gemcitabine chemotherapy coast CIK cell treatment of pancreatic cancerChina Contin Med Educ201685141142

 Google Scholar

LiXDClinical observation of three dimensional conformal radiotherapy concurrent with chemotherapy combined with autologous cytokine induced killer cell immunotherapy for treatment of locally advanced pancreatic cancerChina Clin Prac Med2016726466

 Google Scholar

LiuAHInfluence of chemotherapy combined with DC–CIK cell on the immune function in patients with pancreatic cancerChin J Clin201262063016305

 Google Scholar

MuLZhongXPLiuHMClinical efficacy evaluation of DC–CIK in the treatment of advanced pancreatic cancer after chemotherapyGuizhou Med J2016405532535

 Google Scholar

ShenDLiuTLinQFClinical evaluation of cytokine-induced killer cells combination with chemotherapy in patients with advanced pancreatic cancerJ Prac Med2015311321482151

 Google Scholar

WangJEffects of gemcitabine chemotherapy combined with CIK cells therapy in the treatment of pancreatic cancerMed Pharm Yunnan2015362183185

 Google Scholar

WangMShiSBQiJLTangXYTianJS-1 plus CIK as second-line treatment for advanced pancreatic cancerMed Oncol201330474724122257

 PubMedGoogle Scholar

WangZLiuYLiRAutologous cytokine-induced killer cell transfusion increases overall survival in advanced pancreatic cancerJ Hematol Oncol201691626842696

 PubMedGoogle Scholar

WenQXZhuYXuBWangMFThe study of clinical application of DC–CIK combined with chemotherapy on advanced pancreatic cancerMod J Integr Trad Chin West Med2013223640654066

 Google Scholar

ZhangYHWangMHTianYXuFClinical research of patients with advanced pancreatic cancer treated with CIK cells combined with chemotherapyJ Basic Clin Oncol2013264317319

 Google Scholar

ZhangYLStudy of the influence on immunologic balance and clinical effect by chemotherapy combined with DC–CIK cell to patients with pancreatic cancerChina J Mod Med20142494245

 Google Scholar

ZhangZQWangZYZhengSWangXZHeLJEffect of DC–CIK cell therapy on immune function and clinical efficacy analysis of DC–CIK for treatment of pancreatic cancer after chemotherapyChina Prac Med2016117183184

 Google Scholar

ZhengCYinYLJinHFLiuHQEffect of chemotherapy combined with DC–CIK cell therapy on immune function in patients with pancreatic cancerBao Jian Wen Hui20166153

 Google Scholar