International Immunopharmacology 61 (2018) 363–375

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International Immunopharmacology
journal homepage: www.elsevier.com/locate/intimp

Clinical efficacy and safety of CIK plus radiotherapy for lung cancer: A meta- T
analysis of 16 randomized controlled trials
⁎
Zheng Xiaoa,b, ,1, Cheng-qiong Wanga,b, Ming-hua Zhoua, Na-na Lia,b, Shi-yu Liua, Yue-juan Hea,b,
⁎⁎
Yu-zhi Wangg, Ji-hong Fengd, ,1, Xin-sheng Yaoc, Ling Chena,b, Bin Mah, Song Yua,e,
Xian-tao Zengf, Cheng-wen Lig, Jie Dingi
a
Evidence-Based Medicine Center, MOE Virtual Research Center of Evidence-based Medicine at Zunyi Medical College, Affiliated Hospital of Zunyi Medical College, Zunyi
563000, Guizhou, China
b
Department of Respiratory Medicine (Center for Evidence-Based and Translational Medicine of major infectious diseases), Affiliated Hospital of Zunyi Medical College,
Zunyi 563000, Guizhou, China
c
Department of Immunology, Zunyi Medical College, Zunyi 563000, Guizhou, China
d
Department of Oncology, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China
e
Department of Pediatric Surgery, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China
f
Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, China
g
Department of Immunology, Southwest Medical University, Luzhou 646000, Sichuan, China
h
Evidence-Based Medicine Center of Lanzhou University, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, Gansu, China
i
Outpatient Department of Psychological Counseling Clinic (Center for Evidence-Based and Translational Medicine of major infectious diseases), Affiliated Hospital of
Zunyi Medical College, Zunyi 563000, Guizhou, China

A R T I C LE I N FO A B S T R A C T S

Keywords: Objective: Cytokine-induced killer cells (CIK) therapy is the most commonly used cellular immunotherapy. The
Cytokine-induced killer cells (CIK cells) CIK plus radiotherapy was clinically used in a wide range of treatment, but the efficacy of their combination
Lung cancer against lung cancer is not clear yet. Therefore, we systematically evaluated all the related studies to reveal the
Radiotherapy combination's clinical efficacy and safety in lung cancer.
Cellular immunity
Materials and methods: We collected all the studies about CIK plus radiotherapy for lung cancer in Medline,
Radiotherapy-related toxicity
Embase, Web of Science (ISI), China National Knowledge Infrastructure Database (CNKI), Chinese Scientific
Meta-analysis
Journals Full-Text Database (VIP), Wanfang Database, China Biological Medicine Database (CBM) and Cochrane
Central Register of Controlled Trials (CENTRAL), Chinese clinical trial registry (Chi-CTR), WHO International
Clinical Trials Registry Platform (WHO-ICTRP) and US-clinical trials (March 2017). We evaluated their bias risk
according to the Cochrane evaluation handbook of randomized controlled trials (RCTs), extracted all the data,
and synthesized the data using meta analysis.
Results: We included 16 RCTs involving 1197 patients with lung cancer, and most trials had unclear risk of bias.
Meta-analysis showed that CIK therapy could increase the objective response rate (ORR) (1.32, 1.21 to 1.44), the
disease control rate (DCR) (1.13, 1.04 to 1.23), the 1-year overall survival (OS) rate (1.38, 1.16 to 1.63) and the
2-year OS rate (1.23, 1.11 to 1.35). DCs-CIK cells increased the 3-year OS rate (1.66, 1.20 to 2.29). DCs-CIK
therapy could increase the CD3+T cells (2.27, 1.47 to 3.06), CD4+T cells (1.28, 0.74 to 1.81), NK cells (2.04,
0.74 to 3.33) and CD4+/CD8+ T cells ratio (1.20, 0.64 to 1.76) and decrease the CD8+T cells (−0.84, −1.60 to
−0.08). CIK plus radiotherapy had lower risk of leukopenia (0.85, 0.76 to 0.95) and higher risk of fever (5.50,
2.71 to 11.17) than that of radiotherapy alone. Subgroup analysis showed that CIK plus radiotherapy, mainly
three dimensional conformal radiotherapy (3D-CRT) could increase the ORR, DCR, 1- and 2- year OS rate in non-
small cell lung cancer (NSCLC), and only DCR in small cell lung cancer (SCLC). Compared with CIK plus pure
radiotherapy, except for the ORR, DCR, 1-year OS rate, CIK plus chemoradiotherapy could still increase the 2-
year OS rate. DCs-CIK could increase the ORR, DCR, 1- and 2-year OS rate, CIK cells could only increase the ORR
and the 1-year OS rate.
Conclusions: CIK plus radiotherapy can improve the clinical response, OS and PFS in lung cancer. It may have

⁎
Correspondence to: Z. Xiao, Evidence-Based Medicine Center, MOE Virtual Research Center of Evidence-based Medicine at Zunyi Medical College, Affiliated Hospital of Zunyi Medical
College, Zunyi 563003, Guizhou Province, China.
⁎⁎
Correspondence to: J.-h. Feng, Department of Oncology, Affiliated Hospital of Zunyi Medical College, Zunyi 563003, Guizhou, China.
E-mail addresses: zy426f@163.com (Z. Xiao), fengjh100@163.com (J.-h. Feng).
1
Contributed equally.

https://doi.org/10.1016/j.intimp.2018.06.012
Received 21 November 2017; Received in revised form 17 May 2018; Accepted 5 June 2018
1567-5769/ © 2018 Elsevier B.V. All rights reserved.
Z. Xiao et al.
low risk of leukopenia and high risk of fever. CIK plus chemoradiotherapy, mainly 3D-CRT can improve the
clinical response, OS and PFS in NSCLC. DCs-CIK cells can improve the 1-, 2- and 3-year OS rate, and the 1- and
2-year PFS rate, and CIK cells only improve the 1-year OS rate. DCs-CIK cells can repair the antitumor immunity.
1. Introduction
Most patients with lung cancer have advanced local invasion and
distant metastasis when they are admitted to the hospital for diagnosis
[1,2]. Hence, radiochemotherapy or radiotherapy become important
therapies for lung cancer because they missed the optimal opportunity
for surgery. With a variety of acute/subacute toxicity, systemic radio-
therapy would lead to the destruction of the antitumor immunity and
diminish the clinical efficacy of the treatment. All these resulted in poor
survival rate and reduced quality of life for patients [3–6]. Thus, new
effective strategies are urgently needed. Cytokine-induced killer cells
(CIK) therapy is the most commonly used cellular immunotherapy that
includes DCs-CIK cells and CIK cells. CIK cells are CD3+CD56+ non-
major histocompatibility complex (MHC)-restricted immune effector
cells which show strong cytolytic activity against lots of tumor cells
[7–11]. Dendritic cells (DCs) are the most potent antigen-presenting
cells and major players in specific anti-tumor immune response
[12–15]. DC cells co-cultured or combined with CIK cells can re-
markably increase their cytotoxic activity [11,16–20]. Therefore, DCs-
CIK cells or CIK cells become the most commonly used cellular im-
munotherapy for many malignant tumors. Previous meta-analysis
[21,23] had shown that DCs-CIK cells or CIK cells plus chemotherapy
could improve the clinical response and increase overall survival rate
for lung cancer patients. However, can CIK therapy with radiotherapy
improve the clinical response and long-term survival? Zheng [23] re-
ported that adoptive immunotherapy with chemoradiotherapy im-
proved the 2-year progression-free survival (PFS) and 2-year overall
survival (OS). Both early-stage and advanced non-small cell lung cancer
(NSCLC) patients benefited from adoptive immunotherapy. Qian [24]
reported that adoptive immunotherapy with chemoradiotherapy could
improve the 2-year OS, but not the 2-year PFS. Specifically, early but
not advanced NSCLC patients were likely to acquire much greater
benefit from the adoptive immunotherapy. Results revealed that
adoptive immunotherapy with chemoradiotherapy could increase the
survival rate for patients. But whether it can improve the 2-year PFS is
still controversial. In the two meta-analysis [23,24], adoptive im-
munotherapy had significant clinical heterogeneity, which included CIK
cells, DC-CIK cells, lymphokine-activated killer cell (LAK) and tumor
infiltrating lymphocyte (TIL). Their results only indicated that CIK cells
or DCs-CIK cells plus chemoradiotherapy might have been beneficial to
patients with lung cancer. But, current evidences couldn't help to reveal
the clinical efficacy, OS and PFS of CIK therapy for lung cancer. How-
ever, the application of CIK plus radiotherapy was clinically tired in a
wide range [25–28], and the evaluation of the combination efficacy
against lung cancer is not clear yet. There is a lack of optimal evidence
to prove the efficacy of the treatments. Besides, there was clinical
heterogeneity in pathological types of lung cancer and types of CIK
therapy and radiotherapy. All these are important factors that hinder
the achievement of optimal immunotherapy. So, to further confirm
whether CIK cells plus radiotherapy improve the tumor response and
long-term survival for lung cancer patients, and reveal its optimal
treatment strategy, we attempted to systematically evaluate all the re-
lated studies.
2. Materials and methods
This article followed Preferred Reporting Items for Systematic
Reviews and Meta-Analyses guidelines (PRISMA guidelines). Ethical
approval was not required, as our study was a meta-analysis of pub-
lished or unpublished studies.
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International Immunopharmacology 61 (2018) 363–375
2.1. Inclusion criteria
Included studies must meet the following criteria. Patients with lung
cancer were diagnosed in accordance with histopathological and cyto-
logical criteria and without restriction on the clinical and pathological
stages. Study designs were randomized controlled trials (RCTs).
Interventions group undergone CIK therapy that included CIK cells or
DCs-CIK cells therapy, and control group undergone radiotherapy or
chemoradiotherapy alone. All patients prior to being included in the
study were not treated using other immunotherapy, argon‑helium knife
and microwave ablation. All patients had normal liver and kidney
function. Clinical efficacy was evaluated using tumor responses, long-
term survival and cellular immunity, and safety was evaluated using
acute/subacute toxicity. No restrictions were set on the duration of
follow-ups and types of settings.
2.2. Exclusion criteria
Excluded studies must meet the following criteria: Duplicates;
Unrelated studies including studies concerning animal and in-vitro,
other types of tumors, unrelated CIK cells therapy, CIK plus non
radiotherapy or alone; Non randomized controlled studies including
case control studies (CCS), cross-sectional studies (CSS), and series case
reports; Abstracts and reviews without specific data; Unrelated SR and
meta-analysis including DCs-CIK cells, CIK cells or adoptive im-
munotherapy plus chemotherapy; Studies without usable data which
clinical response, survival or cellular immunity were not reported in the
article, authors were unavailable and data was not extracted in Kaplan-
Meier survival curves using the Engauge Digitizer 4.1.
2.3. Literature search
Two reviewers (Chengqiong Wang and Minghua Zhou) in-
dependently searched records in electronic databases using the search
strategy (“Lung Neoplasms”[Mesh] OR “Carcinoma, Non-Small-Cell
Lung”[Mesh] OR non small cell lung cancer OR non-small cell lung
cancer OR non-small-cell lung cancer OR NSCLC OR pulmonary neo-
plasms OR lung neoplasm OR pulmonary neoplasm OR lung cancer OR
lung cancers OR pulmonary cancer OR pulmonary cancers OR lung
carcinoma OR pulmonary carcinoma) AND (cytokine induced killer OR
cytokine-induced killer OR cytokine activated killer OR cytokine-acti-
vated killer OR OKT3 activated lymphocytes OR CD3 activated killer
OR CD3 activated lymphocytes OR OKT3-activated killer OR CD3AK
cells OR DC-CIK OR DC CIK OR CIK OR CAK) AND
(“Radiotherapy”[Mesh] OR “Radiation”[Mesh] OR irradiation OR ra-
diation OR radiotherapy OR radiotreatment OR intensity modulated
radiation therapy OR gamma knife OR radiosurgery OR SRT OR 3DCRT
OR IMRT OR cyber Knife OR tomotherapy OR γ knife OR three di-
mensional conformal radiotherapy OR stereotactic body radiotherapy
OR SBR OR stereotactic radiotherapy). Published studies were retrieved
in Medline, Embase, Web of Science (ISI), China National Knowledge
Infrastructure Database (CNKI), Chinese Scientific Journals Full-Text
Database (VIP), Wanfang Database, China Biological Medicine
Database (CBM) (established to March 2017) and Cochrane Central
Register of Controlled Trials (CENTRAL) (Issue 3 of 12, March 2017).
Ongoing studies were retrieved in Chinese clinical trial registry (Chi-
CTR, http://www.chictr.org.cn), WHO International Clinical Trials
Registry Platform (WHO-ICTRP, http://apps.who.int/trialsearch/), and
US-clinical trials (https://clinicaltrials.gov/, established to March
2017). All searches were implemented using the Mesh and free word.
Z. Xiao et al. International Immunopharmacology 61 (2018) 363–375

All researches were limited to Chinese and English databases. Finally,
we rigorously evaluated the relevant systematic review (SR) or meta-
analysis, selected all studies meeting inclusion criteria from the refer-
ences.
2.4. Methodological bias evaluation
allocation concealment, the blinding of implementers and patients, the
blinding of outcome assessments, the lost to follow-ups, the selective
reporting. and the other bias was defined as Whether or not the baseline
is comparable. We judged each item on three levels (“Yes” for a low risk
of bias, “No” for a high risk of bias and “Unclear”). Then, we assessed
the trials and categorized them into three levels such as low risk of bias,
high risk of bias, and unclear risk of bias.

We evaluated the methodological bias risk of all the included-stu-

dies according to the Cochrane evaluation handbook of RCTs (5.1.0)
[29]. The bias parameters were the random sequence generation, the
Identification

Published studies Ongoing studies

CBM (n=64); CNKI (n=118);Wanfang Chi-CTR (n=3);
(n=133); VIP (n=157); CENTRAL US-clinical trials (n=0)
(n=4); Pubmed (n=38); ISI (n=15); WHO- ICTRP (n=3)
Embase (n=37)

Identified 566 records

through database searching
and 6 clinical trials
Screening

Read title and excluded 216 duplicated

records and 3 trials.

Included 350 records and 3

clinical trials
Read the abstract and excluded 87 reviews
and 5 unrelated SR or meta-analysis; 1
patent and 12 generic; 111 studies
unrelated CIK therapy; 5 abstract; 34
in-vitro and 11 animal studies; 14 studies
about others or non-classified tumors, and
Eligibility

33 CIK plus non radiotherapy or alone.

Included 35 published
studies, 2 meta-analysis and
3 clinical trials
Read full text and exclude 1 duplicate; 10
case control studies; 3 cross-sectional
studies, 2 series case reports, 3 studies
without usable data ; clinical trials with 1
case series (ChiCTR-ONC-16008786), 1
CCS (ChiCTR-TRC-12002369), and 1
without data ( ChiCTR-IPR-14005434).
16 RCTs from database
Included

2 RCTs from meta-analysis

Excluded the 2duplicates

16 RCTs were included for

meta- analysis

Fig. 1. Articles retrieved and assessed for eligibility.

After successively applying the inclusion and exclusion criteria, 16 RCTs were included, but no clinical trials with usable data.

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2.5. Selection and evaluation of study
Two reviewers (Nana Li and Shiyu Liu) independently selected all
the eligible studies according to the inclusion and exclusion criteria.
Two reviewers (Nana Li and Shiyu Liu) independently evaluated their
methodological bias risk using the Cochrane evaluation handbook of
RCTs (5.1.0) [29]. Any disagreements were resolved by discussing with
each other or with Zheng Xiao.
2.6. Definition of outcome measures
According to the World Health Organization (WHO) guidelines for
solid tumor responses [30] or Response Evaluation Criteria in Solid
Tumors (RECIST) [31], clinical responses were evaluated using objec-
tive response rate (ORR) and disease control rate (DCR). Indicators
were complete response (CR), partial response (PR), no change (NC)
and progressive disease (PD). ORR equals CR plus PR, and DCR equals
CR plus PR and NC. Long-term survival was evaluated using the overall
survival (OS) rate, median survival time (MST), progression free sur-
vival (PFS) rate. Cellular immunity was evaluated using the percentage
of CD3+T cells, CD4+T cells, CD8+T cells, natural killer cells (NK cells)
and CD4+/CD8+ T cells ratio in peripheral blood. All indicators were
detected after radiotherapy without limited detecting method. The
acute/subacute toxicity was evaluated using the WHO standards [30] or
common terminology criteria for adverse events version (CTCAE) [32].
The acute/subacute toxicity included the hematotoxicity as myelosup-
pression, neutropenia and thrombocytopenia; radiation pneumonitis;
radiation esophagitis; gastrointestinal toxicity as gastrointestinal reac-
tions, nausea/vomiting or diarrhea and fever.
2.7. Data extraction
Two reviewers (Yuzhi Wang and Yuejuan He) independently ex-
tracted all the data using a pre-designed data extraction form. Authors
of studies without Kaplan-Meier survival curves and relevant data were
contacted to obtain the relevant data. For the authors who were un-
available, their data was extracted using the Engauge Digitizer 4.1 in
Kaplan-Meier survival curves [33]. All the data included the publishing
time and country, study designs, demographic characteristics, treat-
ment types, usages of CIK cells or DC-CIK cells, radiotherapy types,
follow-up time, sample size of experimental and control group, clinical
response, long-term survival, cellular immunity, and acute/subacute
toxicity.
2.8. Statistical analysis
Meta-analysis was implemented by two reviewers (Chengqiong
Wang and Minghua Zhou) with Review Manager 5.3 (The Cochrane
Collaboration, Oxford, UK). The risk ratios (RR), standardized mean
difference (SMD) and 95% confidence intervals (CI) were calculated.
Statistical heterogeneity of the results across studies was assessed using
Chi-square based Q-statistic test, and the inconsistency was calculated
using I2 and P. When heterogeneity (P ≥ 0.10; I2 ≤ 50%) was rejected,
the fixed-effects model was used. Otherwise, the random effects model
was used. There was clinical heterogeneity between NSCLC and SCLC,
DC-CIK cells and CIK cells therapy, 3D-CRT and gamma knife, radio-
therapy and chemoradiotherapy. Therefore, subgroup analysis was
performed to reveal their influence on the ORR, DCR and OS rate.
Publication bias was evaluated using funnel plots if there were > 10
included studies. The sensitivity was evaluated through excluding the
poor studies and studies with overestimated effectiveness and under-
estimated toxicity [34]. The studies were identified as poor studies
when they had at least one domain considered as high risk of bias. The
studies were identified as over- or under-estimated studies when their
results were statistically different and had positive effects on publica-
tion bias and heterogeneity.
3. Results
3.1. Search results
The initial database search identified 566 published records and 6
ongoing trials using search strategies (Fig. 1). After reading the titles
and excluding the duplicates, 350 records were included. After
screeming the abstracts, we included 35 full-texts, 2 related meta-
analysis [23,24] and 3 ongoing trials. After reading the full-texts, we
included 16 RCTs [25–28,35–46], but did not include any ongoing trials
since they have no usable data. We evaluated the meta-analysis and
included 2 RCTs from the references. Finally, 16 RCTs [25–28,35–46]
were included.

Table 1
Characteristics of included studies.
First author, year Patients Intervention Follow-up Outcomes
(months)
Disease(stage) E/C M/F Years Cells Treating Cell number/times/cycles E C

Xu,Y. 2011 [36] NSCLC(III) 45/40 60/25 45–73 DCs-CIK After RT 9

CIK:1.3–1.6*10 /totality, √ 3D-CRT and NP 11–40 O1,O2,O3,O4
DC:-,10-12times/2 cycles
Han, L.2011 [35] NSCLC(IIIa/b) 40/40 54/26 38–77 CIK cells After CRT 6–8*109/time,4-6times/− √ 3D-CRT 24 O1,O2,O3
Zheng,F.2012 [37] NSCLC(III-IV) 36/36 44/28 – DCs-CIK – 3–6*1010/cycles, 6times/ √ Gamma knife – O1,O3
2 cycles
Yang,Q.2013 [38] NSCLC(III-IV) 31/30 37/24 34–78 CIK cells After CRT −/−,5times/− √ 3D-CRTand TP/GP – O4
Ma,H.2014 [39] SCLC 23/22 – – DCs-CIK After CRT −/−,5times/− √ 3D-CRT and EP 24 O1,O2,O3,O4
Zhu, X.2015 [43] NSCLC(III-IV) 30/33 35/28 50–75 DCs-CIK After CRT −/−,2-3times/4 cycles √ 3D-CRT and DP 12 O1,O2,O3,O4
Dai,W.2015 [40] NSCLC(III) 30/30 39/21 24–80 DCs-CIK After CRT −/−,10-12times/2 cycles √ 3D-CRT and NP _ O1,O3,O4
Miao,X.2015 [41] SCLC 30/30 43/17 25–80 CIK cells After CRT 1*109/time,3times/− √ 3D-CRT and EP 24 O1,O2,O3
Zhao,Y.2015 [42] NSCLC(IIb-III) 30/30 37/23 41–75 DCs-CIK Concurrent −/−,5times/− √ 3D-CRT and TP – O1,O3,O4
CuiY.2016 [44] NSCLC(III-IV) 38/38 43/33 33–74 DCs-CIK After CRT 0.8–1.3*1010/cycles,6times/− √ 3D-CRT 3–36 O2
Geng,J.2016 [45] NSCLC(II-III) 32/32 31/33 50–70 DCs-CIK After CRT DC:5times,CIK:4times/− √ 3D-CRT and TP – O1,O4
He,X.2016 [46] NSCLC(III) 55/55 71/39 49–80 DCs-CIK After CRT −/−2times/2 cycles √ 3D-CRT and TP – O1,O3
Liang,H.2016 [27] SCLC 44/41 43/42 43–63 DCs-CIK Concurrent −/−,−/4 cycles √ 3D-CRT – O1,O3
Liu,Y.2016 [28] LC(III-IV) 60/60 82/38 – CIK cells Concurrent 2 × 109/time,3times/− √ Chemoradiotherapy – O1,O2
Xu, T.2016 [26] NSCLC(III-IV) 35/35 42/28 35–75 DCs-CIK After CRT l × 1010/cycles,2times/2 cycles √ 3D-CRT and PC 24 O1,O2,O3,O4
Zhang,Y.2016 [25] NSCLC(II-III) 43/43 54/32 44–71 DCs-CIK After CRT ≥1 × 1010/cycles,5 times/− √ 3D-CRT and TP – O1,O3,O4

Note: NSCLC: Non-small cell lung cancer; LC: Lung cancer; SCLC: Small cell lung cancer; E: Experimental group (CIK plus radiotherapy); C: Control group (radio-
therapy); DCs-CIK: Dendritic cells and cytokine induced killer cells; CIK cells: Cytokine induced killer cells; 3D-CRT: Three dimensional conformal radiotherapy; TP:
Paclitaxel and cisplatin; GP: Gemcitabine and Cisplatin; NP: Vinorelbine and Cisplatin; PC: Pemetrexed and carboplatin; EP: Etoposide and Cisplatin; Outcomes (O):
O1: Clinical response including the ORR and DCR; O2: Overall survival (OS) rate; O3: Acute/subacute toxicity; O4: Cellular immunity; −: Unclear; √:Yes.

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3.2. Characteristics of included studies
In this meta-analysis, we included sixteen RCTs involving 1197
patients with lung cancer such as NSCLC and SCLC from China
(Table 1). There were 715 males and 437 females with age range be-
tween 24 and 80 years. Interventions were DCs-CIK cells in 12 RCTs
[25–27,36,37,39,40,42–46] and CIK cells in 4 RCTs [28,35,38,41]. The
control group undergone radiotherapy or chemoradiotherapy, and
radiotherapy included the three dimensional conformal radiotherapy
(3D-CRT) and gamma knife. There were 602 cases of CIK plus radio-
therapy and 595 cases of radiotherapy. The usages of DC-CIK cells were
1–6 × 1010/cycle, 2–5 times/cycle and 1–6 cycles, and the CIK cells
were 1–2 × 109/time by intravenous injection. Seven studies lack re-
port of the cells' number. The time for treatment was after the radio-
therapy. The follow-up time was 3–40 months in 7 studies
[26,35,36,39,41,43,44]. The clinical response, OS rate, PFS rate, cel-
lular immunity, and acute/subacute toxicity were respectively eval-
uated in 14 studies with 1060 cases [25–28,35–37,39–43,45,46], 7
studies with 479 cases [26,35,36,39,41,43,44], 2 studies with155 cases
[26,36], 9 studies with 594 cases [25,26,36,38–40,42,43,45], and 12
studies with 876 cases [25–27,35–37,39–43,46].
3.3. Methodological bias of included studies
In 16 studies, only 8 studies [25–27,37–41] clearly reported the
random allocation methods such as random number table
A.Risk of bias summary
B.Risk of bias graph
Fig. 2. Methodological bias of the included studies.
Most trials had unclear risk of bias.
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International Immunopharmacology 61 (2018) 363–375
[25–27,37,39–41] or draw [38] (Fig. 2A). None of the studies
[25–28,35–46] provided the detailed information concerning the allo-
cation concealment and the blinding of participants, personnel and
outcome assessment, and there were selective and implementation bias.
There were lost to follow-up in three studies [36,39,42], and in-
complete report of toxicity in four studies [28,35,36,38], there were
attrition and reporting bias. Except for one study [36], other studies
had comparable baseline. In all, most trials had unclear risk of bias
(Fig. 2B).
3.4. Tumor responses
In 16 studies, 14 studies [25–28,35–37,39–43,45,46] with 1060
patients compared the ORR and DCR between CIK therapy plus radio-
therapy and radiotherapy alone (Fig. 3). Firstly, there was minimal
heterogeneity among the studies (I2 = 39%). Result (Fig. 3A) showed
that CIK therapy significantly increased the ORR via fixed-effects model
(RR = 1.32, 95%CI 1.21 to 1.44, P < 0.00001). Secondly, there was
statistical heterogeneity among the studies (I2 = 77%). Result (Fig. 3B)
showed that CIK therapy significantly increased the DCR via random-
effects model (RR = 1.13, 95%CI 1.04 to 1.23, P = 0.005).
3.5. Long-term survival
Long-term survival was evaluated using the OS rate and PFS rate. In
16 studies, only 7 studies with 479 cases [26,35,36,39,41,43,44]
Z. Xiao et al. International Immunopharmacology 61 (2018) 363–375

a. Objective response rate (ORR)

b. Disease control rate (DCR)

Fig. 3. The analysis of clinical response between the two groups.
CIK therapy remarkably increased the ORR (RR = 1.32, 95%CI 1.21 to 1.44, P < 0.00001) and DCR (RR = 1.13, 95%CI 1.04 to 1.23, P = 0.005).

reported the 1-year OS rate between CIK therapy plus 3D-CRT and 3D-
CRT alone (Fig. 4A). There was no statistical heterogeneity among the
studies (I2 = 0%). The result showed that CIK therapy plus 3D-CRT
significantly increased the 1-year OS rate (RR = 1.23, 95%CI 1.11 to
1.35, P < 0.0001) via fixed-effects model. Only 6 studies with 416
cases [26,35,36,39,41,43,44] reported the 2-year OS rate between the
two groups (Fig. 4B). There was no statistical heterogeneity among the
studies (I2 = 0%). The result showed that CIK therapy plus 3D-CRT
significantly increased the 2-year OS rate (RR = 1.38, 95%CI 1.16 to
1.63, P = 0.0002) via fixed-effects model. Only 3 studies with 231 cases
[26,36,44] reported the 3-year OS rate between DCs-CIK cells plus 3D-
CRT and 3D-CRT alone (Fig. 4C). There was no statistical heterogeneity
among the studies (I2 = 0%). The result showed that DCs-CIK cells plus
3D-CRT significantly increased the 3-year OS rate (RR = 1.66, 95%CI
1.20 to 2.29, P = 0.002) via fixed-effects model.
In 16 studies, only 2 studies with 155 cases [26,36] reported the PFS
rate between DC-CIK plus 3D-CRT and 3D-CRT alone (Fig. 5). There
was minimal statistical heterogeneity among the studies (I2 = 30%).
The result showed that DC-CIK significantly increased the 1-year PFS
rate (RR = 1.46, 95%CI 1.17 to 1.83, P = 0.0009) via fixed-effects
model. Two studies with 155 cases [26,36] reported the 2-year PFS rate
(Fig. 5B). There was no statistical heterogeneity among the studies
(I2 = 0%). The result showed that DC-CIK significantly increased the 2-
year PFS rate (RR = 1.94, 95%CI 1.29 to 2.93, P = 0.002) via fixed-
effects model. Only one study with 70 cases [26] reported the 3-year
PFS rate (Fig. 5C). The result showed that 3-year PFS rate had no sta-
tistical difference between DCs-CIK cells plus 3D-CRT and 3D-CRT
alone (RR = 3.00, 95%CI 0.89 to10.16, P = 0.08).
3.6. Cellular immunity
Cellular immunity was evaluated in eight studies with 533 cases for
DCs-CIK and one study for CIK cells [25,26,36,38–40,42,45] (Fig. 6).
Here, we only evaluated the cellular immunity between DCs-CIK plus
radiotherapy and radiotherapy alone. There was statistical hetero-
geneity among the studies (I2 = 91%, I2 = 82%, I2 = 92%, I2 = 88%
and I2 = 96%), respectively. The results showed that DCs-CIK cells
significantly increased the CD3+T cells (SMD = 2.27, 95%CI 1.47 to
3.06, P < 0.00001), CD4+T cells (SMD = 1.28, 95%CI 0.74 to 1.81,
P < 0.00001), NK cells (SMD = 2.04, 95%CI 0.74 to 3.33, P = 0.002)
and CD4+/CD8+ T cells ratio (SMD = 1.20, 95%CI 0.64 to 1.76,
P < 0.0001), and decreased the CD8+T cells (SMD = −0.84, 95%CI
-1.60 to −0.08, P = 0.03) via random-effects model.
3.7. Acute/subacute toxicity
Acute/subacute toxicity was evaluated in twelve studies with 876
cases [25–27,35–37,39–43,46] (Fig. 7). There was minimal statistical
heterogeneity (I2 = 41% and I2 = 21%) in leukopenia and thrombo-
cytopenia, and no heterogeneity (I2 = 0%) in others. The results in-
dicated that CIK plus radiotherapy had lower risk of leukopenia
(RR = 0.85, 95%CI 0.76 to 0.95, P = 0.003) and higher risk of fever
(RR = 5.50, 95%CI 2.71 to 11.17, P < 0.00001) than that of radio-
therapy alone via fixed-effects model. Differences were not statistically

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Fig. 4. The analysis of overall survival (OS) rate between the two groups.
Results showed that CIK therapy remarkably increased the 1-year OS rate (RR = 1.23, 95%CI 1.11 to 1.35, P < 0.0001) and 2-year OS rate (RR = 1.38, 95%CI 1.16
to 1.63, P = 0.0002), and DCs-CIK cells plus radiotherapy increased the 3-year OS rate via fixed-effects model (RR = 1.66, 95%CI 1.20 to 2.29, P = 0.002).

significant in myelosuppression (RR = 1.02, 95%CI 0.85 to 1.22,
P = 0.82), thrombocytopenia (RR = 0.86, 95%CI 0.61 to 1.21,
P = 0.38), radiation pneumonitis (RR = 0.83, 95%CI 0.67 to 1.03,
P = 0.09), radiation esophagitis (RR = 0.85, 95%CI 0.68 to 1.08,
P = 0.18) and gastrointestinal toxicity (RR = 0.93, 95%CI 0.83 to 1.03,
P = 0.17) between the two groups.
3.8. Subgroup analysis
There was a clinical difference between NSCLC and SCLC, DC-CIK
and CIK therapy, 3D-CRT and gamma knife, radiotherapy and che-
moradiotherapy. Therefore, subgroup analysis was performed to reveal
their influence on the ORR, DCR and OS rate (Table 2A, Figs. S1–6).
Fourteen studies with 1060 patients reported the ORR and DCR.

Fig. 5. The analysis of progression free survival (PFS) rate between the two groups
Result showed that DC-CIK cells significantly increased the 1-year PFS rate (RR = 1.46, 95%CI 1.17 to 1.83, P = 0.0009) and 2-year PFS rate (RR = 1.94, 95%CI 1.29
to 2.93, P = 0.002) via fixed-effects model. But, 3-year PFS rate had no statistical difference between DCs-CIK cells plus 3D-CRT and 3D-CRT alone (RR = 3.00,
95%CI 0.89 to10.16, P = 0.08).

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Fig. 6. The analysis of cellular immunity between the two groups.

Results showed that DCs-CIK cells remarkably increased the CD3+T cells (SMD = 2.27, 95%CI 1.47 to 3.06, P < 0.00001), CD4+T cells (SMD = 1.28, 95%CI 0.74 to
1.81, P < 0.00001), NK cells (SMD = 2.04, 95%CI 0.74 to 3.33, P = 0.002) and CD4+/CD8+ T cells ratio (SMD = 1.20, 95%CI 0.64 to 1.76, P < 0.0001) and
decreased the CD8+T cells (SMD = −0.84, 95%CI -1.60 to −0.08, P = 0.03) via random-effects model.

Subgroup analysis showed that CIK plus radiotherapy could increase
the ORR and DCR in NSCLC, and only the DCR in SCLC. CIK plus
chemoradiotherapy and radiotherapy could all increase the ORR and
DCR. And only CIK plus 3D-CRT could increase the ORR and DCR. DCs-
CIK or CIK cells plus radiotherapy could all increase the ORR, but only
DCs-CIK could increase the DCR. Seven studies with 479 patients
[26,35,36,39,41,43,44] reported the 1- and 2-year OS rate (Table 2B,
Figs. S7–12). The radiotherapy was mainly the 3D-CRT. Subgroup
analysis showed that CIK plus radiotherapy could increase 1- and 2-
year OS rate in only NSCLC, but not in the SCLC. DCs-CIK plus radio-
therapy could increase the 1- and 2-year OS rate, and CIK cells plus
radiotherapy could only increase the 1-year OS rate. CIK plus che-
moradiotherapy could increase the 1- and 2-year OS rate, and CIK plus
pure radiotherapy could only increase the 1-year OS rate.
3.9. Publication bias analysis
3.10. Sensitivity analysis
Six poor studies [28,35,36,38,39,42] had at least one domain con-
sidered as high risk of bias (Table 3A). Three studies [36,39,42] had lost
to follow-up and attrition bias, and four studies [28,35,36,38] had in-
complete report of toxicity and reporting bias. Attrition bias had po-
tential effect on all indicators, and reporting bias had potential effect on
acute/subacute toxicity. But studies with reporting bias were not in-
cluded in the meta-analysis of toxicity. Therefore, the sensitivity was
evaluated by excluding the poor studies. Except for CD8+TCells ratio,
results before and after excluding the poor studies had good stability.
Secondly, there was minimal heterogeneity in ORR and leukopenia, and
significant heterogeneity in DCR, CD3+T cells, CD4+T cells, CD8+T
cells, CD4+/CD8+T Cells ratio. There was publication bias in ORR and
DCR. The sensitivity was evaluated through excluding the studies with
overestimated effectiveness and underestimated toxicity [34]. Except
for DCR and leukopenia, other results had good consistency (Table 3B).

The funnel plots were significantly asymmetric in the studies about

ORR and DCR (Fig. 8A and B) and there was publication bias. ORR and 4. Discussion
DCR were underestimated in one [43] and two studies [25,26], re-
spectively. In this meta-analysis, we finally included 16 RCTs [25–28,35–46]

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Fig. 7. The analysis of acute/subacute toxicity between the two groups.

CIK cells plus radiotherapy had low risk of leukopenia, high risk of fever.
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Table 2
Subgroup analysis.
Table 2a. Subgroup analysis results of ORR and DCR

Subgroups Trials Cases SM Objective response rate (ORR) Trials Cases SM Disease control rate (DCR)

2
RR(95% CI) I p RR(95% CI) I2 P

Total analysis 14 1060 FEM 1.32[1.21,1.44] 39% P < 0.00001 14 1060 REM 1.13[1.04,1.23] 77% P = 0.005

Subgroups analysis via different lung cancers (Figs. S1–2)

Non-small cell lung cancer 10 750 FEM 1.28 [1.16, 1.42] 44% P < 0.00001 10 750 REM 1.10 [1.01, 1.20] 77% P = 0.04
Small cell lung cancer 3 190 FEM 1.26 [0.99, 1.62] 0% P = 0.06 3 190 REM 1.24 [1.04, 1.47] 0% P = 0.02
Lung cancer 1 120 FEM 1.75 [1.23, 2.49] No P = 0.002 1 120 REM 1.18 [0.99, 1.42] No P = 0.07

Subgroups analysis via different CIK therapy (Figs. S3–4)

DC-CIK 11 800 FEM 1.26 [1.14, 1.39] 32% P < 0.00001 11 800 REM 1.11[1.01,1.23] 77% P = 0.03
CIK cells 3 260 FEM 1.54 [1.25, 1.90] 0% P < 0.0001 3 260 REM 1.18[0.98,1.41] 63% P = 0.08

Subgroups analysis via chemoradiotherapy or radiotherapy (Figs. S5–6)

Chemoradiotherapy 11 823 FEM 1.32 [1.19, 1.45] 51% P < 0.00001 11 823 REM 1.14 [1.02, 1.27] 83% P = 0.02
Radiotherapy 3 237 FEM 1.33 [1.08, 1.65] 0% P = 0.008 3 237 REM 1.10 [1.01, 1.20] 0% P = 0.03

Subgroups analysis via different radiotherapy (Figs. S7–8)

3D-CRT 12 868 FEM 1.27 [1.16, 1.39] 29% P < 0.00001 12 868 REM 1.12 [1.02, 1.23] 79% P = 0.02
Gamma knife 1 72 FEM 1.47 [0.92, 2.34] No P = 0.11 1 72 REM 1.15 [0.91, 1.44] No P = 0.24
Uclear 1 120 FEM 1.75 [1.23, 2.49] No P = 0.002 1 120 REM 1.18 [0.99, 1.42] No P = 0.07

Table 2b. Subgroup analysis results of 1-, and 2-year OS rate

Subgroups Trials Cases SM 1-year OS rate Trials Cases SM 2-year OS rate

2
RR(95% CI) I p RR(95% CI) I2 P

Total analysis 7 479 FEM 1.23 [1.11, 1.35] 0% P < 0.0001 6 416 FEM 1.38[1.16,1.63] 0% P = 0.0002

Subgroup analysis results via different lung cancers (Figs. S9–10)

Non-small cell lung cancer 5 374 FEM 1.26 [1.12, 1.42] 0% P < 0.0001 4 311 FEM 1.45 [1.18, 1.78] 26% P = 0.0004
Small cell lung cancer 2 105 FEM 1.13 [0.94, 1.35] 0% P = 0.20 2 105 FEM 1.21 [0.90, 1.62] 0% P = 0.20

Subgroups analysis via different CIK therapy (Figs. S11–12)

DCs-CIK and radiotherapy 5 339 FEM 1.21 [1.08, 1.34] 0% P = 0.0006 4 276 FEM 1.36 [1.12, 1.64] 25% P = 0.002
CIK cells and radiotherapy 2 140 FEM 1.29 [1.03, 1.61] 60% P = 0.03 2 140 FEM 1.42[1.00,2.03] 0% P = 0.05

Subgroups analysis via chemoradiotherapy or radiotherapy (Figs. 13–14)

Chemoradiotherapy 5 323 FEM 1.20 [1.07, 1.35] 0% P = 0.002 4 260 FEM 1.41 [1.14, 1.74] 8% P = 0.001
Radiotherapy 2 156 FEM 1.28 [1.06, 1.54] 64% P = 0.01 2 156 FEM 1.31 [1.00, 1.73] 0% P = 0.05

Note: CIKcells: Cytokine induced killer cells; DC-CIK cells: Dendritic cell and Cytokine induced killer cells; 3D-CRT: Three Dimensional Conformal Radiotherapy;
ORR: Objective response rate; DCR: Disease control rate; OS: Overall survival; SM: Statistical Method; RR: Relative risk; FEM: Fixed-effects model.

with 1197 patients to evaluate the clinical response, OS rate, PFS rate,
cellular immunity, and acute/subacute toxicity between CIK therapy
plus radiotherapy and radiotherapy. Patients with NSCLC and SCLC
were included. The male and female were 715 and 437 cases with age
range between 24 and 80 years. Interventions groups undergone CIK
therapy that included the CIK cells and DCs-CIK. The control groups
undergone radiotherapy or chemoradiotherapy, and radiotherapy in-
cluded 3D-CRT and gamma knife. The usages of DC-CIK cells were
1–6 × 1010/cycle, 2–5 times/cycle and 1–6 cycles, and the CIK cells
were 1–2 × 109/time by intravenous injection. The treating time was
mainly after radiotherapy. Most patients were followed-up for
3–40 months.
CIK therapy is the most commonly used cellular immunotherapy
that included CIK cells and DCs-CIK [12–15]. Previous meta-analysis
[23,24] showed that adoptive immunotherapy such as CIK cells, LAK
and TIL with chemoradiotherapy could improve the OS in NSCLC,

A. ORR B. DCR
Fig. 8. Publication bias analysis.
ORR and DCR were objectively reported without over- or underestimation.

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Table 3
Sensitivity analysis.
Indicators N SM RR(95%CI) I2 Excluded studies [Reference number] SM N RR(95%CI) I2

Table 3A. Sensitivity analysis by excluding the poor studies

ORR 14 FEM 1.32 [1.21, 1.44] 39% Poor* [36,39,42] REM 11 1.29 [1.13, 1.48] 51%
QCR 14 REM 1.13 [1.04, 1.23] 77% Poor* [36,39,42] REM 11 1.14 [1.02, 1.27] 83%
1-year OS rate 7 FEM 1.23 [1.11, 1.35] 0% Poor* [36,39] FEM 5 1.24 [1.10, 1.39] 0%
2-year OS rate 6 FEM 1.38 [1.16, 1.63] 0% Poor* [36,39] FEM 4 1.31 [1.08, 1.59] 0%
Leukopenia 8 FEM 0.85 [0.76, 0.95] 41% Poor* [36,39,42] REM 5 0.79 [0.63, 0.99] 58%
Thrombocytopenia 3 FEM 0.86 [0.61, 1.21] 21% Poor* [39] REM 2 0.83 [0.47, 1.48] 60%
Radiation pneumonitis 9 FEM 0.83 [0.67, 1.03] 0% Poor* [36,39] FEM 6 0.87 [0.67, 1.13] 8%
Radiation esophagitis 7 FEM 0.85 [0.68, 1.08] 0% Poor* [36,42] FEM 5 0.86 [0.67, 1.11] 0%
Gastrointestinal toxicity 10 FEM 0.93 [0.83, 1.03] 0% Poor* [36,39,42] FEM 7 0.89 [0.78, 1.01] 0%
Fever 3 FEM 5.50 [2.71, 11.17] 0% Poor* [42] FEM 2 5.50 [2.43, 12.46] 0%

Indicators N SM SMD(95%CI) I2 Excluded studies SM N SMD(95%CI) I2

CD3+T cells 7 REM 2.27 [1.47, 3.06] 91% Poor* [36,39,42] REM 4 1.80 [0.94, 2.66] 89%
CD4+T cells 6 REM 1.28 [0.74, 1.81] 82% Poor* [36,39] FEM 4 1.26 [0.53, 2.00] 86%
CD8+T cells 6 REM −0.84[−1.60,-0.08] 92% Poor* [36,39] REM 4 −0.51[−1.26, 0.24] 88%
CD4+/CD8+TCells ratio 8 REM 1.20 [0.64, 1.76] 88% Poor* [36,39,42] REM 5 1.27 [0.53, 2.00] 89%
NK cells 6 REM 2.04 [0.74, 3.33] 96% Poor* [36,39,42] REM 4 2.67 [0.88, 4.46] 96%

Table 3B. Sensitivity analysis excluding the under- or over-estimated studies

ORR 14 FEM 1.32 [1.21, 1.44] 39% Over* [28,35,36,39,45,46] FEM 9 1.20 [1.07, 1.34] 0%
QCR 14 REM 1.13 [1.04, 1.23] 77% Over* [40,41,45,46] REM 10 1.07 [1.00, 1.14] 58%
Leukopenia 8 FEM 0.85 [0.76, 0.95] 41% Under* [25,41] FEM 6 0.93 [0.83, 1.05] 0%

Indicators N SM SMD(95%CI) I2 Excluded studies SM N SMD (95%CI) I2

CD3+T cells 7 REM 2.27 [1.47, 3.06] 91% Over* [25,39,42] FEM 4 1.33 [1.07, 1.60] 21%
CD4+T cells 6 REM 1.28 [0.74, 1.81] 82% Over* [39,45] FEM 4 0.84 [0.60, 1.09] 0%
CD8+T cells 6 REM −0.84[−1.60,-0.08] 92% Under* [39,45],Over* [43] REM 3 −0.42 [−0.83,-0.00] 57%
CD4+/CD8+TCells ratio 8 REM 1.20 [0.64, 1.76] 88% Over* [25,42,45] FEM 5 0.63 [0.40, 0.85] 25%
NK cells 6 REM 2.04 [0.74, 3.33] 96% Under* [39];Over* [25,36,42] FEM 2 1.60 [1.21, 1.99] 0%

Note: SM: Statistical Method; ORR: Objective response rate; QOL: Quality of life; FEM: Fixed-effects model; REM: Random-effects model; RR: Relative risk; SMD:
standardized mean difference; N: Number of included studies; CI: Confidence interval; Poor studies (Poor*) had at least one domain considered as high risk of bias;
Over*or Under*: Over-or underestimated studies which results were statistically different and had positive effects on publication bias and heterogeneity.

especially in patients with early-stage NSCLC. Can CIK plus radio-
therapy improve the clinical effectiveness in lung cancer? First, we
included 14 studies [25–28,35–37,39–43,45,46] with 1060 patients to
evaluate the tumor responses. Meta-analysis showed that CIK therapy
could significantly improve the ORR and DCR in lung cancer. Most
studies had unclear bias risk. But the ORR and DCR were under-
estimated, which was beneficial to the conclusion. Sensitivity analysis
showed that results had good stability. Therefore, we believe that CIK
plus radiotherapy could improve the clinical response. However, there
was clinical heterogeneity between NSCLC and SCLC, DC-CIK and CIK
cells therapy, 3D-CRT and gamma knife, radiotherapy and chemor-
adiotherapy. Therefore, we performed the subgroup analysis to reveal
their influence on the ORR and DCR. Subgroup analysis showed that
CIK therapy could increase the ORR and DCR in NSCLC, and only the
DCR in SCLC. The results indicated that NSCLC might be the main
target for CIK therapy. Further analysis revealed that DCs-CIK plus
radiotherapy could significantly improve the ORR and DCR, but CIK
cells could only improve the ORR. Results revealed that CIK cells and
DCs-CIK had different clinical efficacy, DCs-CIK might be better than
CIK cells. Finally, CIK plus chemoradiotherapy and radiotherapy alone
could increase the ORR and DCR. And only CIK therapy plus 3D-CRT
could increase the ORR and DCR. In summary, the results demonstrated
that the pathological types, the types of CIK therapy and radiotherapy
were important influencing factors for tumor response. The radio-
therapy was mainly 3D-CRT, NSCLC might be the main target for CIK
therapy, and DCs-CIK might be better than CIK cells.
However, can CIK plus radiotherapy prolong the survival duration?
Previous studies [23,24] didn't answer this question. To further reveal
it, we included 7 studies with 479 patients [26,35,36,39,41,43,44] to
evaluate the OS rate between CIK therapy plus radiotherapy and
radiotherapy alone. The radiotherapy was mainly the 3D-CRT. Meta-
analysis showed that CIK therapy plus 3D-CRT could significantly in-
crease the 1- and 2-year OS rate, and DCs-CIK cells could improve the 3-
year OS rate in NSCLC. There were limited studies and sample size for
this topic. Most studies had unclear bias risk. The results had good
robustness. In all, CIK therapy could improve the OS rate. Further
subgroup analysis showed that CIK therapy plus 3D-CRT could improve
the 1- and 2-year OS rate in NSCLC, but not in the SCLC. The results
further confirmed that NSCLC was the main target for CIK therapy. DCs-
CIK plus 3D-CRT could increase the 1- and 2-year OS rate, and CIK cells
could only increase the 1-year OS rate. CIK plus chemoradiotherapy
could increase the 1- and 2-year OS rate, and CIK plus radiotherapy
could only increase the 1- year OS rate. All these revealed that the
pathological types, the CIK therapy and radiotherapy were important
influencing factor for OS rate. DCs-CIK might be better than CIK cells,
and CIK plus chemoradiotherapy might be better than radiotherapy
alone. DCs-CIK cells could improve the 1-, 2- and 3-year OS rate, and
CIK cells could only improve the 1-year OS rate. However, can CIK plus
radiotherapy prolong the PFS? Zheng [23] reported that adoptive im-
munotherapy with chemoradiotherapy improved the 2-year PFS. And
Qian [24] reported that adoptive immunotherapy couldn't prolong the
2-year PFS. To further reveal it, we included 2 studies with 155 patients
[26,36] to evaluate the PFS rate between DC-CIK therapy plus 3D-CRT
and 3D-CRT alone. Meta-analysis showed that DC-CIK therapy could
increase the 1- and 2-year PFS rate, but not the 3-year PFS rate. There
were only two studies [26,36] with 155 cases, which had one high risk
study [36]. All these might result in insufficient assessment. The results
further revealed that except for the OS, DC-CIK therapy might also
improve the 1- and 2-year PFS rate, but with limited studies and
sample. And new evidences are needed to substantiate the findings.
Further analysis of other related meta-analysis [47,48] showed that CIK
cells and DCs-CIK plus chemotherapy could improve the clinical

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response and overall survival for NSCLC. The results provide indirect
evidences for this meta-analysis. In vitro and vivo studies [11,16–20]
showed that CIK cells or DCs-CIK had outstanding killing activity
against a wide range of tumor cells. The results provided basic evi-
dences for this meta-analysis. In summary, we believe that CIK plus
radiotherapy can improve the clinical response and survival rate for
lung cancer patients. DCs-CIK plus 3D-CRT can improve the 1-, 2- and
3-year OS rate, and CIK cells can only improve the 1-year OS rate.
Furthermore, DC-CIK therapy might also improve the 1- and 2-year PFS
rate. Unfortunately, current results can not reveal the clinical response,
OS and PFS of CIK therapy for SCLC, CIK cells and CIK therapy plus
gamma knife for lung cancer. NSCLC is its main target, DCs-CIK may be
better than CIK cells, and DCs-CIK plus chemoradiotherapy may be
better than radiotherapy alone. DCs-CIK plus chemoradiotherapy may
be the current optimal treatment strategy for NSCLC, but there is a lack
of direct evidence to support it.
CIK cells and DCs-CIK are important cellular immunotherapy. Can
they repair the tumor immunity in patients receiving radiotherapy?
Cellular immunity was evaluated in eight studies with DCs-CIK cells and
one study with CIK cells. Here, we only evaluated the cellular immunity
between DCs-CIK cells plus radiotherapy and radiotherapy alone. The
results showed that DCs-CIK cells could significantly increase the per-
centage of CD3+T cells, CD4+T cells and CD4+/CD8+ T cells ratio and
decrease the CD8+ T cells in peripheral blood, but with limited studies
and sample. There was high heterogeneity and poor studies in these
findings. Except for the CD8+T cells, sensitivity analysis showed that
results had good stability. Related meta-analysis [49–52] had shown
that DCs-CIK cells could improve the cellular immunity in patients with
hepatocellular carcinoma (HCC) or gastric cancer receiving che-
motherapy. Similar clinical trial [38] had revealed that CIK cells could
also improve the cellular immunity in patient with NSCLC. These stu-
dies provide indirect evidences for the conclusions in this meta-ana-
lysis. In all, we believe that DCs-CIK can repair the cellular immunity
through up-regulating the CD3+T cells, CD4+T cells and CD4+/CD8+
T cells ratio and down-regulating the CD8+T cells in patients with lung
cancer.
CIK therapy is a multitarget immunotherapy. Can CIK with radio-
therapy increase the risk of acute/subacute toxicity in patients? We
included 12 studies with 876 cases [25–27,35–37,39–43,46] to eval-
uate the acute/subacute toxicity. Meta-analysis showed that CIK plus
radiotherapy had lower risk of leukopenia and higher risk of fever than
that of radiotherapy alone. Differences were not statistically significant
in myelosuppression, thrombocytopenia, radiation pneumonitis, radia-
tion esophagitis and gastrointestinal toxicity. But there were limited
studies and sample in these findings, which might lead to insufficient
assessment. Except for the leukopenia, sensitivity analysis showed that
results had good stability. Similar meta-analysis [22,49,53,54] showed
that CIK cells and DCs-CIK cells plus chemotherapy had low risk of
hematotoxicity and gastrointestinal toxicity than that of chemotherapy
alone in patients with lung or gastric cancer. In summary, CIK with
radiotherapy may have low risk of leukopenia and higher risk of fever.
It does not seem to increase the risk of other toxicity.
There were some limitations in this study. Firstly, all studies were
published in China, therefore it might result in ethnical bias. Secondly,
most items concerning methodology were “unclear” in most studies.
Thirdly, limited studies and sample might result in insufficient assess-
ment to overall survival, PFS, cellular immunity and acute/subacute
toxicity. Fourthly, CIK included the autologous CIK cells, semi chimeric
CIK cells, umbilical cord blood CIK cells, and DC-CIK included Ag-DCs-
CIK cells and DCs-CIK cells. All these increased the clinical hetero-
geneity of this study. Fifthly, current evidences couldn't help to reveal
the clinical efficacy, OS and PFS of CIK therapy for SCLC, CIK cells, and
CIK therapy plus gamma knife for lung cancer. Finally, only nine studies
reported the number of cells and usages that had certain homogeneity.
All of these limitations might lead to deficient evaluation to the out-
come indicators.
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International Immunopharmacology 61 (2018) 363–375
5. Conclusions
The available evidences indicate that CIK plus radiotherapy can
improve the clinical response and survival rate for lung cancer patients.
Especially, DCs-CIK plus 3D-CRT can improve the 1-, 2- and 3-year OS
rate, and CIK cells can only improve the 1-year OS rate. Furthermore,
DC-CIK therapy might also improve the 1- and 2-year PFS rate. NSCLC
is the main target of CIK therapy, DCs-CIK may be better than CIK cells,
and CIK plus chemoradiotherapy may be better than radiotherapy
alone. DCs-CIK plus chemoradiotherapy may be the current optimal
treatment strategy for NSCLC. DCs-CIK cells can significantly repair the
antitumor immunity. CIK with radiotherapy may have low risk of leu-
kopenia and high risk of fever. It don't increase the risk of other toxicity.
However, can CIK therapy improve the clinical response, OS and PFS
for SCLC? Can CIK therapy plus gamma knife also improve these effects
for lung cancer? Whether DCs-CIK plus chemoradiotherapy be the
current optimal treatment strategy for NSCLC. What is the difference
between different types of CIK cells or DC-CIK cells plus radiotherapy
for lung cancer? New evidences are needed to these questions. In
consideration of the lack of high quality evidence and some limitations,
the results need to be further confirmed by large sample and well-de-
signed RCTs. Finally, we hope our study will provide valuable evidence
for the evaluation of CIK therapy. CIK therapy may become an im-
portant supplementary therapy for advanced malignant tumors.
Disclosure
All authors declare that they have no conflicts of interest.
Acknowledgments
This work was funded by Joint funds for science and technology of
Guizhou Province science and technology hall, Science and Technology
Bureau and Affiliated Hospital of Zunyi Medical College [No. (2016)
7485], special funds for science and technology research of traditional
Chinese and national medicine in Guizhou (No. QZYY 2017-084), High
level innovative talent program in Guizhou (2015. No. fzc120171001),
Doctoral Fund of Zunyi Medical College (No. F-617) and Planning fund
of philosophy and social science in Guizhou (No. 14GZYB58).
Author contributions
Conception and design: Zheng Xiao, Jihong Feng, Ling Chen and
Xingsheng Yao. Development of methodology: Zheng Xiao, Chengqiong
Wang, Bin Ma and Xiantao Zeng. Literature search: Chengqiong Wang
and Minghua Zhou. Selection and Evaluation of Articles: Nana Li and
Shiyu Liu. Data Extraction: Yuzhi Wang and Yuejuan He. Statistical
Analysis: Chengqiong Wang and Minghua Zhou. Writing, review, and/
or revision of the manuscript: Zheng Xiao, Chengqiong Wang, Xin-
sheng Yao, Ling Chen, Bin Ma, Song Yu, Cheng-wen Li and Jie Ding.
Study supervision: Zheng Xiao.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.intimp.2018.06.012.
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