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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 4  |  Page : 807-814

A meta-analysis of adoptive immunotherapy in postoperative hepatocellular carcinoma


1 Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
2 Department of Colorectal Surgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
3 Department of Gastroenterology, Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China

Date of Web Publication27-Jun-2018

Correspondence Address:
Bimang Fu
Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital of Kunming Medical University, No. 374, Dianmian Road, Kunming 650101, Yunnan
China
Tao Wu
Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital of Kunming Medical University, No. 374, Dianmian Road, Kunming 650101, Yunnan
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_858_17

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 > Abstract 


Background: Adoptive immunotherapy (AIT) has been adopted as an adjuvant treatment for hepatocellular carcinoma (HCC) patients after curative therapy. However, the outcomes of AIT remain controversial.
Purpose: The purpose of this study is to analyze the safety and efficacy of AIT with the recurrence rate and mortality.
Materials and Methods: We identified eight randomized controlled trials (RCTs) that adopted AIT to HCC after curative treatments. A meta-analysis was carried out to assess the recurrence rate and mortality.
Results: Eight RCTs with 964 patients were included in the study. The overall analysis showed that AIT treatment can not only decrease the 1-year (risk ratio [RR] =0.59, 95% confidence interval [95% CI] = 0.48–0.72, P < 0.00001), 2-year (RR = 0.69, 95% CI = 0.60–0.79, P < 0.00001), and 3-year (RR = 0.82, 95% CI = 0.74–091, P = 0.0001) recurrence, but also decrease the 1-year (RR = 0.43, 95% CI = 0.30–0.62, P = 0.00001), 2-year (RR = 0.56, 95% CI = 0.46–0.74, P < 0.00001), and 3-year (RR = 0.85, 95% CI = 0.73–0.99, P = 0.03) mortality. The results also indicate that the group of lymphokine-activated killer (LAK) cells showed lower pooled RR values compared to the group of cytokine-induced killer cells among every subgroups. However, the AIT treatment failed to affect the 5-year recurrence rate and mortality (P > 0.05).
Conclusions: This review provides available evidences that AIT, especially the treatment of LAK, can be used to decrease the early recurrence and mortality of postoperative HCC but may not the long term.

Keywords: Adoptive immunotherapy, cytokine-induced killer, hepatocellular carcinoma, lymphokine-activated killer


How to cite this article:
Zhao H, Zheng M, Wang K, Wang L, He H, Wang M, Shi Y, Huang S, Ji F, Li X, Zhu H, Wang L, Zhang X, Shi X, Zhao S, Fu B, Wu T. A meta-analysis of adoptive immunotherapy in postoperative hepatocellular carcinoma. J Can Res Ther 2018;14:807-14

How to cite this URL:
Zhao H, Zheng M, Wang K, Wang L, He H, Wang M, Shi Y, Huang S, Ji F, Li X, Zhu H, Wang L, Zhang X, Shi X, Zhao S, Fu B, Wu T. A meta-analysis of adoptive immunotherapy in postoperative hepatocellular carcinoma. J Can Res Ther [serial online] 2018 [cited 2019 Aug 26];14:807-14. Available from: http://www.cancerjournal.net/text.asp?2018/14/4/807/235101

Hui Zhao, Min Zheng and Kun Wang contributed equally to this work.





 > Introduction Top


Hepatocellular carcinoma (HCC) is the most common type of all liver cancers, and the occurrence of HCC increased by annually from globally.[1] Now, it is considered the third cause of deaths owing to cancer around the world.[2] Although the now radical treatment, such as liver resection and radiofrequency ablation (RFA), can help improve the 5-year survival rates to 37%,[3],[4] the recurrence of HCC is up to 25%.[5] These data indicate that patients with HCC need for effective adjuvant therapies to improve the outcomes after curative treatment.

The adoptive immunotherapy (AIT) can improve the outcomes of HCC patients by activating and utilizing the immune system to struggle with the cancer cells. Two main strategies are available now for AIT and consist of lymphokine-activated killer (LAK) cells and cytokine-induced killer (CIK) cells.[6] Due to the advantage that avoids the limitation caused by major histocompatibility complex, AIT has been widely used in the postoperative HCC from the first reported in the early 1980s.[7],[8] However, there is still a controversy about the value of AIT for HCC patients after curative treatment, especially in the long-term clinical outcomes.[5],[9],[10],[11] Hence, we performed this meta-analysis with published randomized controlled trials (RCTs) to evaluate the efficacy of AIT in postoperative HCC.


 > Materials and Methods Top


Literature search strategy

The relevant studies were searched in PubMed, Embase, the Cochrane Central Register of Controlled Trials, Science Citation Index, the Chinese BioMedical Literature Database, and the American Society of Clinical Oncology Annual Scientific Meeting proceedings. The keywords were as follows: “liver tumor” or “liver cancer” or “hepatic cancer” or “hepatic tumor” or “hepatocellular carcinoma” and “hepatectomy” or “hepatic resection” or “operation” or “liver resection” and “immunotherapy” or “cytokine-induced killer cells” or “lymphokine-activated killer cells” or “postoperative” or “interleukin-2.” To avoid missing relevant studies, no language restriction and no filter were applied in the search strategy.

Inclusion criteria

The research included in this systematic review satisfied the following criteria: (a) the RCTs comparing patients receiving the immunotherapy or not for the patients with HCC; (b) all the patients received curative treatment before immunotherapy; (c) the patients received otherwise similar treatments both in AIT and non-AIT arms; and (d) the study shows estimating risk ratios (RRs) with 95% confidence intervals (95% CIs). The curative therapies include RFA, percutaneous ethanol injection, and liver resection and not include the liver transplantation.

The studies were excluded if the patients involved were liver metastases and advanced or unresectable HCC. The summary publication or conference abstracts were also excluded.

Data extraction and quality assessment

Two authors (Hui zhao and Min zheng) independently screened the original literature identified on the standard form, and the discrepancies were arbitrated by a third author. The following information was extracted from each publications: author details, country, study design, sample size, surgery method, immunotherapy regimen, hepatitis B/C virus (HBV/HCV), cirrhosis rate, Child–Pugh class, and outcomes (positive and negative findings).

This systematic review was performed based on the Quality of Reporting of Meta-analyses statement.[12] Two authors (Hui zhao and Kun wang) independently evaluate the methods and results of all included RCT publications based on the method of randomization, allocation sequence generation, allocation concealment, blinding of outcome assessors, description of protocol deviations, withdrawals, and dropouts.

Statistical analysis

Review Manager 5.3 (The Cochrane Collaboration, Oxford, England) was used to analyze the data extracted from all included articles. The estimated effect measures for dichotomous outcomes were RR with 95% CI based on the Mantel–Haenszel method, and the point estimates of RR were considered statistically significant when P < 0.05. The homogeneity between studies was determined using Chi-square test, with significance set at P = 0.05. The statistical heterogeneity was evaluated using I2 (I2 = 25%, 50%, and 75% indicate low, moderate, and high heterogeneity, respectively). Meta-analysis was performed with a random-effects model if substantial heterogeneity according to the threshold of I2 was found among all included publications. Otherwise, the analysis was performed with a fixed-effects model.[13] Publication bias was exhibited with funnel plots.


 > Results Top


Description of included trials

Our search identified a total of 925 articles, which decreased to 463 after 462 duplicates or clearly irrelevant references were removed. The remaining 17 articles screened with the titles, and abstracts were evaluated for analysis at full-text level. According to the inclusion criterion, eight articles (three studies focusing on the effect of AIT in patients with advanced HCC, one focusing on different postoperative immunotherapy methods, two articles were repeated studies, and two cohort studies) were excluded from the study. At last, eight RCTs [9],[10],[11],[14],[15],[16],[17],[18] including 964 patients were included in the meta-analysis [Figure 1] and [Table 1].
Figure 1: Flowchart of study selection

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Table 1: Characteristics of included trials

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All patients involved in studies were Asian, and five trials were performed in China, one trial was performed in Korea, and two trials were performed in Japan. All the patients involved had received hepatic resection before AIT. Five trials (685 patients) adopted CIK as AIT, two trials (85 patients) adopted CIK plus interleukin-2 (IL-2) as AIT, and one trial adopted transcatheter arterial chemoembolization (TACE) and LAK plus IL-2. The messages of all studies are summarized in [Table 1].

Efficacy assessment of adoptive immunotherapy

Eight RCT studies retorted the information of 1-year recurrence and mortality, seven RCT studies provided the information of 2-year and 3-year recurrence and mortality, and four RCT studies provided the data of 5-year recurrence and mortality. Our meta-analysis indicated that immunotherapy combined with curative treatment had a significant benefit in HCC recurrence compared with the only curative treatment according to 1-year (RR = 0.59; 95% CI = 0.48–0.72; P < 0.00001, I2 = 0%), 2-year (RR = 0.69; 95% CI = 0.60–0.79; P < 0.00001, I2 = 16%), and 3-year recurrence (RR = 0.82; 95% CI = 0.74–0.91; P = 0.0001, I2 = 29%) [Figure 2]. In addition, the postoperative HCC patients received the treatment of LAK showed better clinical outcomes in HCC recurrence than the treatment of CIK in early prognosis according to 1-year recurrence by CIK (RR = 0.62; 95% CI = 0.50–0.76; P < 0.00001, I2 = 0%), 2-year recurrence by CIK (RR = 0.70; 95% CI = 0.61–0.81; P < 0.00001, I2 = 30%), and 3-year recurrence by CIK (RR = 0.84; 95% CI = 0.75–0.93; P = 0.0008, I2 = 40%) and 1-year recurrence by LAK (RR = 0.42; 95% CI = 0.24–0.75; P = 0.003, I2 = 17%), 2-year recurrence by LAK (RR = 0.53; 95% CI = 0.30–0.93; P = 0.03, I2 = 0%), and 3-year recurrence by LAK (RR = 0.67; 95% CI = 0.47–0.95; P = 0.02, I2 = 0%) [Table 2]. However, there is no significant difference for the 5-year recurrence between patients receiving immunotherapy after curative treatment than receiving curative treatment only (P > 0.05). The corresponding pooled RR was estimated at 0.94 (95% CI = 0.87–1.02; P = 0.13, I2 = 0%). Therefore, the benefits of AIT for HCC patients after curative treatment mainly existed in early stages.
Figure 2: Comparison of recurrence rate between adjuvant adoptive immunotherapy and nonimmunotherapy postoperation

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Table 2: Summary of pooled risk ratios of clinical prognosis by adjuvant immunotherapy methods

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The benefits of AIT for HCC patients after curative treatment were also proved on mortality. The meta-analysis indicated that the AIT group shows a lower 1-year (RR = 0.43; 95% CI = 0.30–0.62; P < 0.00001, I2 = 0%), 2-year (RR = 0.56; 95% CI = 0.46–0.74; P < 0.00001, I2 = 0%), and 3-year mortality (RR = 0.85; 95% CI = 0.73–0.99; P = 0.03, I2 = 57%). Moreover, the LAK subgroup showed lower mortality compared to the subgroup of CIK according to the 1-year mortality by CIK (RR = 0.46; 95% CI = 0.32–0.66; P < 0.0001, I2 = 11%), 2-year mortality by CIK (RR = 0.60; 95% CI = 0.47–0.77; P < 0.0001, I2 = 11%), and 3-year mortality by CIK (RR = 0.87; 95% CI = 0.75–1.02; P < 0.0001, I2 = 67%) and 1-year mortality by LAK (RR = 0.14; 95% CI = 0.02–1.10; P = 0.06, I2 = 0%), 2-year mortality by LAK (RR = 0.36; 95% CI = 0.13–1.02; P = 0.05, I2 = 0%), and 3-year mortality by LAK (RR = 0.61; 95% CI = 0.35–1.07; P = 0.08, I2 = 0%) [Table 2]. However, there is no significant difference for the 5-year mortality between patients receiving immunotherapy after curative treatment than receiving curative treatment only (P > 0.05) [Figure 3].
Figure 3: Comparison of mortality between adjuvant adoptive immunotherapy and nonimmunotherapy postoperation

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Safety assessment of adoptive immunotherapy

None of the eight RCTs included reported serious adverse events caused by AIT. The common AIT agent-related adverse events include fever and chills. Only five patients have not fulfilled AIT for the side effects of persistent fever.[11] Other patients' fever in this meta-analysis had been controlled easily with symptomatic therapies. There are also several rare adverse events, such as myalgia, headache, dizziness, fatigue, and nausea, with the Grade of 1 or 2. None of the patients delay or stop treatment because of the adverse events except for the five patients mentioned above. All eight articles included had not reported hepatic deterioration, infection, or autoimmune disorder.

Assessment of publication bias

Funnel plots of the eight studies were performed to evaluate the publication bias in this meta-analysis, and the symmetrical of the funnel plots indicates minimal risk of publication bias [Figure 4] and [Figure 5].
Figure 4: Funnel plots of adjuvant adoptive immunotherapy and recurrence rate

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Figure 5: Funnel plots of adjuvant adoptive immunotherapy and mortality

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 > Discussion Top


Our meta-analysis suggests that AIT is a safe and efficient treatment strategy that can improve significantly the clinical prognosis (recurrence and survival rate) for postoperative HCC in early stage (<3 years) but not in late stage (5 years). This may mean that AIT may hold a powerful destroy role on tumor cells in a short period but may have no effect in the long term. Hence, the underlying mechanism of AIT in postoperative HThe reason for this is that the immune response is significantly suppressed in HCC patients and tumor cells could escape the host immune surveillance, which make the tumor is difficult to cure. The cellular immunity plays a major role in the fighting with tumor, and the CIK or LAK cells' immunotherapy can play an antitumor role by restoring the patient's cellular immune responses; thus, the AIT treatment may hold a great promise in postoperative HCC.

An early study showed that both the recurrence and mortality were significantly decreased in AIT group compared with control group,[19] and one included study reported that there were no died and no recurrence of patients in the 5-year follow-up.[17] Moreover, another studies showed that the patients received immunotherapy had undergone fewer burden of micrometastases than those controls.[19] Hence, the immunotherapy could improve the clinical outcome for postoperative HCC.

The protective role of postoperative immunotherapy in HCC patients appears to be enhanced by the adjuvant TACE and interferon (IFN).[14],[17],[18] There was a significant reduction both recurrence and mortality in the studies that adjuvant TACE or IFN was used combined with postoperative immunotherapy compared than the studies only used the immunotherapy.[9],[14],[16],[17] This phenomenon may be evaluated with the enhancement of immunity system. Various cytokines including IFN (IFN-α, IFN-β, and IFN-γ) were dysregulated in HCC progression and contribute to HCC progression, and the IFN may play an anticancer effect in HCC by inducing tumor cell apoptosis.[20],[21],[22],[23]

There was no other severe side effect reported except the persistent fever due to the immunotherapy. On the contrary, several symptoms (appetite, sleep, and body weight) were ameliorated in HCC patients receiving the CIK treatment strategy.[24] Therefore, immunotherapy not only improves the clinical prognosis but also improves the quality of life of postoperative HCC patients. Mo et al. investigated the role of AIT for HCC patients and demonstrated that adjuvant AIT for HCC patients after curative therapy reduces the risk of mortality rate and HCC recurrence,[25] which is consistent with the findings of Yuan et al.[26] Previous studies [27],[28],[29],[30],[31] have investigated the clinical efficacy of CIK cell infusions combined with alternative conventional therapies upon HCC patients and found that for HCC patients with Barcelona clinic liver cancer score ≤ B, CIK cell infusions combined with alternative conventional therapies significantly increased the recurrence-free survival and overall survival of HCC patients, suggesting that application of this AIT is highly recommended for the treatment of HCC.

However, there are several limitations in this systematic review. First, all eight included trials were from in Asia. Second, the number of patients involved in the study is not very large and the follow-up period was not very long in several articles. Third, the important features of HCC such as tumor size and HBV or HCV infection are not balanced. Fourth, not all the articles described the clinic random allocation concealment. All of those limitations weaken the strength of this study.


 > Conclusions Top


This systematic review provides a strongly evidence on the safety and efficacy of AIT treatment for postoperative HCC patients and a striking difference between the two main treatment strategies (CIK and LAK). Based on the encouraging evidence, the AIT treatment has showed the power to improve the early clinical outcome (recurrence and survival rate) but has fails to ameliorate the late clinical outcome. Therefore, more studies are needed to investigate the effect of AIT treatment, to improve overall clinical outcome.

Acknowledgements

This research was supported by grants from the National Natural Science Foundation of China (No. 81660407).

Financial support and sponsorship

This research was supported by grants from the National Natural Science Foundation of China (No. 81660407) and The basic Research on the Application of Yunnan Province (No.2017FE468(-056).

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Velázquez RF, Rodríguez M, Navascués CA, Linares A, Pérez R, Sotorríos NG, et al. Prospective analysis of risk factors for hepatocellular carcinoma in patients with liver cirrhosis. Hepatology 2003;37:520-7.  Back to cited text no. 1
    
2.
Nordenstedt H, White DL, El-Serag HB. The changing pattern of epidemiology in hepatocellular carcinoma. Dig Liver Dis 2010;42 Suppl 3:S206-14.  Back to cited text no. 2
[PUBMED]    
3.
Li W, You X, Li L, Zhong J. Hepatic resection for hepatocellular carcinoma involving a single large tumor, multiple tumors or macrovascular invasion. Zhonghua Yi Xue Za Zhi 2015;95:3115-8.  Back to cited text no. 3
[PUBMED]    
4.
Lim KC, Chow PK, Allen JC, Siddiqui FJ, Chan ES, Tan SB, et al. Systematic review of outcomes of liver resection for early hepatocellular carcinoma within the Milan criteria. Br J Surg 2012;99:1622-9.  Back to cited text no. 4
    
5.
Wang H, Liu A, Bo W, Feng X, Hu Y, Tian L, et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma patients after curative resection, a systematic review and meta-analysis. Dig Liver Dis 2016;48:1275-82.  Back to cited text no. 5
[PUBMED]    
6.
Chang HH, Hsieh KY, Yeh CH, Tu YP, Sheu F. Oral administration of an Enoki mushroom protein FVE activates innate and adaptive immunity and induces anti-tumor activity against murine hepatocellular carcinoma. Int Immunopharmacol 2010;10:239-46.  Back to cited text no. 6
[PUBMED]    
7.
Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA. Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. J Exp Med 1982;155:1823-41.  Back to cited text no. 7
[PUBMED]    
8.
Schmidt-Wolf IG, Negrin RS, Kiem HP, Blume KG, Weissman IL. Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity. J Exp Med 1991;174:139-49.  Back to cited text no. 8
[PUBMED]    
9.
Lee JH, Lee JH, Lim YS, Yeon JE, Song TJ, Yu SJ, et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology 2015;148:1383-91.e6.  Back to cited text no. 9
    
10.
Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: A randomised trial. Lancet 2000;356:802-7.  Back to cited text no. 10
[PUBMED]    
11.
Hui D, Qiang L, Jian W, Ti Z, Da-Lu K. A randomized, controlled trial of postoperative adjuvant cytokine-induced killer cells immunotherapy after radical resection of hepatocellular carcinoma. Dig Liver Dis 2009;41:36-41.  Back to cited text no. 11
[PUBMED]    
12.
Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF, et al. Improving the quality of reports of meta-analyses of randomised controlled trials: The QUOROM statement. Quality of reporting of meta-analyses. Lancet 1999;354:1896-900.  Back to cited text no. 12
    
13.
Borenstein M, Hedges LV, Higgins JP, Rothstein HR. A basic introduction to fixed-effect and random-effects models for meta-analysis. Res Synth Methods 2010;1:97-111.  Back to cited text no. 13
[PUBMED]    
14.
Kawata A, Une Y, Hosokawa M, Wakizaka Y, Namieno T, Uchino J, et al. Adjuvant chemoimmunotherapy for hepatocellular carcinoma patients. Adriamycin, interleukin-2, and lymphokine-activated killer cells versus adriamycin alone. Am J Clin Oncol 1995;18:257-62.  Back to cited text no. 14
[PUBMED]    
15.
Xu L, Wang J, Kim Y, Shuang ZY, Zhang YJ, Lao XM, et al. Arandomized controlled trial on patients with or without adjuvant autologous cytokine-induced killer cells after curative resection for hepatocellular carcinoma. Oncoimmunology 2016;5:e1083671.  Back to cited text no. 15
[PUBMED]    
16.
Yu X, Zhao H, Liu L, Cao S, Ren B, Zhang N, et al. Arandomized phase II study of autologous cytokine-induced killer cells in treatment of hepatocellular carcinoma. J Clin Immunol 2014;34:194-203.  Back to cited text no. 16
[PUBMED]    
17.
Xie L, Pang R, Jin Y, Xiang S, Li H. Effects of hepatic artery chemotherapeutic embolization combined with perfusing LAK cells into hepatic artery after radical operation of liver cancer. Zhonghua Gan Zang Bing Za Zhi 2000;8:142-3.  Back to cited text no. 17
[PUBMED]    
18.
Zhou W, Wu M, Chen H. The effects of combined hepatectomy and immuno-chemotherapy on postoperative recurrence rate of primary liver cancer. Zhonghua Wai Ke Za Zhi 1995;33:35-7.  Back to cited text no. 18
[PUBMED]    
19.
Takayama T, Makuuchi M. Prevention of hepatocellular carcinoma recurrence: Actuality and perspectives. Hepatogastroenterology 2002;49:87-90.  Back to cited text no. 19
[PUBMED]    
20.
Budhu A, Wang XW. The role of cytokines in hepatocellular carcinoma. J Leukoc Biol 2006;80:1197-213.  Back to cited text no. 20
[PUBMED]    
21.
Herzer K, Hofmann TG, Teufel A, Schimanski CC, Moehler M, Kanzler S, et al. IFN-alpha-induced apoptosis in hepatocellular carcinoma involves promyelocytic leukemia protein and TRAIL independently of p53. Cancer Res 2009;69:855-62.  Back to cited text no. 21
[PUBMED]    
22.
Li P, Du Q, Cao Z, Guo Z, Evankovich J, Yan W, et al. Interferon-γ induces autophagy with growth inhibition and cell death in human hepatocellular carcinoma (HCC) cells through interferon-regulatory factor-1 (IRF-1). Cancer Lett 2012;314:213-22.  Back to cited text no. 22
[PUBMED]    
23.
Obora A, Shiratori Y, Okuno M, Adachi S, Takano Y, Matsushima-Nishiwaki R, et al. Synergistic induction of apoptosis by acyclic retinoid and interferon-beta in human hepatocellular carcinoma cells. Hepatology 2002;36:1115-24.  Back to cited text no. 23
[PUBMED]    
24.
Shi M, Zhang B, Tang ZR, Lei ZY, Wang HF, Feng YY, et al. Autologous cytokine-induced killer cell therapy in clinical trial phase I is safe in patients with primary hepatocellular carcinoma. World J Gastroenterol 2004;10:1146-51.  Back to cited text no. 24
[PUBMED]    
25.
Mo HY, Liao YY, You XM, Cucchetti A, Yuan BH, Li RH, et al. Timely meta-analysis on the efficacy of adoptive immunotherapy for hepatocellular carcinoma patients after curative therapy. PLoS One 2017;12:e0174222.  Back to cited text no. 25
    
26.
Yuan BH, Li RH, Yuan WP, Yang T, Tong TJ, Peng NF, et al. Harms and benefits of adoptive immunotherapy for postoperative hepatocellular carcinoma: An updated review. Oncotarget 2017;8:18537-49.  Back to cited text no. 26
[PUBMED]    
27.
Li YC, Zhao L, Wu JP, Qu CX, Song QK, Wang RB, et al. Cytokine-induced killer cell infusion combined with conventional treatments produced better prognosis for hepatocellular carcinoma patients with barcelona clinic liver cancer B or earlier stage: A systematic review and meta-analysis. Cytotherapy 2016;18:1525-31.  Back to cited text no. 27
    
28.
Xie F, Zhang X, Li H, Zheng T, Xu F, Shen R, et al. Adoptive immunotherapy in postoperative hepatocellular carcinoma: A systemic review. PLoS One 2012;7:e42879.  Back to cited text no. 28
[PUBMED]    
29.
Zhong JH, Ma L, Wu LC, Zhao W, Yuan WP, Wu FX, et al. Adoptive immunotherapy for postoperative hepatocellular carcinoma: A systematic review. Int J Clin Pract 2012;66:21-7.  Back to cited text no. 29
[PUBMED]    
30.
Zhou X, Liao Y, Li H, Zhao Z, Liu Q. Dendritic cell vaccination enhances antiangiogenesis induced by endostatin in rat glioma. J Cancer Res Ther 2016;12:198-203.  Back to cited text no. 30
[PUBMED]    
31.
Zhao Y, Jin Y, Wu Y. Postoperative infectious complications after liver resection for hepatocellular carcinoma. J Cancer Res Ther 2016;12 (Suppl):C268-C270.  Back to cited text no. 31
    


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