Combined immunotherapy with dendritic cells and cytokine-induced killer cells for malignant tumors: A systematic review and meta-analysis

https://doi.org/10.1016/j.intimp.2014.07.019Get rights and content

Highlights

  • We searched RCTs including published, in press, on-going and unpublished.

  • We included all studies which are completely randomized controlled trials.

  • We combined trials using Review Manager (Version 5.2, 2011).

Abstract

Purpose

A new strategy of adoptive and passive immunotherapy involves combining dendritic cells (DCs) with a subset of natural killer T lymphocytes termed cytokine-induced killer (CIK) cells. The objective of this systematic review and meta-analysis was to evaluate the safety and efficacy of DC–CIK therapy vs. placebo, no intervention, conventional treatments, or other complementary and alternative medicines for malignant tumors.

Method

We searched PubMed, Medline, Embase, Cochrane, Wangfang, Weipu, CNKI databases and reference lists of articles. We selected randomized controlled trials of DC–CIK therapy vs. placebo, no intervention, conventional treatments, or other complementary and alternative medicines in patients with all types and stages of malignant tumor. Primary outcome measures were overall survival and treatment response. Secondary outcome measures were health-related quality of life (HRQoL) assessment, progression free survival (PFS), and adverse events.

Results

Six trials met our inclusion criteria. There was evidence that chemotherapy + DC–CIK increased the 2-year (RR 2.88, 95% CI 1.38 to 5.99, P = 0.005) and 3-year (RR 11.67, 95% CI 2.28 to 59.69, P = 0.003) survival rates and progression free survival (RR 0.64, 95% CI 0.34 to 0.94, P < 0.0001) in patients with non-small cell lung cancer compared to those treated with chemotherapy alone. DC–CIK therapy appears to be well-tolerated by cancer patients and to improve post-treatment patient health related quality of life.

Conclusion

DC–CIK immunotherapy is a safe and effective treatment for patients with malignant tumors. Further clinical trials to provide supportive evidence for the routine use of DC–CIK therapy in clinical practice are warranted.

Introduction

Malignant tumors are a leading cause of disease and death worldwide. In 2008, there were 7.6 million global deaths from cancer, with 45% of these deaths occurring in developed regions [1]. By 2030, the burden of cancer is predicted to increase to 22 million new cases per year [1]. Most patients with advanced malignant disease are not cured by standard forms of cancer therapy such as surgery, radiation, or chemotherapy, some of which are associated with adverse events. Among the available therapeutic regimens for malignant tumors, immunotherapy has recently become the fourth most important treatment modality, resulting in improved clinical outcomes [2], [3]. There have been numerous trials evaluating the safety and efficacy of cancer medications over the past few decades. Among them, dendritic cell (DC) co-culture with cytokine-induced killer (CIK) cells is one option that has been widely studied.

In 2011, Dr. Ralph Steinman was awarded the Nobel Prize for Physiology/Medicine for his discovery of DCs as “gatekeepers of the immune system” [4], [5]. DCs are major antigen presenting cells (APCs), which capture and process antigens including tumor-associated antigens. DCs have been widely implicated in the process of “immunogenic apoptosis, or immunogenic cell death (ICD).” ICD is an apoptotic cell death program that is essential for inciting anti-tumor immunity without involving local or systemic inflammation. DCs have an obligatory contribution to ICD as they engulf, process, and present antigens from dying tumor cells, as well as that of several T lymphocyte populations [6]. DCs can initiate adaptive immune responses and activate antigen specific cytotoxic T lymphocyte responses against cancer, including the secretion of cytokines to initiate the cellular and humoral immune responses [7].

CIK cells are a subset of natural killer T lymphocytes, but their killing is non-major histocompatibility complex (MHC)-restricted. CIK cells have a marked ability to proliferate and are able to eradicate or reduce tumors. Schmidt-Wolf et al. first demonstrated that CIK cells possess superior cytolytic activities against cancer compared to lymphokine-activated killer cells [8]. The increased anti-tumor activity of CIK cells may be attributed to a high proliferation rate of the CD3+CD56 + phenotype, efficacy with low toxicity, and few adverse events [2].

Taken together, these data indicate that the immune system has evolved to recognize (DCs) and eliminate (CIK) dying and dead cells. Therefore, increasing the recruitment of DCs and CIK cells into the tumor bed is essential to effectively eliminate cancer cells. Recently, an increasing number of studies has indicated that DC–CIK immunotherapy can provide a major positive impact on patients with cancer (Fig. 1).

Eliminating cancer cells with chemotherapy or radiotherapy is associated with many adverse events. Programmed cell death, or apoptosis, is a normal process by which self-destruction of healthy cells occurs without activating local or systemic inflammation [9], [10]. DCs have an obligatory contribution to apoptosis, and DCs are required to initiate a tumor-specific immune response to apoptotic cancer cells. Evidence suggests that specific cytotoxic T lymphocytes can be generated in cancer patients by human DCs pulsed with tumor-associated antigens [11]. A meta-analysis indicates that severe lymphopenia (< 1000 lymphocytes/μL) negatively affects the response to chemotherapy of multiple distinct solid cancers [12]. These observations imply that DC co-culture with CIK cells can increase lymphopenia and remove cancer cell-like apoptosis without inflammation. Many studies show that DC co-culture with CIK cells is associated with few side effects and can decrease the incidence of adverse events associated with chemotherapy.

Regenerative anti-tumor immunotherapy is currently still in the testing phase. Several human trials have been evaluated, but most of the relevant DC–CIK clinical trials have been conducted in China. To the best of our knowledge, there is no systematic evaluation of the safety and efficacy of DC–CIK therapy for clinical cancer treatment. Since DC–CIK therapy is being increasingly used, the effectiveness of DC–CIK therapy for clinical cancer treatment must be scrutinized.

We performed this systematic review and meta-analysis to evaluate the safety and efficacy of DC–CIK therapy for malignant tumors and inform future clinical trials.

The objective was to evaluate the safety and efficacy of DC–CIK therapy vs. placebo, no intervention, conventional treatments, or other complementary and alternative medicines for malignant tumors.

Section snippets

Types of studies

We included randomized controlled trials (RCTs) published, in press, on-going, or unpublished that include DC–CIK for treatment of malignant tumor in at least one observational arm and investigate at least one primary or secondary outcome. We excluded; animal and in vitro studies; studies that did not describe a randomization procedure (not true RCTs); studies that included patients without a diagnosis of cancer; studies that did not provide information on the dose of DC–CIK, the method of

Results

The characteristics of the included studies are shown in Table 1.

Discussion

The aim of this systematic review and meta-analysis was to assess the safety and efficacy of DC–CIK therapy vs. placebo, no intervention, conventional treatment, or other complementary and alternative medicines for malignant tumors.

Acknowledgment

This study was supported by International S&T Cooperation Program of China (S2012ZR0128), Key S&T Program of Guangxi Chinese Medicine University (GZKZ-Z1103) and New Century Excellent Talents (NCET-12-0745) project manager.

References (54)

  • C. Hontscha et al.

    Clinical trials on CIK cells: first report of the international registry on CIK cells (IRCC)

    J Cancer Res Clin Oncol

    (2011)
  • R. Li et al.

    Autologous cytokine-induced killer cell immunotherapy in lung cancer: a phase II clinical study

    Cancer Immunol Immunother

    (2012)
  • R.M. Steinman et al.

    Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution

    J Exp Med

    (1973)
  • A. Nobel et al.

    The gatekeepers of the immune system

    Nobel Prize in Physiology or Medicine

    (2011)
  • A.D. Garg et al.

    Cancer immunogenicity, danger signals, and DAMPs: what, when, and how?

    Biofactors

    (2013)
  • J. Banchereau et al.

    Dendritic cells and the control of immunity

    Nature

    (1998)
  • I.G. Schmidt-Wolf et al.

    Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity

    J Exp Med

    (1991)
  • L. Galluzzi et al.

    Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012

    Cell Death Differ

    (2012)
  • D.R. Green et al.

    Immunogenic and tolerogenic cell death

    Nat Rev Immunol

    (2009)
  • R. Zhong et al.

    Dendritic cells combining with cytokine-induced killer cells synergize chemotherapy in patients with late-stage non-small cell lung cancer

    Cancer Immunol Immunother

    (2011)
  • I. Ray-Coquard et al.

    Lymphopenia as a prognostic factor for overall survival in advanced carcinomas, sarcomas, and lymphomas

    Cancer Res

    (2009)
  • J.P.T. Higgins et al.

    Cochrane handbook for systematic reviews of interventions version 5.2.0

    The Cochrane Collaboration

    (2011)
  • W.Y. C. et al.

    DC–CIK cells combined with surgical treatment for hepatocellular carcinoma

    J Chongqing Med Univ

    (2012)
  • L. Yang et al.

    Enhanced antitumor effects of DC-activated CIKs to chemotherapy treatment in a single cohort of advanced non-small-cell lung cancer patients

    Cancer Immunol Immunother

    (2013)
  • H.L. Zhan et al.

    A randomized controlled trial of postoperative tumor lysate-pulsed dendritic cells and cytokine-induced killer cells immunotherapy in patients with localized and locally advanced renal cell carcinoma

    Chin Med J (Engl)

    (2012)
  • F.C. Zheng et al.

    Clinical study of stereotactic conformal body γ-knife combined with adoptive immunotherapy (dendritic cell and cytokine-induced killer cell) in the treatment for advanced

    J Chin Oncology

    (2012)
  • S.B. Shi et al.

    Effect of maintenance therapy with dendritic cells: cytokine-induced killer cells in patients with advanced non-small cell lung cancer

    Tumori

    (2012)
  • Cited by (0)

    View full text