Autologous cytokine-induced killer cell therapy in lung cancer patients: A retrospective study

doi:10.1016/j.biopha.2014.12.025

Biomedicine & Pharmacotherapy

Volume 70, March 2015, Pages 248-252

https://doi.org/10.1016/j.biopha.2014.12.025 Get rights and content

Abstract

Cytokine-induced killer (CIK) cells have the ability to kill tumor cells in vitro and in vivo. This study aimed to evaluate the clinical effect of adjuvant immunotherapy with CIK cells on the prognosis of lung cancer patients. In the present study, we investigated the clinical outcomes of autologous CIK cell immunotherapy for patients with lung cancer in a case–control study. Our study included 60 patients who received chemotherapy combined with autologous CIK cell adoptive immunotherapy in CIK treatment group and 60 patients who received chemotherapy alone in the control group. Progression-free survival (PFS) and overall survival (OS) of these two groups were evaluated. After 14 days of incubation in vitro, the percentages of CD3⁺, CD3⁺CD8⁺, CD3⁺CD56⁺ and CD3⁻CD56⁺ were significantly increased (P < 0.05). The clinical symptoms of 60 patients were apparently improved. No severe toxicity and side effects were observed in the CIK treatment group. The 3-year, 5-year PFS rates were 44.7% and 26.8% and the 3-year, 5-year OS rates were 74% and 62% in the CIK group, respectively, which were significantly improved compared to that in the control group. The median PFS and OS in the CIK group were significantly improved than those in the control group (PFS, 24 months vs. 14 months, P = 0.014; OS, 72 months vs. 44 months, P = 0.006). Our results indicated that autologous CIK cells can efficiently improve the immunological status and prolong PFS and OS in patients with lung cancer.

Introduction

Lung cancer is the leading cause of cancer-related death worldwide [1]. Non-small-cell lung cancer (NSCLC) accounts for about 80% of all types of lung cancer and has only 14% of 5-year survival rate [2]. Although current therapeutic regimens including surgery, chemotherapy and radiotherapy for lung cancer have improved greatly in the past years, they still have particular limited efficacy, and tumors tend to have high recurrence and metastatic rates. Immune function deficiency is an important reason [3]. Immunotherapy is becoming a promising and effective therapy for cancer patients, especially for patients with later stage disease and showing encouraging efficacy and minimal adverse events in cancer therapy [4]. Cellular immunity dysfunction is one important reason why tumors are incurable, and easy to relapse or metastasize, and antitumor immunity mainly depends on cellular immune response [5]. Cytokine-induced killer (CIK) cells are generated in vitro from peripheral blood mononuclear cells (PBMCs) cultured with some cytokines, which are shown to be a heterogeneous population, and the major population expresses the CD3⁺CD56⁺, and is termed NKT cells. These cells, which have demonstrated high proliferative and cytolytic activities, are non-MHC restricted in target cell recognition and killing [6], [7], [8]. CIK cells are demonstrated to have significant antitumor activity in both clinical trials and animal studies against different tumor cells, including Hodgkin disease, non-Hodgkin lymphoma, and hepatoma [9]. Therefore, to evaluate the role of CIK cells in antitumor effect and prolonging overall survival and improving the quality of patient's life, we conducted a retrospective study with autologous CIK cells in patients with lung cancer.

Section snippets

Patients

We retrospectively reviewed the medical record data of 60 lung cancer patients who received chemotherapy combined with autologous CIK cell adoptive immunotherapy (CIK treatment) from March 2003 to July 2013 in the CIK treatment group. In addition, the medical records were obtained from another 60 lung cancer patients of the corresponding period who received chemotherapy alone in the control group. The CIK treatment was approved by the Affiliated Hospital of Nanjing Medical University. Before

The characteristics of patients

Our study population included 120 eligible patients, 60 in the control group, and 60 in the CIK group. The characteristics of patients are summarized in Table 1. No statistical difference was found in sex and age of patients, histological type, clinical stage, radiotherapy and surgery nor between CIK group and the control group (P for all >0.05).

Quality of CIK cells

All CIK cells were administered according to the following criteria: the percentages of CD3⁺ and CD3⁺CD8⁺ cells must reach 70% and 40%, respectively,

Discussion

Despite current advances in chemotherapeutic treatment, the prognosis for patients with lung cancer remains poor [11], [12]. One of the reasons why malignant tumors are incurable, proliferation and metastasis is in vivo, is cellular immunity dysfunction [5]. Therefore, CIK cells therapy is a promising and safe modality for treating malignancies.

CIK cells can regulate and increase cellular immune function in vivo [13], and they exhibited antitumor activity against various tumor cells in in vitro

Funding

This study was partially supported by the Jiangsu Province Clinical Science and Technology Projects (Clinical Research Center, BL2012008) and the Program for Development of Innovative Research Team in the First Affiliated Hospital of NJMU and the Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (JX10231801).

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Adoptive cell therapy has been proving to be an effective therapeutic strategy against certain cancers. It involves the reinfusion of autologous cultured immune cells and is considered a viable alternative therapeutic for patients with cancer [4-7]. Various immune cells have been applied in clinical trials, including tumor-infiltrating lymphocytes (TILs), cytokine-induced killer (CIK) cells, natural killer cells and chimeric antigen receptor (CAR) T cells.
Clinical studies have shown the efficacy of combination therapy for various malignancies. In this study, the characteristics, safety and feasibility of use of cascade-primed (CAPRI) cells for the combination treatment of non–small-cell lung cancer (NSCLC) were evaluated both in vitro and in vivo.
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CD83, CD1a, CD80 and CD86 marker levels were significantly upregulated in CAPRI cells. Interferon-γ expression levels were highest in CD3⁺CD8⁺ cells (33.77% ± 4.40%). Furthermore, interleukin-2 levels were highest in CD3⁺CD56⁺ cells (26.73% ± 6.63%), whereas perforin expression levels were similar in CD3⁺CD8⁺ and CD3⁺CD56⁺ cells. Furthermore, CAPRI cells had a better anti-tumor potential in CD3⁺CD56⁺ cells and displayed the highest expression levels of CD107a to H460 and A549 cell lines. The 5-year OS was significantly greater in the CAPRI group than in the control group (P = 0.008), and the PFS of two groups exhibited a significant difference (P = 0.007). Median OS (48 versus 31.6 months; P = 0.004) and PFS (48 versus 36.4 months; P = 0.016) differed between these two groups. Moreover, treatment-associated toxicities were mild and well-tolerated by patients with NSCLC.
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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].
Cytokine-induced killer cells (CIK) therapy is the most commonly used cellular immunotherapy. The CIK plus radiotherapy was clinically used in a wide range of treatment, but the efficacy of their combination against lung cancer is not clear yet. Therefore, we systematically evaluated all the related studies to reveal the combination's clinical efficacy and safety in lung cancer.
We collected all the studies about CIK plus radiotherapy for lung cancer 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) 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.
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.
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70 patients with advanced lung cancer (stage IIIB to IV) admitted to the First Affiliated Hospital of Third Military Medical University in Chongqing from Nov. 2011 to Jan. 2015 and treated with CIKs were enrolled as a CIKs group (T group), and another 70 advanced lung cancer patients treated with optimal supportive care during the same period were enrolled as a control group(C group). The changes of immune system, response rate, disease control rate, overall survival, and side effects were compared between the two groups. Furthermore, the factors that might influence the efficacy of CIKs therapy were evaluated.
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¹: These authors contributed equally to this work.

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Original articleAutologous cytokine-induced killer cell therapy in lung cancer patients: A retrospective study

Abstract

Introduction

Section snippets

Patients

The characteristics of patients

Quality of CIK cells

Discussion

Funding

Cytotherapy

Semin Radiat Oncol

Dig Liver Dis

Updates in non-small cell lung cancer

Clin J Oncol Nurs

Multidisciplinary management of lung cancer

N Engl J Med

An analysis of variability in the manufacturing of dexosomes: implications for development of an autologous therapy

Biotechnol Bioeng

Autologous cytokine-induced killer cell therapy in clinical trial phase I is safe in patients with primary hepatocellular carcinoma

World J Gastroenterol

Propagation of large numbers of T cells with natural killer cell markers

Br J Haematol

Generation of cytokine-induced killer cells from leukaemic samples with in vitro cytotoxicity against autologous and allogeneic leukaemic blasts

Br J Haematol

Cytokine-induced killer cells: NK-like T cells with cytotolytic specificity against leukemia

Leuk Lymphoma

CIK cells from patients with HCC possess strong cytotoxicity to multidrug-resistant cell line Bel-7402/R

World J Gastroenterol

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

Cancer Immunol Immunother

Unexpected long-term survival after low-dose palliative radiotherapy for non-small cell lung cancer

Cancer

Inhibition of human ovarian tumor growth by cytokine-induced killer cells

Arch Pharm Res

Original article
Autologous cytokine-induced killer cell therapy in lung cancer patients: A retrospective study