Cytokine-induced killer cell/dendritic cell combined with cytokine-induced killer cell immunotherapy for treating advanced gastrointestinal cancer

Gastrointestinal cancers (GICs) are one of the leading causes of cancer-related mortality in the world, which majorly include cancers of colorectum and stomach (CRC and GC). In addition to growth and aging of global population, behavioral risk factors, such as smoking and dietary patterns, played an important role in the rising global burden of GIC [1]. Many treatment strategies, such as surgery, neoadjuvant chemotherapy, and adjuvant chemotherapy [2], are available for GIC patients. Moreover, early GIC patients can be cured by appropriate treatment, and the 5-year overall survival (OS) rate is 90%; however, for patients with advanced-stage GIC, the 5-year OC rate is still very low [3, 4].

Surgery, radiotherapy, and chemotherapy are routine treatments for GIC in most patients; they have the efficacy of eliminating and destroying primary tumors. However, these traditional treatments are often ineffective for advanced-stage cancers [5]. Cancer immunotherapy is a promising treatment method, which has made great progress in improving anti-tumor immunity [6]. Autoimmune therapy for malignant tumors is considered to be a feasible method, which mainly depends on the interference and inhibition effects of killer cells induced by the tumor, infiltrating lymphocytes and lymphokines, and CD3 monoclonal antibody [7, 8]. Dendritic cells (DCs) have the ability to present antigens, making them an attractive vehicle for the delivery and development of therapeutic tumor vaccines [9] . Cytokine-induced killer cells (CIK) is a heterogeneous effector CD3 + CD56 + NKT cell population that can be expanded from peripheral blood mononuclear cells (PBMC) in vitro [10, 11]. CIK cells have a strong MHC non-restrictive cytotoxicity, which inhibits both blood and solid malignancies, identifying and killing tumor targets without exposure or initiation. At present, CIK therapy or DC–CIK cell co-cultivation has been broadly applied in clinical trials for the treatment of GICs [12‐20]; however, the results are not entirely consistent. Therefore, we conducted a systematic review and meta-analysis of published literature to evaluate the efficacy and safety of CIK/DC–CIK cells combined with chemotherapy for the treatment with advanced GIC cancer.

GIC is still a fatal threat to human health due to metastasis, with recurrence inducing refractory advanced tumor stage and poor prognosis. Yan et al. [22] proved that the recurrence rate of patients with GC ranged from 40 to 65% due to distant metastasis and local recurrence. Adoptive cellular immunotherapy can be used in combination with standard therapy as adjuvant and palliative treatment after operation to improve the survival rate and QOL of patients with GIC. The CIK cells have shown the best efficacy in this treatment. Compared with lymphokine-activated killer cells, CIK cells are more readily available and show higher tumor-specific cytotoxic activity [23‐27]. To date, several clinical trials have used chemotherapy plus DC–CIK immunotherapy to treat advanced GIC. However, in these trials, the clinical protocol applied was not standard, blurring the evaluation of treatment effects. In this study, a large number of comprehensive trials were investigated to achieve higher statistical reliability. This meta-analysis showed that chemotherapy combined with CIK/DC–CIK immunotherapy improved the OS, PFS, and QOL without causing serious adverse events.

This study confirmed the safety of CIK/DC–CIK immunotherapy for advanced GIC patients, and the adverse events caused were tolerated by all patients. No significant difference was observed in terms of common adverse events, such as thrombocytopenia (RR = 1.04, 95% CI = 0.93–1.16, P_{heterogeneity} = 0.497, I² = 0%), nausea, vomiting (RR = 0.67, 95% CI = 0.35–1.28, P_{heterogeneity} = 0.003, I² = 82.9%), abnormal liver function (RR = 1.08, 95% CI = 0.95–1.23, P_{heterogeneity} = 0.373, I² = 0%), neutropenia (RR = 0.55, 95% CI = 0.31–1.00, P_{heterogeneity} = 0.955, I² = 0%), and myelosuppression (RR = 0.73, 95% CI = 0.48–1.11, P_{heterogeneity} = 0.088, I² = 65.7%) in the CIK/DC–CIK immunotherapy group compared with the chemotherapy-alone group. The CIK/DC–CIK immunotherapy enhanced the efficiency of conventional therapy in treating advanced GIC. Compared with the conventional therapy group, the 1-year OS, 3-year OS, 5-year OS, 1-year PFS, 3-year PFS, and 5-year PFS of patients in the combination therapy group improved remarkably. Moreover, the combination therapy improved the QOL (WMD = 16.09, 95% CI = 1.66–30.52, P_{heterogeneity} < 0.001, I² = 98.8%) of the patients by relieving pain, decreasing fatigue and insomnia, and improving appetite.

Chemotherapy is thought to damage the immune system. Immunotherapy is a type of cancer treatment that helps the body’s own immune system fight cancer, many clinical trials of immunotherapy have been conducted in multiple centers. DCs are an important immunotherapeutic cell type. Ishigami et al. [28] demonstrated that patients with GC having a high level of DC cell infiltration were less likely to have lymph node metastasis and a significantly increased 5-year survival rate. In addition, CIK cells exhibit strong cytotoxicity against a variety of tumor cell lines as well as newly isolated tumor samples (e.g. liver cancer [29], lung cancer [30], glioma [31], and GC [32]). Compared with other immune cells, CIK cells proliferate rapidly and exhibit strong antitumor activity and a broad spectrum of targeted tumors [14, 33]. Therefore, CIK/DC–CIK cell-based immunotherapy is a promising treatment for a number of cancers. Zhao et al. [34] showed that “GP regimen combined with DC–CIK immunotherapy could reduce postoperative recurrence and prolong survival in patients with non-small-cell lung cancer.” Ma et al. [35] demonstrated that CIK cell therapy had significant advantages in prolonging the median OS rate, PFS, DCR, ORR, and QOL of patients with hepatocellular carcinoma. Other studies of gastric cancer [13], advanced renal cancer [36], and metastatic nasopharyngeal carcinoma [37] demonstrated that DC–CIK cells could improve the prognosis of patients. CIK cells have become a promising immunotherapy method in tumor therapy due to their easy availability and strong antitumor activity, which is of great significance for tumor prognosis [38].

Heterogeneity is a problem with most meta-analyses. In the present meta-analysis, heterogeneity was found in overall analyses; thus, the random-effects model was used. Sensitivity analysis was performed to assess the stability of the results by sequentially removing each study. The removal of any single study did not change the overall statistical results, indicating that the results of this study were statistically robust. Furthermore, this study probed the detailed results in subgroup analyses stratified by cancer type (GC or CRC). Based on the data collected, this study suggested that the cancer type at least partly contributed to the between-study heterogeneity.

This meta-analysis had some limitations that might have affected the interpretation of results. First, the efficacy of CIK/DC–CIK immunotherapy was affected by many factors, such as injection mode, tumor stage, and metastasis cycle. Further, a detailed analysis needs to be carried out on the basis of complete literature, standardization of treatment options, and limitation of patient participation criteria. Second, some data on adverse events could only be used in two trials, which might have led to bias. Third, publishing bias existed in this study. Although the trim-and-fill method was used in this study to confirm the results, some negative data that were possibly omitted might have affected the results. Finally, the heterogeneity could not be completely eliminated in the analysis.

In summary, this meta-analysis confirmed that the combination of CIK/DC–CIK immunotherapy and chemotherapy was safe and applicable for patients with advanced GIC, and hence might serve a feasible choice to prolong survival and improve QOL. Therefore, CIK/DC–CIK immunotherapy is an effective therapy for advanced GIC treatment.