Cytokine-induced Killer Cell Immunotherapy Research Articles

Effect and safety of cytokine-induced killer (CIK) cell immunotherapy in patients with breast cancer

Background:Breast cancer (BC) is considered a systemic disease with a primarily locoregional component. The accumulation of basic researches and clinical studies related to cytokine-induced killer (CIK) cells has confirmed their safety and feasibility in treating BC. By searching the PubMed, Embase, CNKI, and Wanfang databases, we conducted a meta-analysis to assess the efficacy and safety of DC/CIK plus chemotherapy regimen (Exp) compared with chemotherapy (Con) alone regimen for breast carcinoma. Studies were pooled, and the relative risk (RR) and its corresponding 95% confidence interval (CI) were calculated.Methods:Eleven relevant articles were included in this meta-analysis. We observed that complete response (CR) (RR = 1.54, 95% CI: 1.09–2.19, Pheterogeneity = .994, I2 = 0%), partial response (PR) (RR = 1.33, 95% CI: 1.11–1.59, Pheterogeneity = .802, I2 = 0%) and overall response rate (ORR) (RR = 1.37, 95% CI: 1.20–1.57, Pheterogeneity = .619, I2 = 0%) in BC patients treatment with DC/CIK plus chemotherapy regimen was improved than that with chemotherapy alone. There was no difference in the incidence of leukopenia, thrombocytopenia, hair loss, nausea/vomiting, hepatic complications, and neurologic complications in BC patient's treatment with DC/CIK plus chemotherapy regimen and with chemotherapy alone.Results:Compared to chemotherapy alone, DC/CIK plus chemotherapy treatment significantly increased CR, PR, and ORR; however, there was no difference between the safeties.Conclusion:DC/CIK plus chemotherapy treatment may be a valuable new option for the treatment of breast carcinoma in women. The present study, therefore, provides valuable information to help physicians make treatment decisions for their patients with BC.

Clinical applications of dendritic cells-cytokine-induced killer cells mediated immunotherapy for pancreatic cancer: an up-to-date meta-analysis.

PurposeThis study aimed to systematically evaluate the efficacy and safety of dendritic cells–cytokine-induced killer (DC–CIK) cells immunotherapy in treating pancreatic cancer (PC) patients.MethodsData were collected from published articles of clinical trials. Databases including Web of Science, EMBASE, PubMed, Cochrane Library, Wanfang, and CNKI were searched. The main outcome measures in this research included the overall response rate (ORR), disease control rate (DCR), overall survival (OS), patients’ quality of life (QoL), immune function, and adverse events. Comparative analysis was conducted between DC–CIK immunotherapy and chemotherapy (combined therapy) and chemotherapy alone.ResultsThis analysis covered 14 trials with 1,088 PC patients involved. The combined therapy showed advantages over chemotherapy alone in ORR (odds ratio [OR] =1.69, 95% confidence interval [CI] =1.20–2.38, P=0.003), DCR (OR =2.33, 95% CI =1.63–3.33, P<0.00001), OS (1-year OS, OR =3.61, 95% CI =2.41–5.40, P<0.00001; 3-year OS, OR =2.65, 95% CI =1.56–4.50, P=0.0003) and patients’ QoL (P<0.01) with statistical significance. After immunotherapy, lymphocyte subsets’ percentages of CD3+ (P<0.00001), CD4+ (P=0.01), CD3+CD56+ (P<0.00001), and cytokine levels of IFN-γ (P<0.00001) were significantly increased, and the percentages of CD4+CD25+CD127low (P<0.00001) and levels of IL-4 (P<0.0001) were significantly decreased, whereas analysis on CD8+ (P=0.59) and CD4+/CD8+ ratio (P=0.64) did not show a significant difference.ConclusionThe combination of DC–CIK immunotherapy and chemotherapy is effective for PC treatment, indicated by prolonging the PC patients’ survival time, which benefit from reconstructed immune function of patients.

The interventional effect of new drugs combined with the Stupp protocol on glioblastoma: A network meta-analysis

ObjectiveNew therapeutic agents in combination with the standard Stupp protocol (a protocol about the temozolomide combined with radiotherapy treatment with glioblastoma was research by Stupp R in 2005) were assessed to evaluate whether they were superior to the Stupp protocol alone, to determine the optimum treatment regimen for patients with newly diagnosed glioblastoma. Patients and methodsWe implemented a search strategy to identify studies in the following databases: PubMed, Cochrane Library, EMBASE, CNKI, CBM, Wanfang, and VIP, and assessed the quality of extracted data from the trials included. Statistical software was used to perform network meta-analysis. ResultsThe use of novel therapeutic agents in combination with the Stupp protocol were all shown to be superior than the Stupp protocol alone for the treatment of newly diagnosed glioblastoma, ranked as follows: cilengitide 2000mg/5/week, bevacizumab in combination with irinotecan, nimotuzumab, bevacizumab, cilengitide 2000mg/2/week, cytokine-induced killer cell immunotherapy, and the Stupp protocol. In terms of serious adverse effects, the intervention group showed a 29% increase in the incidence of adverse events compared with the control group (patients treated only with Stupp protocol) with a statistically significant difference (RR=1.29; 95%CI 1.17–1.43; P<0.001). The most common adverse events were thrombocytopenia, lymphopenia, neutropenia, pneumonia, nausea, and vomiting, none of which were significantly different between the groups except for neutropenia, pneumonia, and embolism. ConclusionsAll intervention drugs evaluated in our study were superior to the Stupp protocol alone when used in combination with it. However, we could not conclusively confirm whether cilengitide 2000mg/5/week was the optimum regime, as only one trial using this protocol was included in our study.

Cancer Immunotherapy with Cytokine-Induced Killer Cells.

Cytokine-induced killer (CIK) cells form under certain stimulation conditions in cultures of peripheral blood mononuclear cells (PBMCs). They are a heterogeneous immune cell population and contain a high percentage of cells with a mixed T-NK phenotype (CD3+CD56+). The ready availability of a lymphocyte source, together with the high proliferative rate and potent anti-tumor activity of CIK cells, has allowed their use as immunotherapy in a wide variety of neoplasms. Cytotoxicity mediated by CD3+CD56+ T cells depends on the major histocompatibility antigen (MHC)-independent recognition of tumor cells and the activation of signaling pathways through the natural killer group 2 member D (NKG2D) cell-surface receptor. Clinical trials have demonstrated the feasibility and efficacy of CIK cell immunotherapy even in advanced stage cancer patients or those that have not responded to first-line treatment. This review summarizes biological and technical aspects of CIK cells, as well as past and current clinical trials and future trends in this form of immunotherapy.

FOLFOX regimen plus dendritic cells-cytokine-induced killer cells immunotherapy for the treatment of colorectal cancer: a meta-analysis.

PurposeTo systematically investigate the efficacy and safety of the combination of FOLFOX (oxaliplatin, 5-fluorouracil, and leucovorin) regimen and cocultured dendritic cells and cytokine-induced killer cells (DC-CIK) immunotherapy for the treatment of colorectal cancer (CRC).MethodsPublications reporting the clinical trials’ responses or safety of FOLFOX regimen combined with DC-CIK immunotherapy in treating CRC patients were searched in PubMed, Embase, Cochrane Library, China National Knowledge Internet, and Wanfang databases. Trials meeting the selection criteria were analyzed. The overall survival (OS), overall response rate (ORR), disease control rate (DCR), tumor markers, immune function, and adverse events were evaluated.ResultsTen trials including 881 CRC patients were analyzed in this meta-analysis. The combined therapy showed advantages over FOLFOX treatment-alone in 2-year OS (odds ratio [OR] =2.77, confidence interval [CI] =1.58–4.86, P=0.0004), ORR (OR =1.85, CI =1.34–2.56, P=0.0002), and DCR (OR =2.54, CI =1.76–3.67, P<0.00001), with statistical significance. After immunotherapy, lymphocyte subset percentages of CD3+ (P=0.0006) and CD4+ (P=0.01), CD4+/CD8+ ratio (P=0.0003), and levels of cytokines IFN-γ (P=0.003) and IL-2 (P=0.01) were significantly increased, whereas analysis of CD8+, CD3−CD56+, CD3+CD56+, CD4+CD25+, IL-6, and TNF-α did not show any significant difference (P>0.05). Moreover, the level of carcinoembryonic antigen was also decreased significantly upon immunotherapy (P<0.00001).ConclusionThe combination of FOLFOX regimen and DC-CIK immunotherapy was safe and effective for CRC patients.

OS09.7 Phase III radomized trial of autologous cytokine-induced killer cell immunotherapy for newly diagnosed glioblastoma in Korea

OS09.7 Phase III radomized trial of autologous cytokine-induced killer cell immunotherapy for newly diagnosed glioblastoma in Korea

Cytokine-induced killer cells/dendritic cells and cytokine-induced killer cells immunotherapy for the treatment of esophageal cancer in China: a meta-analysis.

BackgroundImmunotherapy based on cytokine-induced killer cells or combination of dendritic cells and cytokine-induced killer cells (CIK/DC-CIK) showed promising clinical outcomes for treating esophageal cancer (EC). However, the clinical benefit varies among previous studies. Therefore, it is necessary to systematically evaluate the curative efficacy and safety of CIK/DC-CIK immunotherapy as an adjuvant therapy for conventional therapeutic strategies in the treatment of EC.Materials and methodsClinical trials published before October 2016 and reporting CIK/DC-CIK immunotherapy treatment responses or safety for EC were searched in Cochrane Library, EMBASE, PubMed, Wanfang and China National Knowledge Internet databases. Research quality and heterogeneity were evaluated before analysis, and pooled analyses were performed using random- or fixed-effect models.ResultsThis research covered 11 trials including 994 EC patients. Results of this meta-analysis indicated that compared with conventional therapy, the combination of conventional therapy with CIK/DC-CIK immunotherapy significantly prolonged the 1-year overall survival (OS) rate, overall response rate (ORR) and disease control rate (DCR) (1-year OS: P=0.0005; ORR and DCR: P<0.00001). Patients with combination therapy also showed significantly improved quality of life (QoL) (P=0.02). After CIK/DC-CIK immunotherapy, lymphocyte percentages of CD3+ and CD3−CD56+ subsets (P<0.01) and cytokines levels of IFN-γ, -2, TNF-α and IL-12 (P<0.00001) were significantly increased, and the percentage of cluster of differentiation (CD)4+CD25+CD127− subset was significantly decreased, whereas analysis of CD4+, CD8+, CD4+/CD8+ and CD3+CD56+ did not show significant difference (P>0.05).ConclusionThe combination of CIK/DC-CIK immunotherapy and conventional therapy is safe and markedly prolongs survival time, enhances immune function and improves the treatment efficacy for EC.

In-vitro influence of mycophenolate mofetil (MMF) and Ciclosporin A (CsA) on cytokine induced killer (CIK) cell immunotherapy.

BackgroundCytokine-induced-killer (CIK) cells are a promising immunotherapeutic approach for impending relapse following hematopoietic stem cell transplantation (HSCT). However, there is a high risk for treatment failure associated with severe graft versus host disease (GvHD) necessitating pharmaceutical intervention post-transplant. Whether immunosuppression with mycophenolate mofetil (MMF) or Ciclosporin A (CsA) influences the cytotoxic effect of CIK cell immunotherapy is still an open issue.MethodsCIK cells were generated from PBMC as previously described followed by co-incubation with mycophenolic acid (MPA) or CsA. Proliferation, cytotoxicity and receptor expression were investigated following short- (24 h), intermediate- (3 days) and long-term (7 days) MPA incubation with the intention to simulate the in vivo situation when CIK cells were given to a patient with relevant MPA/CsA plasma levels.ResultsShort-term MPA treatment led to unchanged proliferation capacity and barely had any effect on viability and cytotoxic capability in vitro. The composition of CIK cells with respect to T-, NK-like T- and NK cells remained stable. Intermediate MPA treatment lacked effects on NKG2D, FasL and TRAIL receptor expression, while an influence on proliferation and viability was detectable. Furthermore, long-term treatment significantly impaired proliferation, restricted viability and drastically reduced migration-relevant receptors accompanied by an alteration in the CD4/CD8 ratio. CD3+CD56+ cells upregulated receptors relevant for CIK cell killing and migration, whereas T cells showed the most interference through significant reductions in receptor expression. Interestingly, CsA treatment had no significant influence on CIK cell viability and the cytotoxic potential against K562.ConclusionsOur data indicate that if immunosuppressant therapy is indispensable, efficacy of CIK cells is maintained at least short-term, although more frequent dosing might be necessary.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-1024-4) contains supplementary material, which is available to authorized users.

PD-L1 expression as a predictive biomarker for cytokine-induced killer cell immunotherapy in patients with hepatocellular carcinoma

ABSTRACTCytokine-induced killer (CIK) cell immunotherapy represents an effective treatment strategy for treating hepatocellular carcinoma (HCC). However, the therapeutic benefits of CIK cell treatment can be influenced by differences in complex immune microenvironment between patients. Herein, we investigated the relationship between PD-L1 expression and survival benefits of CIK cell immunotherapy in HCC patients. This retrospective study included 448 HCC patients: 217 cases underwent hepatectomy alone; 231 cases received hepatectomy and post-operative CIK cell transfusion. Immunohistochemistry was used to measure PD-L1 expression in tumor tissue sections from all patients. Meanwhile, flow cytometry was performed to explore the relationship between PD-L1 expression and localized inflammatory response in HCC microenvironment. We found a significantly improved prognosis in CIK treatment group compared with surgery alone group. In the CIK treatment group, higher PD-L1 expression was observed in patients who exhibited long-term survival benefit. Survival analysis showed patients with ≥5% PD-L1 expression had better overall survival (OS) and recurrence-free survival (RFS) than patients with 1–5% or <1% PD-L1 expression, particularly in the subgroup with high hepatitis B viral load. By contrast, PD-L1 expression did not show direct impact on the survival of patients in surgery alone group. Additionally, PD-L1 expression was found to be highly associated with hepatitis B viral load and the proportion of tumor-infiltrating lymphocytes in HCC patients. In conclusions, our study indicates that PD-L1 expression may reflect the presence of endogenous host immune response to tumor and serve as a biomarker for predicting survival benefits from adjuvant CIK cell immunotherapy in HCC patients.

Research progress of cytokine-induced killer cells in treatment of hematological malignancies

Cytokine-induced killer (CIK) cells prossess phenotypic and functional hallmarks of both T cells and natural killer (NK) cells. The easy availability, high proliferation rate and widely major histocompatibility complex (MHC)-unrestricted antitumor activity of CIK cells contribute to their particularly advantageous profile, making them an attractive approach for adoptive immunotherapy. Initial clinical experiences demonstrated the efficacy of CIK cells immunotherapy in cancer patients. Likewise, the clinical application of CIK cells in combination with standard therapeutic procedures revealed synergistic antitumor effects. CIK cells demonstrated a crucial impact on the treatment of patients with hematological malignancies, as evidenced by complete remission (CR), prolonged survival durations and improved quality of life. This article reviews literatures on progress of CIK cells in treatment of hematological malignancies. Key words: Cytokine-induced killer cells; Clinical trials; Interleukin-2; Immunotherapy

Autologous Cytokine-Induced Killer Cells Improves Overall Survival of Metastatic Colorectal Cancer Patients: Results From a Phase II Clinical Trial

BackgroundThis randomized clinical study was conducted to evaluate the therapeutic benefits of cytokine-induced killer (CIK) cell immunotherapy in combination with chemotherapy in metastatic colorectal cancer (mCRC) patients. Patients and MethodsSixty-one patients in group 1 (cell therapy group) received autologous CIK cell immunotherapy in combination with chemotherapy (5-Fluorouridine, leucovorin and oxaliplatin [FOLFOX4] plan). Another 61 patients in group 2 (the control group) received chemotherapy (FOLFOX4 plan) alone. The primary study end points were overall survival (OS) and progression-free survival (PFS). The secondary end points were treatment response and adverse events. ResultsThe 3-year PFS and OS in group 1 were 20% and 48%, respectively, compared with 13% and 23%, respectively, in group 2 (P = .131 and P < .001, respectively). The median OS in group 1 was significantly increased compared with that in group 2 (OS, 36 vs. 16 months; P < .001). Furthermore, there was a trend toward superior PFS in group 1 compared with that in group 2 (PFS, 16 vs. 10 months; P = .072). Using univariate analysis, we found that Karnofsky performance status <80, number of metastases >1, and increased platelet levels were significantly associated with poorer prognosis in group 1. Alternatively, the cycle count of CIK cell treatment was significantly associated with good prognosis in group 1. Toxicity was mild in patients who received CIK therapy. ConclusionThis study shows that CIK cell immunotherapy in combination with chemotherapy is well tolerated and improves the OS of mCRC patients.

Autologous cytokine-induced killer (CIK) cell immunotherapy combined with cyclophosphamide in five patients with POEMS syndrome.

The primary objective of this study was to evaluate the safety and clinical efficacy of autologous cytokine-induced killer (CIK) cells combined with cyclophosphamide in the treatment of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS) syndrome patients. We evaluated five POEMS syndrome patients treated with autologous CIK cell immunotherapy combined with cyclophosphamide from 1May 2012 to 30November 2014. The Overall Neuropathy Limitation Scale (ONLS), computed tomography of the chest and abdomen, ultrasound of the abdomen, serum vascular endothelial growth factor (VEGF) level and lymphocyte count findings in the five patients were recorded. The median age of the patients was 40 years (range: 25-62), and all the patients were male. CIK cells were generated routinely from peripheral blood mononuclear cells (PBMCs) of all five patients, and the numbers of CIK cells increased by approximately 105-fold after 14 days of culture. All five patients (100%) responded to their neuropathy treatment, the ONLS scores were reduced by at least 1 and a paired-sample t-test revealed a significant difference (t=5·715, P=0·003<0·01). The extravascular volume overload responses indicated partial remission (PR=60%) or stable disease (SD=40%), and no cases of progressive disease (PD) or complete remission (CR) were observed. During clinical treatment, the serum VEGF of patient 5 decreased after one cycle of transfusion within 1 month. The lymphocyte counts of all the patients increased significantly after CIK transfusion, and a paired-sample t-test revealed a significant difference (t=5·101, P=0·004<0·01). Autologous CIK cell infusion combined with cyclophosphamide was found to be highly safe and elicited no adverse reactions. CIK cells can improve both the symptoms and quality of life, decrease serum VEGF levels and increase lymphocyte counts in patients with POEMS syndrome.

The Efficacy and Safety of Dendritic Cells Co-Cultured with Cytokine-Induced Killer Cell Therapy in Combination with TACE-Predominant Minimally-Invasive Treatment for Hepatocellular Carcinoma: a Meta-Analysis.

To evaluate the efficacy and safety of dendritic cells (DCs) co-cultured with cytokine-induced killer cell (CIK) immunotherapy combined with transcatheter arterial chemoembolization (TACE) or TACE plus local ablation therapy for hepatocellular carcinoma (HCC). Our meta-analysis included a comprehensive search for relevant studies published through December 12, 2014. We used Cochrane Library, PubMed, CBM, VIP, CNKI, and Wanfang data. Depending on the heterogeneity among the included studies, we calculated the pooled odds ratio (OR) and mean difference (MD) using fixed- or random-effects models. Publication biases were assessed using funnel plots and Begg's tests. Sensitivity analyses were also performed. Seven randomized controlled trials (RCTs) and one controlled clinical trial (CCT) that included 693 patients and met the inclusion criteria were analyzed. Pooled results showed that DC-CIK immunotherapy combined with TACE or TACE plus local ablation therapy significantly improved 1-year (OR = 2.00, p = 0.02) and 2-year overall survival (OR = 1.77, p = 0.04). A favored overall response rate (ORR) (OR = 1.51, p = 0.03), disease control rate (DCR) (OR = 1.81, p = 0.01), and better quality of life (OR = 3.30, p < 0.01) were observed in the DC-CIK group. Additionally, when tumor-associated T lymphocyte subsets were compared, our analyses demonstrated that the percentage of CD3+ T cells (MD(CD3+) = 21.37, p = 0.005) and the ratio of CD4+/CD8+ (MD(CD4+/CD8+) = 2.83, p = 0.02) were significantly increased in the DC-CIK therapy group. The combination of DC-CIK immunotherapy and TACE or TACE plus local ablation therapy improves 1- and 2-year overall survival, ORR, DCR, and provides a better quality of life for patients with HCC.

MDSC-decreasing chemotherapy increases the efficacy of cytokine-induced killer cell immunotherapy in metastatic renal cell carcinoma and pancreatic cancer.

Adoptive immunotherapy using cytokine-induced killer (CIK) cells is a promising cancer treatment, but its efficacy is restricted by various factors, including the accumulation of myeloid-derived suppressor cells (MDSCs). In this study, we determine whether chemotherapeutic drugs that reduce MDSC levels enhance the efficacy of CIK cell therapy in the treatment of solid tumors. Fifty-three patients were included in this study; 17 were diagnosed with metastatic renal cell carcinoma (MRCC), 10 with advanced pancreatic cancer (PC), and 26 with metastatic melanoma (MM). These patients were divided into two groups: CIK cell therapy alone and CIK cell therapy combined with chemotherapy. Combining CIK cell therapy and chemotherapy increased 1-year survival rates and median survival times in MRCC and PC patients, but not in MM patients. The disease control rate did not differ between treatment groups for MRCC or MM patients, but was higher in PC patients receiving combined treatment than CIK cell treatment alone. These data suggest that addition of MDSC-decreasing chemotherapy to CIK cell therapy improves survival in MRCC and PC patients.

Sequential Cytokine-Induced Killer Cell Immunotherapy Enhances the Efficacy of the Gemcitabine Plus Cisplatin Chemotherapy Regimen for Metastatic Nasopharyngeal Carcinoma

In this study, we investigated the efficacy of sequential cytokine-induced killer cell (CIK) immunotherapy with gemcitabine plus cisplatin (GC) regimen chemotherapy in metastatic nasopharyngeal carcinoma (NPC) patients. Between September 2006 and April 2010, 222 NPC patients with distant metastasis after radiotherapy completion were retrospectively analyzed: 112 patients received 4–6 cycles of GC chemotherapy at 4-week intervals, followed by at least 4 cycles of CIK immunotherapy at 2-week intervals (GC+CIK group); the remaining 110 patients received 4–6 cycles of GC chemotherapy alone (GC group). The evaluation of long-term efficacy showed that the progression-free survival (PFS) rate was significantly higher in the GC+CIK group (log-rank test; p = 0.009), as was the overall survival (OS) rate (p = 0.006). In conclusion, sequential CIK treatment may be effective in enhancing the therapeutic efficacy of GC chemotherapy for metastatic NPC patients. This study provides a basis for alternative therapeutic strategies for metastatic NPC.

Efficacy and safety of dendritic cells co-cultured with cytokine-induced killer cells immunotherapy for non-small-cell lung cancer.

Dendritic cells co-cultured with cytokine-induced killer cells (DC-CIK) immunotherapy has been widely studied and might be a new therapeutic strategy for non-small-cell lung cancer (NSCLC). We aimed to comprehensively and quantitatively evaluate the efficacy and safety of DC-CIK immunotherapy in NSCLC. Pubmed, Embase, Cochrane Library, and Web of Science were searched for randomized controlled trials comparing DC-CIK immunotherapy with control therapies in NSCLC. A total of 505 patients from 6 trials were enrolled. Compared with control therapies, DC-CIK immunotherapy significantly improved progression-free survival (PFS) [hazard ratio (HR): 0.528, 95% confidence interval (CI): 0.390-0.715, P<0.001], overall survival (OS) (HR: 0.619, 95% CI: 0.487-0.786, P<0.001), and disease control rates (DCR) [relative risk (RR): 1.250, 95% CI: 1.058-1.477, P=0.009], but objective response rates (ORR) (RR: 1.190, 95% CI: 0.561-2.526, P=0.650) was not improved for DC-CIK immunotherapy. The risks of all-grade anemia, leukopenia, dermatosis, diarrhea, nausea, acratia, and chest distress in patients receiving DC-CIK immunotherapy were comparable to those receiving control therapies. This meta-analysis demonstrates DC-CIK immunotherapy has superiority in PFS, OS, and DCR for NSCLC patients, and no more serious adverse events appeared. Further studies to provide solid evidence for the routine clinical use of DC-CIK immunotherapy are urgently needed.

A nomogram for predicting the benefit of adjuvant cytokine-induced killer cell immunotherapy in patients with hepatocellular carcinoma.

The benefits of adjuvant cytokine-induced killer (CIK) cell immunotherapy for hepatocellular carcinoma (HCC) remain mixed among patients. Here, we constructed a prognostic nomogram to enable individualized predictions of survival benefit of adjuvant CIK cell treatment for HCC patients. Survival analysis showed that the median overall survival (OS) and progression-free survival (PFS) for patients in the hepatectomy/CIK combination group were 41 and 16 months, respectively, compared to 28 and 12 months for patients in the hepatectomy alone group (control). Based on multivariate analysis of the entire cohort, independent factors for OS were tumor size, tumor capsule, pathological grades, total bilirubin, albumin, prothrombin time, alpha-fetoprotein, and tumor number, which were incorporated into the nomogram. The survival prediction model performed well, as assessed by the c-index and calibration curve. Internal validation revealed a c-index of 0.698, which was significantly greater than the c-index value of the TNM (tumor–node–metastasis) staging systems of 0.634. The calibration curves fitted well. In conclusions, our developed nomogram resulted in more accurate individualized predictions of the survival benefit from adjuvant CIK cell treatment after hepatectomy. The model may provide valuable information to aid in the decision making regarding the application of adjuvant CIK cell immunotherapy.

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

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.

Comparative study of different procedures for the separation of peripheral blood mononuclear cells in cytokine-induced killer cell immunotherapy for hepatocarcinoma.

Cytokine-induced killer (CIK) cell immunotherapy exhibits significant advantages in the clinical treatment of tumors. This study was designed to compare the biological characteristics of autologous CIK cells from patients with hepatocarcinoma following different procedures for the separation of peripheral blood mononuclear cells (PBMCs). Forty-four hepatocarcinoma patients were enrolled and distributed into two groups. PBMCs were isolated either using a blood cell separator (apheresis method) or Ficoll lymphocyte separation medium (Ficoll method). The total amount, collection efficacy, and cell status of PBMCs in the two groups were determined. According to the number and status of collected PBMCs, different cultivation procedures were used for their amplification and activation and the proliferation ability, phenotype, and killing activity of CIK cells in the two groups were evaluated. Our results indicated that the number of collected PBMCs in the apheresis group was far more than that in the Ficoll group. However, the isolation rate was lower, and more cellular debris was observed in the apheresis group, which may be the cause of some untoward effects. Following in vitro culture, the enrichment time of CIK cells was longer in the Ficoll group, and the percentages of CD3(+)CD4(+) (Th) and CD4(+)CD25(+) (Treg) cells were higher. In the apheresis group, the percentages of CD3(-)CD56(+) (NK) and CD3(+)CD56(+) (NKT) cells were higher, and the CIK cells exhibited a higher cytolytic activity against HepG2 hepatoma cells. In conclusion, different procedures for PBMCs separation can influence the biological activities of CIK cells, and the apheresis method is more effective at enhancing the antitumor efficacy of CIK cells. However, significant attention should be paid to the possibility of adverse reactions in apheresis donors.

Effectiveness and safety of chemotherapy combined with dendritic cells co-cultured with cytokine-induced killer cells in the treatment of advanced non-small-cell lung cancer: a systematic review and meta-analysis.

BackgroundLung cancer, particularly non-small-cell lung cancer (NSCLC) is the leading cause of cancer mortality. Chemotherapy combined dendritic cells co-cultured with cytokine-induced killer cells (DC-CIK) immunotherapy has been applied in advanced NSCLC patients' treatment, but couldn't provide consistent beneficial results. Therefore, it is necessary to evaluate the efficiency and safety of combination therapy to promote the application.MethodsA literature search for randomized controlled trials of NSCLC was conducted in PubMed database. Before meta-analysis was performed, studies were evaluated heterogeneity. Pooled risk ratios (RRs) were estimated and 95% confidence intervals (CIs) were calculated using a fixed-effect model. Sensitivity analysis was also performed.ResultsSix eligible trials were enrolled. Efficiency and safety of chemotherapy followed by DC-CIK immunotherapy (experimental group) and chemotherapy alone (control group) were compared. 1-year overall survival (OS) (P = 0.02) and progression free survival (PFS) (P = 0.005) in the experimental group were significantly increased compared with the control. Disease control rate (DCR) (P = 0.006) rose significantly in experimental group. However, no significant differences between the two groups were observed in 2-year OS (P = 0.21), 2-year PFS (P = 0.10), overall response rate (ORR) (P = 0.76) and partial response (PR) (P = 0.22). Temporary fever, anemia, leukopenia and nausea were the four major adverse events (AEs) treated by chemotherapy. The incidence of anemia, leukopenia and nausea in the experimental group was obviously lower than the control group. Temporary fever rate was higher in experimental group than that in the control, but could be alleviated by taking sufficient rest.ConclusionsChemotherapy combined with DC-CIK immunotherapy showed superiority in DCR, 1-year OS and PFS, and no more AEs appeared, however, there was no significant improvement in ORR, PR, 2-year OS and PFS. As a whole, the combination therapy is safer but modest in efficacy for advanced NSCLC patients.