Autologous Cytokine-induced Killer Cells Research Articles

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.

Biological Character of RetroNectin Activated Cytokine-Induced Killer Cells.

Adoptive cell therapy (ACT) using autologous cytokine-induced killer (CIK) cells is a promising treatment for metastatic carcinomas. In this study, we investigated the impact of RetroNectin on the proliferation, phenotype alternation, cytokine secretion, and cytotoxic activity of CIK cells from pancreatic cancer patients. Furthermore, we treated 13 patients with metastatic or locally advanced pancreatic cancer using autologous RetroNectin-activated CIK cells (R-CIK cells) alone or in combination with chemotherapy. Compared with only CD3 activated CIK cells (OKT-CIK cells), R-CIK cells showed stronger and faster proliferative ability, with a lower ratio of spontaneous apoptosis. Moreover, this ability continued after IL-2 was withdrawn from the culture system. R-CIK cells could also secrete higher levels of IL-2 and lower levels of IL-4 and IL-5 versus OKT-CIK cells. There was no difference between OKT-CIK and R-CIK cells in cytotoxic ability against lymphoma cell line K562. In patients who received auto-R-CIK cell infusion therapy, the overall objective response rate was 23.1%. Median survival time (mOS) after first R-CIK cell infusion was 10.57 months; the 1-year survival rate was 38.5%. No serious toxicity was associated with R-CIK cell infusion. In conclusion, RetroNectin may enhance antitumor activity of CIK cells: it is safe for use in treating pancreatic cancer.

Rapid Response of Advanced Squamous Non-Small Cell Lung Cancer with Thrombocytopenia after First-Line Treatment with Pembrolizumab Plus Autologous Cytokine-Induced Killer Cells.

We present the first clinical evidence of advanced squamous non-small cell lung cancer with severe thrombocytopenia showing dramatic improvement after first-line treatment with pembrolizumab plus autologous cytokine-induced killer cells.

Combination of cytokine-induced killer and dendritic cells pulsed with antigenic α-1,3-galactosyl epitope–enhanced lymphoma cell membrane for effective B-cell lymphoma immunotherapy

Background aimsRefractory B-cell lymphomas are difficult to successfully treat with current chemotherapeutic regimens; however, immunotherapy may be an effective form of treatment for these patients. MethodsFourteen refractory lymphoma patients (age, 29–74 y) were enrolled in the trial. α-1,3-galactosyl (α-Gal) epitopes were synthesized on lymphoma cell membranes with the use of bovine recombinant α-1,3-galactosyltransferase (α-GT) and neuraminidase to enhance tumor immunogenicity. Subsequent incubation of processed cell membranes with autologous dendritic cells (DCs) in the presence of human serum containing abundant natural anti–α-Gal immunoglobulin G led to the effective phagocytosis of tumor membranes by DCs. The pulsed DCs and autologous cytokine-induced killer cells were then co-cultured to promote maximum cytotoxicity to lymphoma cells and were infused back into the donor lymphoma patients. Therapeutic responses were assessed by clinical observation, laboratory tests and a computed tomography scan at 6 months after treatment. ResultsComplete and partial remission occurred in four and three patients, respectively. The disease status remained unchanged in five patients, and disease progression was observed in two patients. No serious side effects or autoimmune diseases were observed in any participants. Serum lactate dehydrogenase and β2-macroglobulin decreased in 11 and 14 patients, respectively. All patients showed robust systemic cytotoxicity in response to tumor lysate as measured by interferon-γ expression in peripheral blood mononuclear cells after treatment (P < 0.001). The number of peripheral immune effector cells (CD3+/CD4+, CD8+/CD28+ and CD16+/CD56+ cells) increased significantly (P < 0.05) 3 months after treatment. ConclusionsLymphoma cell–specific α-Gal immunotherapy is safe, effective and has great potential for the treatment of refractory B-cell lymphoma.

A randomized controlled trial on patients with or without adjuvant autologous cytokine-induced killer cells after curative resection for hepatocellular carcinoma

ABSTRACTBackground & Aims: There is no generally accepted adjuvant therapy for hepatocellular carcinoma (HCC) after curative resection. Autologous cytokine-induced killer (CIK) cells therapy has been reported to improve outcomes of patients with HCC, but its role as an adjuvant therapy remains unclear. This study aimed to evaluate the efficacy and safety of CIK as an adjuvant therapy for HCC after curative resection. Methods: This is a single center, phase 3, open label, randomized controlled trial (RCT). Two hundred patients who were initially diagnosed with HCC of Barcelona Clinic Liver Cancer (BCLC) stage A or B, and underwent curative hepatectomy were randomly assigned to receive four cycles of CIK treatment (the CIK group, n = 100) or no treatment (the control group, n = 100). The primary outcome was time to recurrence. The secondary outcomes included disease-free survival (DFS), overall survival (OS) and adverse events. Results: All patients in the CIK group finished the treatment by protocol. The median time to recurrence (TTR) was 13.6 (IQR 6.5–25.2) mo in the CIK group and 7.8 (IQR 2.7–17.0) mo in the control group (p = 0.01). There were no significant differences between the groups in DFS and OS. All adverse events were grade 1 or 2. There were no significant differences in incidence between the two groups.Conclusions: Four cycles of CIK therapy were safe and effective to prolong the median TTR in patients with HCC after curative resection, but the treatment did not improve the DFS and OS.

근치적인 수술 이후 조기 재발하였으나 서로 다른 예후를 보인 간세포암종 2예

Hepatocellular carcinoma (HCC) has poor prognosis, even after curative resection. Early recurrence after curative treatment is a major cause of the poor prognosis. Pathologic factors such as vessel invasion, satellite nodule, size of tumor and pathologic grade are prognostic factors predicting early recurrence and poor prognosis. We share our experience of twocases which both showed early recurrence after curative hepatic resection, but eventually demonstrated different prognosis. Since the most common cause of death after potentially curative treatment is tumor recurrence, suppression of tumor recurrence might be linked to survival gain. Currently, there is no adjuvant therapy for HCC endorsed by international guidelines. However, recent studies have shown that antiviral treatment for hepatitis B virusrelated HCC and immunotherapy using autologous cytokine-induced killer cell reduced HCC recurrence. Further study is needed to select patients who will benefit from adjuvant treatments.

Anti-Tumor Effect of Autologous Cytokine-Induced Killer (CIK) Cells in Patients With Advanced Primary Hepotic Carcinoma

Anti-Tumor Effect of Autologous Cytokine-Induced Killer (CIK) Cells in Patients With Advanced Primary Hepotic Carcinoma

Autologous cytokine-induced killer cells combined with conventional therapy to treat malignant melanoma-a retrospective study

Background aims: Cytokine-induced killer (CIK) cells therapy has been evaluated as an effective treatment for patients with malignant tumors. In this study, we aimed to assess the efficacy of CIK cell-based therapy compared with traditional treatment in patients with advanced primary hepatic carcinoma (PHC). Methods: A total of 93 patients with advanced PHC administrated in our hospital were studied retrospectively (October 2010 to October 2013), including 51 patients with traditional treatment plus CIK cells therapy (CIK group) and 42 patients with traditional treatment only (control group). Since one month after the last treatment, the follow-up was performed every two months. KaplaneMeier analysis was used to explore the differences in overall survival (OS) between two groups. Results: There was no significant difference in median OS between the CIK group and the control group (9 months vs. 7 months, P1⁄40.176). In subgroup analysis, patients who received more than 4 cycles of CIK cell transfusion exhibited significantly better survival than the less than 4 cycle group (P1⁄40.001), and patients with hepatic cirrhotic had a better prognosis (P1⁄40.002). No severe toxicity was observed after infusion of CIK cells. Conclusions: Our results demonstrate CIK cells therapy could improve the prognosis of patients with advanced PHC. More cycles of CIK cells transfusion could further enhance the beneficial effect.

Combined cellular immunotherapy and chemotherapy improves clinical outcome in patients with gastric carcinoma

Background aimsDespite the availability of multiple treatment strategies, patients with gastric carcinoma (GC) have a dismal prognosis. The aim of this study was to evaluate the efficacy and safety of cellular immunotherapy (CIT) with the use of autologous natural killer cells, γδT cells and cytokine-induced killer cells in combination with chemotherapy in patients with GC. MethodsIn this open-label pilot cohort study, patients were treated with the combination therapy (chemo/CIT group) or chemotherapy alone (control group). Progression-free survival (PFS), overall survival (OS), quality of life (QOL) and adverse events were investigated. ResultsFifty-eight patients were analyzed, 30 in the chemo/CIT group and 28 in the control group. The median PFS of the chemo/CIT group was significantly longer compared with the control group (P = 0.021). In subgroup analysis, in patients with stage III GC, node-positive metastasis or poorly differentiated carcinoma, the 2-year PFS rate in chemo/CIT versus control groups was 62.5% versus 26.7% (P = 0.022), 50% versus 27.3% (P = 0.016) and 56.3% versus 28.6% (P = 0.005), respectively. The median OS in either group has not yet been reached, and there was no significant difference in OS between the groups. The QOL was improved in the patients treated with chemo/CIT compared with the control group. CIT was well tolerated and not related to any significant adverse events. ConclusionsA combination of CIT and chemotherapy for patients with GC was safe, improved QOL, and might prevent recurrence, especially in GC patients with advanced stage, poorly differentiated carcinoma or lymph node metastasis.

The influence of autologous cytokine-induced killer cell treatment on the objective efficacy and safety of gefitinib in advanced non-small cell lung cancer

Abstract Objective The aim of the study was to observe the influence of autologous cytokine-induced killer cell (CIK) treatment on the objective efficacy and safety of gefitinib in advanced non-small cell lung cancer (NSCLC). Methods Sixty-six patients with NSCLC received gefitinib as second-line treatment. They were randomly divided into 2 groups, and informed consent forms were signed before grouping. Gefitinib was administrated to the control group, and autologous CIK treatment was added to the observation group. The objective treatment and adverse reactions were evaluated in both groups. Results The objective response rate (ORR) and the disease control rate (DCR) of the observation group were slightly higher than those of the control group, although no statistical differences were found between the 2 groups (P &gt; 0.05). The incidences of diarrhea, fatigue, anorexia, oral ulcers, and myelosuppression in the observation group were much lower than those in the control group (P &lt; 0.05). However, there were no statistical differences between the incidences of skin rash, and liver and kidney toxicities (P &gt; 0.05). Conclusion Autologous CIK in combination with gefitinib is effective as second-line treatment for advanced NSCLC, and can significantly reduce adverse reactions and improve the objective efficacy.

Cytokine-induced killer (CIK) cells: from basic research to clinical translation.

The accumulation of basic researches and clinical studies related to cytokine-induced killer (CIK) cells has confirmed their safety and feasibility in treating malignant diseases. This review summarizes the available published literature related to the biological characteristics and clinical applications of CIK cells in recent years. A number of clinical trials with CIK cells have been implemented during the progressive phases of cancer, presenting potential widespread applications of CIK cells for the future. Furthermore, this review briefly compares clinical applications of CIK cells with those of other adoptive immunotherapeutic cells. However, at present, there are no uniform criteria or large-scale preparations of CIK cells. The overall clinical response is difficult to evaluate because of the use of autologous CIK cells. Based on these observations, several suggestions regarding uniform criteria and universal sources for CIK cell preparations and the use of CIK cells either combined with chemotherapy or alone as a primary strategy are briefly proposed in this review. Large-scale, controlled, grouped, and multi-center clinical trials on CIK cell-based immunotherapy should be conducted under strict supervision. These interventions might help to improve future clinical applications and increase the clinical curative effects of CIK cells for a broad range of malignancies in the future.

Adjuvant Immunotherapy With Autologous Cytokine-Induced Killer Cells for Hepatocellular Carcinoma

No adjuvant therapy has been shown to extend the survival of patients with hepatocellular carcinoma (HCC) receiving curative treatment. We investigated whether injections of activated cytokine-induced killer (CIK) cells (CD3+/CD56+ and CD3+/CD56- T cells and CD3-/CD56+ natural killer cells) prolongs recurrence-free survival of patients after curative therapy for HCC. We performed a multicenter, randomized, open-label, phase 3 trial of the efficacy and safety of adjuvant immunotherapy with activated CIK cells (created by incubation of patients' peripheral blood mononuclear cells with interleukin 2 and an antibody against CD3). The study included 230 patients with HCC treated by surgical resection, radiofrequency ablation, or percutaneous ethanol injection at university-affiliated hospitals in Korea. Patients were assigned randomly to receive immunotherapy (injection of 6.4 × 10(9) autologous CIK cells, 16 times during 60 weeks) or no adjuvant therapy (controls). The primary end point was recurrence-free survival; secondary end points included overall survival, cancer-specific survival, and safety. The median time of recurrence-free survival was 44.0 months in the immunotherapy group and 30.0 months in the control group (hazard ratio with immunotherapy, 0.63; 95% confidence interval [CI], 0.43-0.94; P = .010 by 1-sided log-rank test). Hazard ratios also were lower in the immunotherapy than in the control group for all-cause death (0.21; 95% CI, 0.06-0.75; P = .008) and cancer-related death (0.19; 95% CI, 0.04-0.87; P = .02). A significantly higher proportion of patients in the immunotherapy group than in the control group had an adverse event (62% vs 41%; P = .002), but the proportion of patients with serious adverse events did not differ significantly between groups (7.8% vs 3.5%; P = .15). In patients who underwent curative treatment for HCC, adjuvant immunotherapy with activated CIK cells increased recurrence-free and overall survival. ClinicalTrials.gov number: NCT00699816.

Enhanced specific antitumor immunity of dendritic cells transduced with the glypican 3 gene and co-cultured with cytokine-induced killer cells against hepatocellular carcinoma cells.

Dendritic cell (DC)-based cancer immunotherapy requires an immunogenic tumor-associated antigen and an effective therapeutic strategy. Glypican 3 (GPC3) is a valuable diagnostic marker and a potential therapeutic target in hepatocellular carcinoma (HCC). The present study investigated whether DCs transduced with the GPC3 gene (DCs-GPC3) and co-cultured with autologous cytokine-induced killer cells (CIKs) may induce a marked specific immune response against GPC3-expressing HCC cells in vitro and in vivo. Human DCs were transfected with a green fluorescent protein plasmid with GPC3 by nucleofection and then co-cultured with autologous CIKs. Flow cytometry was used to measure the phenotypes of DCs and CIKs. The co-cultured cells were harvested and incubated with HCC cells and the cytotoxicity of the CIKs was assessed by nonradioactive cytotoxicity assay. The anti-tumor activity of these effector cells was further evaluated using a nude mouse tumor model. The results demonstrated that DCs-GPC3 significantly promoted the autologous CIKs differentiation, as well as anti-tumor cytokine interferon-γ secretion. In addition, DCs-GPC3-CIKs significantly enhanced the cytotoxic activity against GPC3-expressing HepG2 cells, indicating a GPC3-specific marked immune response against HCC cells. The in vivo data indicated that DCs-GPC3-CIKs exhibited significant HepG2 cell-induced tumor growth inhibition in nude mice. The results of the present study provided a new insight into the design of personalizing adoptive immunotherapy for GPC3-expressing HCC cells.

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.

Clinical Study of Autologous Cytokine-Induced Killer Cells for the Consolidation Treatment of Elderly Patients with Diffuse Large B-Cell Lymphoma

Cytokine-induced killer (CIK) cells are activated T cells with natural killer (NK) properties that can be expanded in vitro in presence of recombinant human interleukin-2 (rhIL-2) starting from peripheral blood mononuclear cells stimulated by interferon-γ and anti-CD3 antibody. They express CD3 and CD56 as well as the NKG2D antigen and show major histocompatibility complex (MHC)–unrestricted cytotoxicity toward neoplastic but not normal targets. CIK cells express several chemokine receptors, and in vivo models suggest that they can migrate to the site of tumors after intravenous administration, there carrying out their cytotoxic potential and helping to control tumor growth. CIK cells have shown cytotoxic activity in vitro and in vivo against hematopoietic neoplastic cells, including AML (acute myeloid leukemia), CML (chronic myelogenous leukemia), and CLL (chronic lymphocytic leukemia). Their cytotoxicity against patient with B-NHL (B-cell non-Hodgkin lymphoma) , however, has not been fully investigated. The elderly population is susceptible to haematological malignancies, and these elderly patients are intolerant to cytotoxic drugs. Therefore, the exploration of a safe and reliable strategy reduse dose of chemotherapy is critical in improving the prognosis of elderly patients with haematological malignancies. To evaluate the effectiveness and safety of autologous cytokine-induced killer (CIK) cells for consolidation treatmemt in elderly patients with diffuse large B-cell lymphoma. Peripheral blood mononuclear cells (PBMC) were isolated from 20 elderly patients with diffuse large B-cell lymphoma. PBMCs were augmented by priming with interferon gamma (IFN-γ) followed by IL-2 and monoclonal antibody (mAb) against CD3. Autologous CIK cells (range 5 × 10(9)-1 × 10(10)) were then infused back to individual patients. The regimen was repeated every 4 weeks. The host cellular immune function, tumour-related biological parameters, imaging characteristics, disease condition, quality of life and survival time were assessed. Fourteen patients received 6 cycles of transfusion and 6 received 4 cycles. After treatment of CIK cells plus IL-2, the general conditions of 20 patients were to different extent improved No adverse effects were observed. The percentages of CD3(+), CD3(+) CD8(+) and CD3(+) CD56(+) cells were significantly increased (p < 0.05), and the levels of serum β2 microglobulin and lactate dehydrogenase (LDH) were markedly decreased (p < 0.05) after autologous CIK cell transfusion. Cancer-related symptoms were profoundly alleviated, as demonstrated by the improved quality of life (p < 0.01)., Complete remission(CR) observed in 11 patients before the treatmemt of CIK was still CR; Partial remission(PR) in 9 patients ,After the treatmemt of CIK, the transformation of disease state from partial remission to complete remission was seen in 4 patients. At the end of follow-up, the mean survival time was 24 months. Transfusion with autologous CIK cells is safe and effective for treating haematological malignancies in elderly patients. DisclosuresNo relevant conflicts of interest to declare.

Analysis of adverse events following the treatment of autologous cytokine-induced killer cells for adoptive immunotherapy in malignant tumour sufferers

Background: Adoptive immune cell transfer such as cytokine-induced killer (CIK) cells has become an important adjuvant approach in patients with tumours.Objectives: The aim of this study was to analyse the adverse events (AEs) that occur during the transfusion of autologous CIK cells and to identify the risk factors associated with these AEs.Methods: Cell infusion-associated AEs were evaluated according to National Cancer Institute Common Terminology Criteria. Analysis was performed from a single-centre data on 893 malignant tumour patients who received a total of 4088 transfusions from March 2008 to October 2013.Results: A total of 215/4088 (5.26%) transfusion cases from 893 patients presented with AEs (Grade 1 – 4); 204/215 (94.88%) were Grade 1 – 2, and 156/215 (72.56%) occurred within 24 h. The most common AEs were fever (0.88%), chills (0.56%) and fatigue (0.49%). The rare but severe AEs included anaphylactoid purpura, tumour lysis syndrome, anaphylactic shock, arthralgia. No transfusion-associated death was noticed. The mainly relative risk factors for AEs included transfer cycles and clinical stages.Conclusion: This study is a large-sample AEs research, to our knowledge, relative to immune cell transfusion from a single centre data analysis, revealing that autologous CIK cell therapy represents a fairly safe and well-tolerated treatment modality for malignant tumour patients, even rare severe, but not lethal AEs were observed in few patients.

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.

Effects of cytokine-induced killer cell treatment in colorectal cancer patients: A retrospective study

Cytokine-induced killer (CIK) cells are ex vivo generated heterogeneous NK-like T-lymphocytes, which have anti-tumor effects in vitro and in vivo. This present study was conducted to evaluate the effects of autologous CIK cell immunotherapy on the prognosis of colorectal cancer patients. Progression-free survival (PFS), overall survival (OS) and immune cells were assessed. We found that the percentages of CD8+, CD3+ CD56+, CD3− CD56+ cell subsets were significantly increased from 19.7±6.3%, 13.8±7.9%, 1.0±1.2% to 35.8±11.6% (P<0.001), 20.9±12.5 (P<0.001), 14.4±9.5% (P<0.001), respectively in the CIK group after 14 days of incubation. The median PFS and median OS in the CIK group were 25.8 months and 41.3 months respectively, while 12.0 months and 30.8 months in the control group. The PFS and OS curves of the CIK group and control group indicated that there were also statistically differences between two groups in PFS (log-rank, P=0.01) and OS (log-rank, P=0.037). Our results indicate that CIK cell immunotherapy in combination with chemotherapy can reduce the recurrence rate and promote the survival time of patients with colorectal cancer.

Modification of chemokine receptor expression to enhance levels of trafficking receptors on autologous cytokine-induced killer cells derived from patients with colorectal cancer

Cytokine-induced killer (CIK) cells have achieved therapeutic benefit in treatment of solid tumors in clinic. However, some patients show no response after CIK treatment. Animal assays have shown that successful infiltration of CIK cells to the tumor sites could affect the outcome. Chemokines play important roles in lymphocyte trafficking. Understanding the molecular mechanism of chemokines in the process of CIK cell homing is important for further modification of CIK therapy. In this study, we investigated the spectrum of chemokine ligands in the colorectal cancer sites and observed that chemokine ligands CCL20 and CXCL10 were overexpressed in the CRC tumor tissues compared with adjacent tissues. Although the corresponding receptors CCR6 and CXCR3 increased on CIK cells compared with PBMCs, their expression on CIK cells derived from CRC patients had lower levels than healthy donors, which might be a limited factor for autologous-CIK cells trafficking to tumor site. Importantly, stimulation with chemokines CCL20 and CXCL10 promotes the expression levels of CCR6 and CXCR3 on CIK cells, thus augmenting the relative migration of CIK cells in vitro. Our results suggest that modification of surface chemokine receptors may enhance the homing ability of CIK cells for better therapeutic achievements.

Maintenance Therapy With Autologous Cytokine-induced Killer Cells in Patients With Advanced Epithelial Ovarian Cancer After First-line Treatment

Cytokine-induced killer (CIK) cells have shown cytolytic ability against ovarian cancer cells in vitro and in vivo. This study was aimed to evaluate the clinical efficacy of maintenance therapy of CIK cells in patients with advanced epithelial ovarian cancer after first-line treatment. A paired study was performed in patients with stages IIB-IV epithelial ovarian cancer after cytoreductive surgery followed by 6-8 courses of carboplatin/paclitaxel chemotherapy. A total of 92 patients who achieved complete remission after first-line treatment were enrolled in this study. Forty-six patients in the treatment group received CIK cells transfusion monthly, whereas the other 46 patients in the control group received observation with follow-up. Progression-free survival (PFS), overall survival (OS), and toxicity were evaluated. Our results showed that median PFS was 37.7 months in the treatment group and 22.2 months in the control group (P=0.004). However, although median OS in the treatment group (61.5 mo) was longer than that in the control group (55.9 mo), there was no significant difference (P=0.289). The subgroup analysis revealed that the survival advantage of PFS from immunotherapy was independent of the extent of debulking surgery and pathologic stage. After 2 courses of CIK cells transfusion, the proportion of CD4CD25CD127 regular T cells in the peripheral blood significantly decreased (P=0.006). No grades III and IV adverse reaction were found during CIK cells infusion. Maintenance therapy with CIK cells improved the PFS in patients with advanced ovarian cancer after first-line treatment with slight side effects. However, the benefits with respect to OS are still pending.