Objective To clarify the effect and mechanism of tumor antigen-loaded dendritic cells (Ag-DCs) combined with cytokine-induced killers (CIKs) on the killing of esophageal cancer tumor cells. Methods Peripheral blood DCs and CIKs were induced and cultured, and the DCs were loaded with tumor antigen to obtain Ag-DCs, and Ag-DCs were co-cultured with CIKs. The experiment was divided into CIK group, DC combined with CIK group, Ag-DC combined with CIK group. Flow cytometry was used to detect the phenotype of cells. MTT assay was employed to determine the killing activity against EC9706 cells. Annexin V-FITC/PI double staining was used to detect the apoptosis rate of cells, immunofluorescence staining to detect the expression of phosphorylated apoptotic signal-regulated kinase 1 (p-ASK1) and Western blot analysis to detect the expression of ASK1 pathway related proteins. A nude mouse model of esophageal cancer transplantation tumor was constructed and divided into control group, DC combined with CIK group and Ag-DC combined with CIK group. The corresponding immune cells were injected into the tail vein for treatment and the tumor volume was measured every 2 days. After 21 days, all nude mice were sacrificed with the tumors taken out. HE staining was used to observe the tumor pathological changes and immunohistochemical staining was performed to detect the expression of ki67 and ASK1 in the tumor tissue. Results Comparedwith the CIK group alone and the DC combined with CIK group, the ratio of CD3⁺ CD8⁺ and CD3⁺ CD56⁺ in the cells significantly increased after Ag-DCs and CIKs co-culture, along with the increased killing rate of EC9706 cells, increased apoptosis rate of EC9706 cells, and the improved activation level of ASK1. Compared with the CIK group and the DC combined with CIK group, the growth of the transplanted tumor in nude mice treated with Ag-DCs combined with CIKs was significantly inhibited, and after 21 days, it was observed that the tumor tissue mass in this group was relatively smaller, with sparsely arranged cells in the tumor tissue and a decline in the positive rate of ki67 in tumor tissue, while the positive rate of ASK1 was significantly increased. Conclusion Co-cultivation of tumor antigen-loaded DCs with CIKs can significantly increase the killing activity of esophageal cancer tumor cells. The mechanism of action may be related to the activation of the ASK1 pathway.
Animals ; Humans ; Mice ; Antigens, Neoplasm ; Cytokine-Induced Killer Cells ; Cytokines/metabolism* ; Cytotoxicity, Immunologic ; Dendritic Cells ; Esophageal Neoplasms/therapy* ; Ki-67 Antigen ; Mice, Nude

OBJECTIVE: To investigate the safety and clinical efficacy of autologous DC-CIK cells combined with other immune cells for patients with hematological malignancies and analyze patient prognosis. METHODS: 50 patients with hematological malignancies who received cellular immunotherapy from September 2014 to April 2016 were retrospectively studied in the First Affiliated Hospital of Xi'an Jiaotong University, 115 cases times of cellular immunotherapy were performed. According to the selected treatment, the patients were divided into the dual cell group (DC-CIK cell treatment) and the multi-cell group (DC-CIK cell combined with other immune cells); According to the treatment course, the patients were divided into the single course group (completed by ＜3 times) and the multiple course group. The changes of T lymphocyte subsets, blood routine indicators and KPS scores as well as the overall survival time before and after treatment were compared and analyzed. RESULTS: [WTB1]The difference of general conditions before treatment including the number of patients, sex, age, T lymphocyte subsets, blood routine indicators, KPS scores and so on in 2 groups divided according to 2 kinds of treatment methods were not statistically significant, indicating that the 2 groups were comparable. Grouped by selected treatment, the CD4/CD8 ratio, Hb and Plt levels decreased in the dual cell group, compared with those before treatment(P＜0.05). The CD3CD4 ratio after treatment in multiple cell group decreased, compared with that before treatment (P＜0.05). The 3-year survival rate of patients in dual cell and multiple cell groups was 61.3% vs 69.8%, the overall survival time of patients in 2 groups was 32.4 months vs 39.6 months, there were no statisticall differences between 2 groups(P>0.05). Grouped by treatment course, the CD3 ratio after treatment increased, while the Hb level after treatment decreased in single course group, compared with level before treatment(P＜0.05). The CD3CD4 ratio, Plt level decreased, while the KPS scores increased after treatment in multiple course group, compared with those before treatment(P＜0.05). The 3-year survival rate in single course and multiple course groups was 52% vs 76.4%, the overall survival time was 28.7 months vs 40.9 months respectively, statistically significant with difference (P＜0.05). CONCLUSION Autologous DC-CIK cells combined with other immune cells in the treatment of hematological malignancies can change the immune function of the patients and improve the antitumor activity. The multi-course treatment can improve the quality of life, prolong the overall survival time, thus worthing clinical promotion.
Cytokine-Induced Killer Cells ; Dendritic Cells ; Hematologic Neoplasms ; Humans ; Immunotherapy, Adoptive ; Quality of Life ; Retrospective Studies ; Treatment Outcome

Systemic target therapeutic drugs, such as sorafenib, lenvatinib, or regorafenib are the only drugs that are known to be effective against advanced hepatocellular carcinoma (HCC). However, these agents show a limited efficacy in killing residual tumors. Immunotherapy is an alternative approach to this treatment and has been used to successfully treat different cancers, including HCC. HCC is an inflammation-induced cancer and represents a very interesting target for immunotherapeutics. Immunotherapies aim to reverse the immune tolerance and suppression found in tumor microenvironments and include approaches, such as adoptive cell therapy, immune checkpoint inhibition, and cancer vaccination. Adoptive cell therapy uses autologous natural killer or cytokine-induced killer cells by cultivating them ex vivo and subsequently reinfusing them into the patient. Immune checkpoint inhibitors reactivate tumor-specific T cells by suppressing checkpoint-mediated inhibitory signaling. Cancer vaccination induces a tumor-specific immune response by activating effector T lymphocytes. A wide range of potential immunotherapy-related adverse events occur; therefore, a multidisciplinary collaborative management is required across the clinical spectrum. This review summarizes the current status of immunotherapy for HCC and provides a perspective on its future applications.
Carcinoma, Hepatocellular ; Cell- and Tissue-Based Therapy ; Cytokine-Induced Killer Cells ; Homicide ; Humans ; Immune Tolerance ; Immunotherapy ; Neoplasm, Residual ; Oncolytic Viruses ; T-Lymphocytes ; Tumor Microenvironment ; Vaccination

In recent years, with the incidence of malignant tumors increasing year by year, its treatment has been made great progress on the basis of traditional treatments such as surgery, radiotherapy and chemotherapy, it mainly focuses on rapid development of cellular immunotherapy. The efficacy of dendritic cells combined with cytokine induced killer cell (DC-CIK) immunotherapy for cancer patients is positive, it shows good antitumor activities and the abilities to reconstruct and enhance the immune system of tumor patients in clinical application, it has potential application value. In the treatment of hematologic malignancies which are chemotherapy-based and high-grade malignant, what is the effect of DC-CIK cells immunotherapy for them? In this review, we searched Chinese and abroad literatures from 2012 to 2018 and further focused on 18 clinical research articles about hematologic malignancies in order to analyze the characteristics of DC-CIK cells immunotherapy. It was found that DC-CIK cells can be an effective and promising treatment for patients with hematologic malignancies, and thus, if the process and unified plan are further standardized and improved, the efficacy will be more obvious. For this purpose, this paper reviews the biological characteristic of DC cells, CIK cells and the clinical research progress of DC-CIK cell immunotherapy for hematological malignancies.
Combined Modality Therapy ; Cytokine-Induced Killer Cells ; Dendritic Cells ; Hematologic Neoplasms ; Humans ; Immunotherapy ; Immunotherapy, Adoptive

POEMS syndrome is a rare multiple organ involvement of the parasympathetic syndrome associated with abnormal plasma cells, mostly with high-dose chemotherapy and stem cell transplantation for the treatment. Recently, more treatment attempts to treat POEMS syndrome have been utilized so as to improve the efficacy and safety for the patients with POEMS syndrome, such as immunomodulator, alkylating agent, cytokine-induced killer cells and so on. Lenalidomide has a significant effect on relapse/refractory POEMS syndrome and patients with endocrinopathy. Cytokine-induced killer cells are also a safe and effective regimen for the treatment of POEMS syndrome. This review described the efficacy and safety of immunomodulatos, alkylators, cytokine-induced killer cells, ASCT, proteasome inhibitors and monoclonal antibodies for POEMS syndrome, and the newest clinical research and progress of POEMS syndrome ware summarized briefly.
Cytokine-Induced Killer Cells ; Humans ; Immunologic Factors ; POEMS Syndrome ; Stem Cell Transplantation ; Transplantation, Autologous

OBJECTIVETo investigate the efficiency of inducing CIK from peripheral blood mononuclear cells(PBMNC) by using immune cell serum replacement(immune cell SR), so as to provide a new strategy for the industrialized production of immune cells.

METHODSThe PBMNC of healthy volunteers were collected, and these cells were thawed after short-term cryopreservation and cultured to induce CIK cells. The cells viability was measured by trypan blue exclusion, the phenotypes were analyzed by flow cytometry, and the cytotoxicity was determined by Calcein-AM/PI double staining.

RESULTSIn cryopreserved PBMNC, the control group cells failed to normally proliferate. Cell proliferation ratio was low in 2% SR group in comparison with the fresh group, and the difference was significant (P<0.05), however, differences were not statistically significant between 5% SR and fresh group or between 10% AP and fresh group. CD3, CD3CD8 and CD3CD56 cell subsets were not significantly different before and after cryopreservation (P>0.05). After being cultured, CD3, CD3CD4, CD3CD8, CD3CD56 and CD3CD56 subsets and the cytotoxicity in vitro were not significantly different among all group(P>0.05).

CONCLUSION5% SR without the protein of animal origin can be safely used as a substitute for autologous plasma in CIK induced from cryopreserved PBMNC by culture, thus providing a basis for the application of cryopreservation technique of immune cells to cell therapy.

Cell Proliferation ; Cell Survival ; Cryopreservation ; Cytokine-Induced Killer Cells ; Flow Cytometry ; Humans

PURPOSE: The treatment of triple-negative breast cancer (TNBC) remains challenging, due to the absence of estrogen, progesterone, and human epidermal growth factor receptors. This study was designed to evaluate the efficiency and safety of cytokine-induced killer (CIK) cell immunotherapy, following regular chemotherapy, for patients with TNBC. METHODS: A total of 340 patients with postmastectomy TNBC, from January 1, 2010 to June 30, 2014, were included in this retrospective study. Seventy-seven patients received CIK cell immunotherapy, following regular chemotherapy (arm 1), and 263 patients received regular chemotherapy alone (arm 2). The primary aim was overall survival (OS) and disease-free survival (DFS), and the treatment responses and adverse events were also evaluated. RESULTS: The 5-year DFS and OS rates in arm 1 were 77.9% and 94.3%, compared with 69.8% and 85.6% in arm 2, respectively (p=0.159 and p=0.035, respectively). This clearly shows that there was no statistical difference in the 5-year DFS between the two groups. Multivariate analyses of arm 1 indicated that a Karnofsky performance score (KPS) ≥90 and stage I/IIA disease were significantly associated with a prolonged DFS period (hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.09–0.74; p=0.012; and HR 0.21; 95% CI, 0.06–0.82; p=0.024, respectively), but a KPS ≥90 and stage I/IIA disease were not independent prognostic factors for OS. Toxicity was mild in patients who received the CIK therapy. CONCLUSION: The data suggested that CIK cell immunotherapy improved the efficiency of regular chemotherapy in patients with TNBC, and the side effects of CIK cell immunotherapy were mild.
Arm ; Cytokine-Induced Killer Cells* ; Disease-Free Survival ; Drug Therapy* ; Estrogens ; Humans ; Immunotherapy ; Multivariate Analysis ; Progesterone ; Prognosis ; Receptor, Epidermal Growth Factor ; Retrospective Studies ; Triple Negative Breast Neoplasms*

The treatment outcomes of relapsed or refractory neuroblastoma have been unsatisfactory till date. We reported two cases of adoptive immunotherapy using cytokine-induced killer (CIK) cells against relapsed or refractory neuroblastoma. CIK cell production was attempted in three patients, out of which two patients exhibited adequate levels of CIK cell production. Two patients completed full term of CIK cell infusions (weekly for 6 weeks and then biweekly for 8 wk) without serious adverse events. The progression-free survivals for the two patients were 1.9 and 4.1 months. Their overall survivals were 16.7 and 28.7 months. Although the efficacy was unclear, CIK cell infusion combined with other treatment strategies may have prolonged overall survival in refractory neuroblastoma patients. Further studies are needed to determine the exact role of CIK cell-based immunotherapy in relapsed or refractory neuroblastoma patients.
Cytokine-Induced Killer Cells* ; Disease-Free Survival ; Humans ; Immunotherapy* ; Immunotherapy, Adoptive ; Neuroblastoma*

Hepatocellular carcinoma (HCC) has extremely poor prognosis. Immunotherapy has emerged as a new treatment for a number of cancers. Adoptive immunotherapy is one of the important cancer immunotherapy, which relies on the various lymphocytes including cytotoxic T lymphocytes, natural killer (NK) and cytokine induced killer cells. Also, there has been advance in techniques of NK cell activation to more effectively kill the cancer cells. Of note, recently the blocking antibodies targeting programmed cell death protein 1 (PD-1) have shown promising results in diverse cancers including HCC. We report our recent experience of a patient accompanying advanced HCC with extrahepatic metastases. Disease progression had occurred after sorafenib administration, while the patient showed local tumor control and tumor marker decrease by NK cell immunotherapy combined with PD-1 inhibitor therapy. Though, there was no definite survival advantage due to impaired liver function, which might be caused by treatment related toxicities as well as cancer progression.
Antibodies, Blocking ; Carcinoma, Hepatocellular ; Cell Death ; Cytokine-Induced Killer Cells ; Disease Progression ; Humans ; Immunotherapy ; Immunotherapy, Adoptive ; Killer Cells, Natural ; Liver ; Lymphocytes ; Neoplasm Metastasis ; Prognosis ; Programmed Cell Death 1 Receptor ; T-Lymphocytes, Cytotoxic

OBJECTIVETo explore the values of autologous cytokine-induced killer cells combined with rhIL-2 for therapy of elderly patients with B-cell malignant lymphoma.

METHODSEighty-five elderly patients with B-cell malignant lymphoma were treated by cytokine induced killer cells combine with rhIL-2 (CIK+IL-2 group), 85 elderly patients with B-cell malignant lymphoma treated without cytokine induced killer cells combined with rhIL-2 were used as the control group. The patients in CIK+IL-2 group and control group were divided into 4 subgroups accerding to lymphoma types: group A: diffuse large B cell lymphoma (DLBCL), group B: mucosa-associated lymphoid tissue type (MALT), group C: lymphoplas macytic lymphoma (LPL) and group D: hodgkin's lymphma (HL). The clinical effects, T-lymphocyte, β2 microglobulin level, quality of life and long-term survival were observed.

RESULTSThe levels of CD3+, CD3+/CD8+, CD3+/CD56+ after treatment in the 4 subgroups of CIK+IL-2 group were higher than levels before treatment and the control group (P<0.05); the levels of β2 microglobulin after treatment for the 4 groups were lower than before treatment and the control group (P<0.05); with 1 case death, 16 cases were turned from CRu and PR to CR; the CR rate was not significantly different among the 4 subgroups (P>0.05); the scores of physical performance, role function, cognitive function, emotional functioning, and social function after treatment in the 4 subgroups were higher than the those before treatment (P<0.05); the survival time of patients in the CIK+IL-2 group lasted for 8-76 months, their median survival time was (22.36±5.38) months; the survival of the control group lasted for 7-55 months, their median survival time was (16.15±3.62) months. The survival time of the CIK+IL-2 group was longer than that of the control group (P<0.05).

CONCLUSIONThe treatment of aged patients with B-cell malignant lymphoma by autologous cytokine-induced killer cells combined with rhIL-2 can effectively improve the T-lymphocyte subsets, β2 microglobulin level and quality of life, and can prolong survival time of patients.

Aged ; Cytokine-Induced Killer Cells ; cytology ; Humans ; Interleukin-2 ; therapeutic use ; Lymphoma, Large B-Cell, Diffuse ; therapy ; Quality of Life ; Recombinant Proteins ; therapeutic use ; T-Lymphocyte Subsets