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Background: Cytokine‐induced killer (CIK) cell therapy has proven successful in clinical trials regarding glioblastoma. Equally important are the hints suggesting peroxisome proliferator‐activated receptors (PPARs) ligands being co‐expressed in the central nervous system (CNS). This provides a rationale about investigating the possible synergistic effect of CIK cells and PPARs. Methodology: We investigated neuroblastoma and glioblastoma cell lines with mature CIK cells and the PPARγ antagonist GW‐9662 to assess the effects on cell viability, candidate gene expression (Wnt/β‐catenin signalling, DNMT1) and global methylation levels (5‐methylcytosine, LINE‐1). Results: Using a clinical applicable PPAR‐γ inhibitor, we showed that (1) PPARγ‐antagonist GW‐9662 suppressed tumor cell growth in both neuroblastoma and glioblastoma cells, (2) PPARγ inhibition had restricted effect on the expression of Wnt/β‐catenin associated genes, (3) inhibition of PPARγ led to downregulation of DNMT1 expression, supporting their hypothesized interaction in cancer, (4) a partial modulation of global LINE‐1 methylation levels was observed, indicating their role in epigenetic processes, and (5) Combining PPARγ inhibition with CIK cell immunotherapy enhanced cell lysis significantly. Conclusion: We provide evidence that PPAR ligands in combination with CIK cell immunotherapy could be a valuable option for malignant CNS tumors. [ABSTRACT FROM AUTHOR]

Undeniably, cancer immunotherapies have expanded the spectrum of cancer treatment, however, some patients do not respond to immunotherapies. This scenario is no different for lung cancer, whose two main types, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), still pose a serious clinical challenge. Adoptive T-cell therapies (ATC), which primarily include cytokine-induced killer (CIK) cell therapy, chimeric antigen receptor T-cell (CAR T-cell) therapy and γδ-T-cell therapy, strengthen the patient's immune system in combating cancer. Combining ATC with immune checkpoint inhibitors (ICI) further enhances the effectiveness of this approach to eradicate cancer. With a particular emphasis on CIK cell therapy, which recently completed 30 years, we highlight the role of the PD-1/PD-L1 axis in NSCLC and SCLC. Besides, we provide insights into the potential synergies of PD-1/PD-L1 inhibitors with adoptive T-cell immunotherapy in reshaping the treatment paradigm for lung cancer. [ABSTRACT FROM AUTHOR]

Objectives: The rapid recognition of epigenetic manipulation's potential in restricting cancer cell capabilities spurred translational initiatives, including histone deacetylase inhibitors (HDACis). Clinical trials on multiple myeloma (MM) demonstrated substantial benefits of HDACis, coupled with promising outcomes from cytokine‐induced killer cell (CIK) immunotherapy. Intriguingly, the unexplored synergy of HDACis and CIK cell immunotherapy in MM prompted our study. Methods: We examined clinically relevant HDACis (panobinostat/LBH589 and romidepsin) alongside CIK cells derived from peripheral blood mononuclear cells across diverse MM cell lines (U266, RPMI8226, OPM‐2 and NCI‐H929). Utilising various in vitro methodologies, we investigated how HDACis enhance CIK cell lysis of myeloma cells through NKG2D/NKG2D ligand interactions. Results: The results of our analysis indicated several key findings. (1) Enhanced cytotoxicity of CIK cells in MM cells when combined with HDACis. (2) Significant increase in apoptosis, suggesting HDACis and CIK may together enhance apoptotic effects in specific MM cell lines. (3) Elevated IFN‐γ secretion and alterations in granzyme B secretion because of the independent activity of HDACis. (4) Notably, HDACis increased the expression of MICA/B and ULBP2, crucial for inducing antitumor cytotoxicity of NKT cells. Validation through NKG2D receptor blocking in CIK cells with a purified mouse antihuman NKG2D antibody further supported our findings. Conclusions: Our analyses provide sufficient evidence to consider this clinically forgotten instance (HDACis‐CIK cell combination) as a therapeutic priority for MM treatment. Furthermore, we suggest that NKG2D/NKG2D‐ligand interactions activating NK/NKT cells may contribute to enhanced myeloma cell lysis in response to HDACis treatment by CIK cells. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. Cytokine-induced killer (CIK) cells are an adoptive immunotherapy reported to have strong anti-tumour activity across a range of cancers. They are a heterogeneous mix of lymphoid cells generated by culturing human peripheral blood mononuclear cells with cytokines and monoclonal antibodies in vitro. In this study, we investigated the yield and function of CIK cells generated from patients with CRC liver metastases. We first showed that CIK cells generated in serum free medium X-VIVO 15 were comparable to those from RPMI medium with 10% FBS in terms of the number and percentages of the main subsets of cells in the CIK culture, and the intracellular levels of granzyme B and perforin, and the pro-inflammatory cytokines IL-2, IFN-γ and TNF-α. The CIK cells were cytotoxic to CRC cell lines grown in 2D cultures or as spheroids, and against autologous patient-derived tumour organoids. Donor attributes such as age, sex, or prior chemotherapy exposure had no significant impact on CIK cell numbers or function. These results suggest that functional CIK cells can be generated from patients with CRC liver metastatic disease, and support further investigations into the therapeutic application of autologous CIK cells in the management of patients with CRC liver metastases. [ABSTRACT FROM AUTHOR]

Background and Objectives Despite the success of CAR-T cells in the treatment of hematologic malignancies, the use of allogeneic sources of T lymphocytes to produce these cells is associated with risk of GvHD. Cytokine induced killer (CIK) cells are a population with a lower risk of GvHD. Therefore, CAR-CIK cells can be evaluated as a potential alternative for CAR-T cells. Materials and Methods In this experimental study, after isolation and culture of mononuclear cells isolated from the peripheral blood of two healthy donors, T and CIK cells are transduced with CD19 gene containing lentiviral vector. On the 16th day of culture, to compare the cytotoxicity of CAR-T and CAR-CIK cells, these cells were co-cultured with CD19+ K562 target cells, and the death rate among the target cells was measured using a lactate dehydrogenase release assay kit. Student T-test, Anova and post-hoc Tukey were used for statistical analysis using Graph Pad prism software 8. A p-value less than 0.05 was considered statistically significant. Results In both CAR-CIK and CAR-T cell, CAR receptor caused a significant increase in cytotoxicity. So that no significant difference was observed between the cytotoxicity of CAR-T cells (67.8% ± 1.7) and CAR-CIK (65.1% ± 1.8). Conclusions CAR-CIK cells show a suitable in vitro cytotoxicity, so they can be considered as a potential alternative for CAR-T cells. However, more preclinical and clinical studies are needed to compare other effective dimensions in the function of these two cell types. [ABSTRACT FROM AUTHOR]

Background: Dendritic Cell Cytokine-induced killer cell (DC-CIK) coculture treatment in cancer immunotherapy has been shown to be effective. However, the cost of DC- CIK therapy is prohibitive for many patients, and the lack of standard manufacturing processes and treatment strategies are major limitations. Our study used tumor lysate as a tumor-associated antigen source and DCs and CIK cells in coculture. We developed an efficient method to obtain autologous DCs- and CIK cells from peripheral blood. We used flow cytometry to assess DC activation and the cytometric bead array assay to quantify cytokines secreted by CIK cells. Results: We evaluated the antitumor activity of DC- CIK coculture in vitro with the K562 cell line. We demonstrated that a manufacturing process employing frozen immature DCs can yield the lowest loss with the highest economic benefits. DC-CIK coculture can effectively upgrade CIK cells' immunological specificity to tumors in the presence of tumor-associated antigens. Conclusion: In vitro experiments revealed that when the DC- CIK cell ratio was 1: 20 in the coculture, CIK cells secreted the highest number of cytokines on the 14th day and the antitumor immune effect showed the highest potency. CIK cells' cytotoxicity to K562 cells was highest when the CIK: K562 cell ratio was 25: 1. We developed an efficient manufacturing process for DC- CIK coculture, while also establishing the optimal DC- CIK cell ratio for immunological activity and the best cytotoxic CIK: K562 cell ratio. [ABSTRACT FROM AUTHOR]

Gastrointestinal stromal tumors (GISTs) are rare, mesenchymal tumors of the gastrointestinal tract, characterized by either KIT or PDGFRA mutation in about 85% of cases. KIT/PDGFRA wild type gastrointestinal stromal tumors (wtGIST) account for the remaining 15% of GIST and represent an unmet medical need: their prevalence and potential medical vulnerabilities are not completely defined, and effective therapeutic strategies are still lacking. In this study we set a patient-derived preclinical model of wtGIST to investigate their phenotypic features, along with their susceptibility to cellular immunotherapy with cytokine-induced killer lymphocytes (CIK) and interferons (IFN). We generated 11 wtGIST primary cell lines (wtGISTc). The main CIK ligands (MIC A/B; ULBPs), along with PD-L1/2, were expressed by wtGISTc and the expression of HLA-I molecules was preserved. Patient-derived CIK were capable of intense killing in vitro against wtGISTc resistant to both imatinib and sunitinib. We found that CIK produce a high level of granzyme B, IFNα and IFNγ. CIK-conditioned supernatant was responsible for part of the observed tumoricidal effect, along with positive bystander modulatory activities enhancing the expression of PD-L1/2 and HLA-I molecules. IFNα, but not In, had direct antitumor effects on 50% (4/8) of TKI-resistant wtGISTc, positively correlated with the tumor expression of IFN receptors. wtGIST cells that survived IFNα were still sensitive to CIK immunotherapy. Our data support the exploration of CIK immunotherapy in clinical studies for TKI-resistant wtGIST, proposing reevaluation for IFNα within this challenging setting. [ABSTRACT FROM AUTHOR]

Despite numerous studies conducted over the past decade, the exact role of the cannabinoid system in cancer development remains unclear. Though research has focused on two cannabinoid receptors (CB1, CB2) activated by most cannabinoids, CB2 holds greater attention due to its expression in cells of the immune system. In particular, cytokine-induced killer cells (CIKs), which are pivotal cytotoxic immunological effector cells, express a high-level of CB2 receptors. Herein, we sought to investigate whether inducing CIK cells with cannabidiol can enhance their cytotoxicity and if there are any possible counter effects in its downstream cascade of phosphorylated p38 and CREB using a pancreatic ductal adenocarcinoma cell line (PANC-1). Our results showed that IL-2 modulates primarily the expression of the CB2 receptor on CIK cells used during ex vivo CIK expansion. The autophagosomal-associated scaffold protein p62 was found to co-localize with CB2 receptors in CIK cells and the PANC-1 cell line. CIK cells showed a low level of intracellular phospho-p38 and, when stimulated with cannabidiol (CBD), a donor specific variability in phospho-CREB. CBD significantly decreases the viability of PANC-1 cells presumably by increasing the cytotoxicity of CIK cells. Taken together, in our preclinical in vitro study, we propose that a low effective dose of CBD is sufficient to stimulate the cytotoxic function of CIK without exerting any associated mediator. Thus, the combinatorial approach of non-psychoactive CBD and CIK cells appears to be safe and can be considered for a clinical perspective in pancreatic cancer. [ABSTRACT FROM AUTHOR]

Our center performs experimental clinical studies with advanced therapy medicinal products (ATMPs) based on polyclonal T cells, all of which are currently expanded in standard T-flasks. Given the need to increase the efficiency and safety of large-scale T cell expansion for clinical use, we have optimized the method to expand in G-Rex devices both cytokine-induced killer cells (CIKs) from peripheral or cord blood and blinatumomab-expanded T cells (BETs). We show that the G-Rex reproducibly allowed the expansion of >30 × 106 CD3+ cells/cm2 of gas-permeable membrane in a mean of 10 to 11 days in a single unit, without manipulation, except for addition of cytokines and sampling of supernatant for lactate measurement every 3 to 4 days. In contrast, 21 to 24 days, twice-weekly cell resuspension and dilution into 48 to 72 T-flasks were required to complete expansions using the standard method. We show that the CIKs produced in G-Rex (CIK-G) were phenotypically very similar, for a large panel of markers, to those expanded in T-flasks, although CIK-G products had lower expression of CD56 and higher expression of CD27 and CD28. Functionally, CIK-Gs were strongly cytotoxic in vitro against the NK cell target K562 and the REH pre-B ALL cell line in the presence of blinatumomab. CIK-Gs also showed therapeutic activity in vivo in the Ph+ pre-B ALL-2 model in mice. The expansion of both CIKs and BETs in G-Rex was validated in good manufacturing practices (GMP) conditions, and we plan to use G-Rex for T cell expansion in future clinical studies. [ABSTRACT FROM AUTHOR]

The authors describe here a novel therapeutic strategy combining a bispecific antibody (bsAb) with cytokine-induced killer (CIK) cells. The authors have designed, produced and purified a novel tetravalent IgG1-like CD20 × CD5 bsAb called BL-01. The bsAb is composed of a fused heavy chain and two free light chains that pair correctly to the heavy chain sequences thanks to complementary mutations in the monoclonal antibody 2 CH1/CL sequences. The authors show that BL-01 can bind specifically to CD20 and CD5 with an affinity of 4–6 nM, demonstrating correct pairing of two light chains to the fused heavy chain. The CD20 × CD5 BL-01 bsAb has a functional human IgG1 Fc and can induce up to 65% complement-dependent cytotoxicity of a CD20+ lymphoma cell line in the presence of human complement, similar to anti-CD20 rituximab. The bsAb also induces significant natural killer cell activation and antibody-dependent cytotoxicity of up to 25% as well as up to 65% phagocytosis by human macrophages in the presence of CD20+ tumor cells. The BL-01 bsAb binds to CD20 and CD5 simultaneously and can redirect CIK cells in vitro to kill CD20+ targets, increasing the cytotoxicity of CIK cells by about 3-fold. The authors finally show that the CD20 × CD5 BL-01 bsAb synergizes with CIK cells in vivo in controlling tumor growth and prolonging survival of nonobese diabetic/severe combined immunodeficiency mice inoculated with a patient-derived, aggressive diffuse large B-cell lymphoma xenograft. The authors suggest that the efficacy of bsAb in vivo is due to the combined activation of innate immunity by Fc and redirection of CIK cells to kill the tumor target. [ABSTRACT FROM AUTHOR]

Objectives: Even though postoperative chemotherapy can eliminate residual tumor cells in patients with colorectal cancer (CRC), severe adversity, weakened immunity and drug resistance are still problems. Adjuvant cytokine‐induced killer (CIK) cell therapy is an alternative to CRC patients after surgery. The present study investigated the efficacy of adjuvant CIK cell therapy combined with chemotherapy in postoperative CRC patients. Methods: This retrospective analysis included 137 postoperative CRC patients, including 71 who received adjuvant chemotherapy alone (control group) and 66 who received adjuvant immunotherapy based on CIK cells combined with chemotherapy (CIT group). Results: Long‐term follow‐up study indicated that overall survival (OS) and progression‐free survival (PFS) were significantly longer in the CIT group than in the control group. Subgroup analyses showed that CIT treatment significantly improved OS and PFS of CRC patients classified as stage II and N0 stage and in patients with primary tumors in the rectum. Increasing the number of CIK infusions resulted in better prognosis. CRC patients aged < 65 years were found to benefit more from CIT‐based therapy than patients aged ≥ 65 years. A retrospective case–control study indicated that the primary tumor expression of signalling lymphocytes activating molecule family 7 (SLAMF7) was associated with increased efficacy of CIT treatment. Conclusions: Adjuvant CIT therapy was an effective therapeutic strategy for postoperative CRC patients prolonging OS and PFS. Patient age, tumor stage and expression of SLAMF7 may be potential indicators of the efficacy of CIT therapy. [ABSTRACT FROM AUTHOR]

Background: Cytokine-induced killer cells induced with tumor antigen-pulsed dendritic cells (DC-CIK) immunotherapy is a promising strategy for the treatment of malignant tumors. However, it sefficacy is restricted by the immunosuppression, which is mediated by the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) pathway. In order to overcome the negative co-stimulation from these T cells, we screened a nanobody targeted for CTLA-4 (Nb36) and blocked the CTLA-4 signaling with Nb36. Methods: Peripheral blood mononuclear cells (PBMCs) were collected from healthy donors to beused to induce CIK cells in vitro, after which they were co-cultured with DC cells that had received tumor antigens. In addition, we tested whether blocking CTLA-4 signaling with Nb36 could promote in vitro DC-CIK cells proliferation, pro-inflammatory cytokine production and cytotoxicity, or not. For the in vivo experiments, we constructed a subcutaneously transplanted tumor model and placed it in NOD/SCID mice to verify the anti-tumor effect of this therapy. Results: After stimulation with Nb36, the DC-CIK cells presented enhanced proliferation and production of IFN-γ in vitro, which strengthened the killing effect on the tumor cells. For the in vivo experiments, it was found that Nb36-treated DC-CIK cells significantly inhibited the growth of subcutaneously transplanted livercancer tumors, as well as reduced the tumor weight and prolonged the survival of tumor-bearing NOD/SCID mice. Conclusions: Our findings demonstrated that in response to CTLA-4 specific nanobody stimulation, DC-CIK cells exhibited a better anti-tumor effect. In fact, this Nb-based CTLA-4 blocking strategy achieved an anti-tumor efficacy close to that of monoclonal antibodies. Our findings suggest that DC-CIK cells + Nb36 have the potential to treat malignant tumors through in vivo adoptive therapy. [ABSTRACT FROM AUTHOR]

Background: Cytokine-induced killer cells induced with tumor antigen-pulsed dendritic cells (DC-CIK) immunotherapy is a promising strategy for the treatment of malignant tumors. However, itsefficacy isrestricted by the immunosuppression, which is mediated by the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) pathway. In order to overcome the negative co-stimulation from these T cells,we screened a nanobody targeted for CTLA-4 (Nb36) and blocked the CTLA-4 signaling with Nb36.Methods: Peripheral blood mononuclear cells (PBMCs) were collected from healthy donors to beused to induce CIK cells in vitro, after which they were co-cultured with DC cells that had received tumor antigens. In addition, wetested whether blocking CTLA-4 signaling with Nb36 could promote in vitro DC-CIK cells proliferation, pro-inflammatory cytokine production and cytotoxicity,or not. For the in vivo experiments, we constructed a subcutaneously transplanted tumor model and placed it in NOD/SCID mice to verify the anti-tumor effect of this therapy.Results: After stimulation with Nb36, the DC-CIK cells presented enhanced proliferation and production of IFN-γ in vitro, which strengthened the killing effect on the tumor cells. For the in vivo experiments, it was found that Nb36-treated DC-CIK cells significantly inhibited the growth of subcutaneously transplanted livercancer tumors, as well as reduced the tumor weight and prolonged the survival of tumor-bearing NOD/SCID mice.Conclusions: Ourfindings demonstrated that in response to CTLA-4 specific nanobody stimulation, DC-CIK cells exhibited a better anti-tumor effect. In fact, this Nb-based CTLA-4 blocking strategy achieved an anti-tumor efficacy close to that of monoclonal antibodies. Our findings suggest that DC-CIK cells + Nb36 have the potential totreatmalignant tumors through in vivo adoptive therapy. [ABSTRACT FROM AUTHOR]

Cytokine‐induced killer (CIK) cells represent an exceptional T‐cell population uniting a T cell and natural killer cell‐like phenotype in their terminally differentiated CD3+CD56+ subset, which features non‐MHC‐restricted tumor‐killing activity. CIK cells have provided encouraging results in initial clinical studies and revealed synergistic antitumor effects when combined with standard therapeutic procedures. We established the international registry on CIK cells (IRCC) to collect and evaluate clinical trials for the treatment of cancer patients in 2010. Moreover, our registry set new standards on the reporting of results from clinical trials using CIK cells. In the present update, a total of 106 clinical trials including 10,225 patients were enrolled in IRCC, of which 4,889 patients in over 30 distinct tumor entities were treated with CIK cells alone or in combination with conventional or novel therapies. Significantly improved median progression‐free survival and overall survival were shown in 27 trials, and 9 trials reported a significantly increased 5‐year survival rate. Mild adverse effects and graft‐versus‐host diseases were also observed in the studies. Recently, more efforts have been put into the improvement of antitumoral efficacy by CIK cells including the administration of immune checkpoint inhibitors and modification with chimeric antigen receptorc. The minimal toxicity and multiple improvements on their tumor‐killing activity both make CIK cells a favorable therapeutic tool in the clinical practice of cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Objective: To investigate the safety and therapeutic efficacy of adjuvant cytokine-induced killer (CIK) cells to minimally invasive therapies in unresectable hepatocellular carcinoma (u-HCC).Materials and Methods: Hundred patients diagnosed with having u-HCC in our department from January 1, 2001, to July 31, 2018, were recruited. Forty-three patients received microwave ablation (MWA) and transcatheter arterial chemoembolization (TACE) together with autologous CIK cell treatment (TACE + MWA + CIK group), whereas 57 patients received TACE and MWA only (TACE + MWA group). Postprocedural complications and cumulative therapeutic effects were assessed in all patients. The disease control rate, median survival time (MST), and cumulative survival rate were compared between the cohorts using the Kaplan-Meier method and unpaired Student's t-tests.Results: The overall response (complete response [CR] + partial response [PR]) rate was 74.42% (32/43) and 77.19% (44/57) for TACE + MWA + CIK and TACE + MWA groups, respectively (P = 0.243). Those of the TACE + MWA + CIK group had better rates of disease control (CR + PR + stable disease) in contrast to the TACE + MWA group (87.72% vs. 79.07%, respectively) but this failed to achieve statistical significance (P = 0.748). Based on the Kaplan-Meier survival graphs, those of the TACE + MWA + CIK groups possessed markedly increased overall survival (41 months vs. 24 months, P = 0.002) and progression-free survival (17 months vs. 10 months, P = 0.023) rates in compared to the TACE + MWA group. Survival rates were raised also TACE + MWA + CIK group than in TACE + MWA group (P = 0.002), with a MST of 6.13 ± 0.83 months and 11.61 ± 1.59 months in the TACE + MWA + CIK and TACE + MWA groups, respectively. Patients in the TACE + MWA + CIK group were not reported to have any severe complications.Conclusion: CIK cell immunotherapy as an adjuvant to TACE and MWA enhanced long-term prognosis and improved quality of life in patients with u-HCC. This regimen may be recommended as a novel treatment regime in u-HCC patients. [ABSTRACT FROM AUTHOR]

Cytokine-Induced (CIK) cells represent an attractive approach for cell-based immunotherapy, as they show several advantages compared with other strategies. Here we describe an original serum-free protocol for CIK cell expansion that employs G-Rex devices and compare the resulting growth, viability, phenotypic profile and cytotoxic activity with conventional culture in tissue flasks. CIK cells were obtained from buffy coats, seeded in parallel in G-Rex and tissue flasks, and stimulated with clinical-grade IFN-γ, anti-CD3 antibody and IL-2. G-Rex led to large numbers of CIK cells, with a minimal need for technical interventions, thus reducing the time and costs of culture manipulation. CIK cells generated in G-Rex showed a less differentiated phenotype, with a significantly higher expression of naive-associated markers such as CD62L, CD45RA and CCR7, which correlates with a remarkable expansion potential in culture and could lead to longer persistence and a more sustained anti-tumor response in vivo. The described procedure can be easily translated to large-scale production under Good Manufacturing Practice. Overall, this protocol has strong advantages over existing procedures, as it allows easier, time-saving and cost-effective production of CIK effector cells, fostering their clinical application. [ABSTRACT FROM AUTHOR]

The purpose of this study is to investigate whether the DC cells combined with CIK cells (DC/CIK) and DC activated cytotoxic T cells (DC-ACT) treatment can promote antitumor response and change the immune indicators by targeting the heterogeneous tumor cell populations at a system level. In this study, 112 patients with cancer were assigned to the DC/CIK treatment and 116 patients received the DC-ACT therapy. We detected the lymphocyte subsets and other immune indicators pre- and post-treatment to evaluate the changes of patient's immunity and compare the differences in immune status between two adoptive cellular immunotherapies. DC/CIK therapy elevated the percentage of CD3+ HLA-DR+ T cells, NK cells and several serological cytokines such as IL-2, IL-6 after cell infusion (p <.05). DC-ACT therapy could increase the total CD3 + T cells, CD8 + T cells, CD3+ HLA-DR+ cells and IL-12 cytokines after cell infusion (p <.05). The levels of IL-4/IFN-γ, IL-4/IL-12 and IL-6/IL-12 were reduced significantly in the DC-ACT group compared with DC/CIK group. These observations suggested that DC-ACT therapy has more dominance to induce Th1 cytokine response instead of skewing toward the Th2 cytokine profile based on the immunomodulatory properties. These results indicated that DC, CIK, and DC-ACT cells exert anti-tumor activity through the different pathways. Thus, this work may provide valuable insights into the clinical curative effect evaluation of immunocyte therapy and the design of combined immunotherapeutic strategies for malignant tumors. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate whether autologous cytokine-induced killer (CIK) cell immunotherapy improves the prognosis of patients with high-risk diffuse large B cell lymphoma (DLBCL) after the first complete remission (CR). Patients and Methods: Peripheral blood mononuclear cells (PBMCs) were extracted from 20 patients with high-risk DLBCL (IPI≥ 3) after the first CR. Twenty CR patients who were age- and sex-matched during the same period were selected as controls. PBMCs were cultured with IFN-γ, IL-2 and anti-CD3 mAb to generate CIK cells. These obtained cells were then transfused back into the patients; the transfusion was repeated every 3 months up to a total of four courses. Changes in peripheral blood lymphocyte subgroups and survival were assessed. Results: Compared with the baseline proportions, the proportion of CD3+ T cells, CD3+CD8+ T cells, and NK cells in the peripheral blood were significantly higher after transfusions (p< 0.05). The 5-year DFS was improved from 45.0 ± 11.1% to 79.3 ± 9.2% in the CIK group (HR favoring CIK, 0.29; 95% CI, 0.09 to 0.92; p = 0.035), and the 5-year OS was estimated at 90 ± 6.7% for CIK versus 55 ± 11.1% for control (HR favoring CIK, 0.20; 95% CI, 0.04 to 0.93; p = 0.040). No severe side effects were observed related to CIK treatment. Conclusion: Autologous CIK cell immunotherapy has emerged as a safe and efficacious option to improve the prognosis of patients with high-risk DLBCL after the first CR. [ABSTRACT FROM AUTHOR]

At present, coronavirus disease 2019(COVID-19) caused by 2019 novel coronavirus(2019-nCoV) infection has spread rapidly in China and more than 70 countries around the world and thus become a public health event of international concern. In addition to fever and respiratory symptoms, varying degrees of liver injury is also observed after 2019-nCoV infection. This article reviews the clinical features, pathology, pathogenic mechanism, and therapeutic strategies of liver injury associated with COVID-19, hoping to provide a reference for clinical decision-making on the prevention and treatment of COVID-19. [ABSTRACT FROM AUTHOR]

Background: Autologous cellular immunotherapy or immune enhancement therapy has demonstrated some promising benefits for prostate cancer. T cell-based immunotherapy or sipuleucel-T therapy has yielded certain beneficial responses and a slight improvement on the overall survival of patients with metastatic castration-resistant prostate cancer (mCRPC) as shown in some clinical trials, suggesting that prostate cancer is immunoresponsive. Methods: In this study, we developed an adaptive cytokine-induced killer cell (CIK)-based immunotherapeutic application targeting the prostate cancer stem-like cells (PCSCs). In this therapeutic platform, dendritic cells (DC) were isolated from the peripheral blood mononuclear cells (PBMCs) and preloaded or sensitized with immunogenic peptides derived from two PCSC-associated cell membrane molecules, CD44 and EpCAM, followed by co-culture with the expanded peripheral blood lymphocyte (PBL)-derived CIK cells. The in vitro cytotoxic activity of DC-activated CIK cells against PCSCs was determined by CCK8 and TUNEL assays, and the in vivo anti-tumor effect of DC-activated CIK cells on prostate cancer xenograft tumors was evaluated in subcutaneous and orthotopic xenograft models. Results: Our results showed that the peptide-sensitized DC-CIK cell preparation manifested significant in vitro cytotoxic activity against the PCSC-enriched prostatospheroids and also in vivo anti-tumor effect against prostate cancer xenografts derived from the PCSC-enriched prostatospheroids. Conclusions: Together, our established immunogenic peptide-sensitized DC-CIK-based cell preparation platform manifests its potential immunotherapeutic application in targeting the PCSCs and also prostate cancer. [ABSTRACT FROM AUTHOR]

Cytokine-induced killer (CIK) cells are an ex vivo –expanded cellular therapy product with potent anti-tumor activity in a subset of patients with solid and hematologic malignancies. We hypothesize that directing CIK cells to a specific tumor antigen will enhance CIK cell anti-tumor cytotoxicity. We present a newly developed method for affixing antibodies directly to cell surface proteins. First, we evaluated the anti-tumor potential of CIK cells after affixing tumor-antigen targeting monoclonal antibodies. Second, we evaluated whether this antibody-conjugation method can profile the surface proteome of CIK cells. We demonstrated that affixing rituximab or daratumumab to CIK cells enhances cytotoxic killing of multiple lymphoma cell lines in vitro. These 'armed' CIK cells exhibited enhanced intracellular signaling after engaging tumor targets. Cell surface proteome profiling suggested mechanisms by which antibody-armed CIK cells concurrently activated multiple surface proteins, leading to enhanced cytolytic activity. Our surface proteome analysis indicated that CIK cells display enhanced protein signatures indicative of immune responses, cellular activation and leukocyte migration. Here, we characterize the cell surface proteome of CIK cells using a novel methodology that can be rapidly applied to other cell types. Our study also demonstrates that without genetic modification CIK cells can be rapidly armed with monoclonal antibodies, which endows them with high specificity to kill tumor targets. [ABSTRACT FROM AUTHOR]

Objectives: Fluoropyrimidine‐based chemotherapy regimens are the current first‐line treatment for metastatic colorectal cancer (mCRC); however, the outcome is often unsatisfactory. The present study aimed to determine the effect of combined cytokine‐induced killer (CIK) cell immunotherapy and first‐line chemotherapy in patients with mCRC. Methods: This retrospective study included 252 patients with mCRC treated with first‐line chemotherapy. Among them, 126 patients received first‐line chemotherapy only (control group), while the other 126 patients, with similar demographic and clinical characteristics, received CIK cell immunotherapy combined with first‐line chemotherapy (CIK group). Overall survival (OS) and progression‐free survival (PFS) were compared between the two groups using the Kaplan–Meier method. Results: The median OS for the CIK group was 54.7 versus 24.1 months for the controls, and the median PFS for the CIK group was 25.7 versus 14.6 months for the controls. Univariate and multivariate analyses indicated that CIK cell treatment was an independent prognostic factor for patients' OS and PFS. Subgroup analyses showed that CIK cell treatment significantly improved the OS and PFS of patients with metastatic colon cancer, but not those with metastatic rectal cancer. Additionally, the change in CD3+CD56+ subsets after the fourth treatment cycle might be an indicator of successful CIK cell treatment: Patients with increased CD3+CD56+ subsets had better survival than those with decreased CD3+CD56+ subsets. Conclusion: Cytokine‐induced killer cell immunotherapy combined with first‐line chemotherapy could significantly improve the OS and PFS of patients with mCRC, particularly for patients with metastatic colon cancer. [ABSTRACT FROM AUTHOR]

Adjuvant chemotherapy after surgery is the standard treatment modality for stage III and part of stage II or stage IV colorectal cancer (CRC) patients. However, the 5-year overall survival (OS) rate remains unsatisfactory. Thus, developing combination therapies is essential to improve the prognosis of patients with CRC. The present study aimed to determine the effect of a sequential combination of cytokine-induced killer cell (CIK) infusion and chemotherapy for patients with CRC. 122 patients with CRC treated with postoperative adjuvant chemotherapy were retrospectively included in this study. Among them, 62 patients received adjuvant chemotherapy only (control group), while the other 60 patients, with similar demographic and clinical characteristics, received adjuvant chemotherapy and sequential CIK cell immunotherapy (CIK group). Survival analysis showed significantly improved disease free survival (DFS) and OS rates in the CIK group compared with the control group (log-rank test, P =.0024; P =.008, respectively). Univariate and multivariate analyses indicated that sequential CIK cell treatment was an independent prognostic factor for patients' DFS and OS. Subgroup analyses showed that sequential CIK cell treatment significantly improved the DFS and OS of patients with high-risk T4 stage and insufficient chemotherapy duration. In conclusion, these data indicate that sequential adjuvant CIK cell treatment combined with chemotherapy is an effective therapeutic strategy to prevent disease recurrence and prolong survival of patients with CRC, particularly for patients with high-risk T4 stage and insufficient chemotherapy duration. [ABSTRACT FROM AUTHOR]

Neuroblastoma (NB) is one of the most common extracranial, solid, pediatric malignancies. Despite improvements in conventional therapies, including surgery, chemotherapy and radiation therapy, the prognosis of stage IV NB remains poor, indicating that novel treatment strategies are required. Immunotherapies, such as anti-GD2 monoclonal antibodies, used alone or in combination with cytokines, and peripheral blood mononuclear cells or cord blood mononuclear cells (CBMNCs), have been indicated to cause NB cell death and to prolong patient survival in high-risk NB; however, they remain limited by severe cytotoxicity and side effects. In the present study, it was determined that anti-GD2 monoclonal antibody alone or CBMNC-isolated cytokine-induced killer (CIK)/natural killer (NK) cells alone significantly induced cell death of NB SK-N-SH cells, and the combination of anti-GD2 antibody and CIK/NK cells could significantly increase the cell death rate compared with either treatment alone. In addition, based on a method referred to our previous study, it was identified that a two-cytokine culture system, using interleukin IL-2 and IL-7, effectively stimulated the proliferation of CIK/NK cells. These results serve to suggest a novel treatment strategy for relapsed/refractory NB with high efficiency and few side effects. [ABSTRACT FROM AUTHOR]

• DC-CIK immunotherapy clinical trial meta-analysis for PC treatment was conducted. • Compared with traditional treatment, DC-CIK immunotherapy improved the clinical indices. • It also reduced mortality and negative immunoregulatory index and showed mild adverse reactions. Although promising results have recently been reported using dendritic cells (DCs) and cytokine-induced killer cells (CIKs) to treat pancreatic cancer (PC), its clinical effect and safety are associated with some controversy, and lack sufficient evidence. Here, we conducted a meta-analysis of 21 clinical trials to better evaluate the efficacy of DC-CIK immunotherapy in clinical practice to treat PC. PubMed, Cochrane Library, China National Knowledge Infrastructure (CNKI) and Wanfang Data Knowledge Service Platform (WANFANG Data) were searched to identify clinical trials that used DC-CIK immunotherapy for PC. Meta-analysis was performed using RevMan 5.3 and Stata 12.0. A total of 21 clinical trials involving 1549 patients were included. Compared with traditional treatment, DC-CIK immunotherapy improved and increased the clinical indices such as complete remission, partial remission, overall response rate, disease control rate, overall survival (0.5-y OS, 1-y OS, 1.5-y OS, 2-y OS and 3-y OS), interferon γ and CD3+, CD4+, CD4+/CD8+ and CD3+CD56+ lymphocyte. Additionally, DC-CIK immunotherapy reduced stable disease, progression disease, mortality, CD8+, CD4+CD25+CD127 low lymphocyte and interleukin-4. Furthermore, it showed a low incidence of adverse reactions (22%). In contrast to traditional therapy, DC-CIK immunotherapy not only shows improved short-term effect, long-term effect and immunologic function, but also reduces mortality and negative immunoregulatory index, and shows mild adverse reactions. This is the first study to evaluate the clinical effect and safety of DC-CIK immunotherapy for PC, and it indicated that DC-CIK immunotherapy may be suitable for patients with advanced PC or intolerance to radiotherapy and chemotherapy. [ABSTRACT FROM AUTHOR]

We describe a method of rendering polyclonal cytokine-induced killer cells (CIK) specific against cytomegalovirus (CMV), focusing on GMP compliance. Peripheral blood mononuclear cells (PBMNC) are stimulated with pooled CMV peptides pp65 and IE-1 for 16–24 h and the reactive T cell subset which up-regulate CD137 is further co-stimulated with anti-CD137, followed by expansion in G-Rex flasks under standard CIK culture condition. This method generates a large number CMV-specific CIK with superior potency compared to published method currently in clinical trials. The cytotoxicity as measured by chromium release assay correlates with the upregulation of CD107a upon peptide re-challenge as measured by flow cytometry. CMV-CIK at maturity consist of mainly late effector memory CD8 T cells and have a skewed TCR repertoire with preferential expansion of a few families. Such CMV-CIK retain their function after freezing and thawing. CMV-CIK thus generated is ready for clinical trial against drug-resistant CMV disease. • Pooled overlapping peptides are able to stimulate antigen specific T cells. • 4–1BB co-stimulation further activate and expand these activated T cells. • Cytokine-induced killer cells with CMV specificity (CMV-CIK) can be thus generated. • CMV-CIK are majority CD8 T cells and are oligoclonal expansion of starting cells. • CMV-CIK are more potent than CMV-specific T cells generated by other cytokines. [ABSTRACT FROM AUTHOR]

• We report a phase II study of cytokine-induced killer (CIK) cell therapy after total lymphoid irradiation and antithymocyte globulin conditioning for myeloid neoplasms. • Donor-derived CIK cells were produced from both related and unrelated donors. • A one-time CIK cell infusion as early post-transplant consolidation was safe. • Early donor chimerism and relapse/survival rates were similar to historical rates. Non-myeloablative conditioning, such as with total lymphoid irradiation and antithymocyte globulin (TLI-ATG), has allowed allogeneic hematopoietic cell transplantation (allo-HCT) with curative potential for older patients and those with comorbid medical conditions with myeloid neoplasms. However, early achievement of full donor chimerism (FDC) and relapse remain challenging. Cytokine-induced killer (CIK) cells have been shown to have antitumor cytotoxicity. Infusion of donor-derived CIK cells has been studied for hematologic malignancies relapsed after allo-HCT but has not been evaluated as post-transplant consolidation. In this phase II study, we prospectively studied whether a one-time infusion of 1 × 108/kg CD3+ donor-derived CIK cells administered between day +21 and day +35 after TLI-ATG conditioning could improve achievement of FDC by day +90 and 2-year clinical outcomes in patients with myeloid neoplasms. CIK cells, containing predominantly CD3+CD8+NKG2D+ cells along with significantly expanded CD3+CD56+ cells, were infused in 31 of 44 patients. Study outcomes were compared to outcomes of a retrospective historical cohort of 100 patients. We found that this one-time CIK infusion did not increase the rate of FDC by day +90. On an intention-to-treat analysis, 2-year non-relapse mortality (6.8%; 95% confidence interval [CI], 0-14.5%), event-free survival (27.3%; 95% CI, 16.8-44.2%), and overall survival (50.6%; 95% CI, 37.5-68.2%) were similar to the values seen in the historical cohort. The cumulative incidence of grade II-IV acute graft-versus-host disease at 1-year was 25.1% (95% CI, 12-38.2%). On univariate analysis, the presence of monosomal or complex karyotype was adversely associated with relapse-free survival and overall survival. Given the favorable safety profile of CIK cell infusion, strategies such as repeat dosing or genetic modification merit exploration. This trial was registered at ClinicalTrials.gov (NCT01392989). Image, graphical abstract [ABSTRACT FROM AUTHOR]

Cancer is a severe lethal disease. Currently, immunotherapy has become an effective alternative therapeutic approach for cancers. Cytokine-induced killer (CIK) cells have a higher proliferation rate, increased efficacy with few side-effects, and non-MHC-restricted killing after co-culturing with dendritic cells (DCs). Therefore, it has been widely studied and applied in the treatment of cancers. In our study, we explored the antitumor effects of CIK cells co-culturing with DCs pulsed with non-cell derived targeting peptides, which could specifically bind to certain tumor cells. Our results indicated that targeting peptide-loaded DCs could enhance the differentiation and cytotoxicity of CIK cells. Moreover, CIK cells, which were treated with specific targeting peptide-loaded DCs, could effectively and specifically kill tumor cells in vitro and in vivo, as long as tumor cells were pre-coated with the specific binding peptides. In conclusion, targeting peptides could guide DC-CIK to effectively and specifically kill tumor cells which were pre-coated with these targeting peptides and non-cell derived targeting peptide-loaded-DC-CIK may work as a novel means for cancer therapy. [ABSTRACT FROM AUTHOR]

Since the publication of a novel protocol in 1991, cytokine-induced killer (CIK) cells have shown promising results in the treatment against neoplastic diseases. Despite ongoing preclinical and clinical studies, CIK cell treatment in the context of human monoclonal antibodies targeting tumor-necrosis factor receptors remains overlooked. The present study investigated whether a combination of CIK cells with human monoclonal antibody anti-CD40 and anti-Glucocorticoid-induced TNF-related protein (GITR) would lead to further cytotoxicity against tumor cells expressing CD40 and GITR ligand (L). Therefore, in vitro experiments with human lymphoma cell lines SU-DHL-4 and Daudi (both CD40 positive) and human breast adenocarcinoma MCF-7 (GITRL positive) were performed and the secretion of interferon (IFN)-γ was measured. Three interesting results emerged: i) a combination of CIK cells and anti-CD40 mAb is more effective than CIK cell treatment alone; ii) the use of anti-GITR mAb and CIK cells significantly enhanced the cytotoxicity of CIK cells against MCF-7 compared with single CIK cell treatment and iii) the combination of both antibodies and CIK cells abrogates the anti tumoral effect of CIK cells on all three cell lines. By performing an ELISA for IFN-γ measurement, a lower secretion was observed when anti-CD40 or anti-GITR mAb was added. This outcome indicates that further studies in vitro and in vivo may aid in understanding the synergistic molecular mechanisms of CIK cells, and anti-CD40 and anti-GITR mAb. [ABSTRACT FROM AUTHOR]

Objective The efficient and stable cytokine induced killer cell (CIK) culture medium and the effective target ratio of killing hepatocellular carcinoma cells were selected. Methods The peripheral blood mononuclear cells (PB-MCs) from 5 healthy people were cultured in vitro by using RPMI1640 and GT-T551 , and IL-2 (0, 200, and 500 IU/mL) was added to the two media, respectively. The morphology of the cells was observed by the optical microscope, and Trypan blue staining was used to count and draw the growth curve, and we calculated the cell amplification multiple. CIK was cocultured with liver cancer 7721 cell line, and the effector-target ratio was adjusted to 10:1, 20:1, 40:1, and 80:1. After 72 h, we did the CCK8 test and measured OD450 by enzyme labeling instrument to calculate the killing rate. Results Compared with 1640 medium, the cell amplification multiples in the GT-T551 medium group at various concentrations of IL-2 increased (all P<0.05). Compared with the effector-target ratio of 80:1 , the killing rate of CIK was low when the effector-target ratio was 10:1 , 20:1 and 40:1 ( all P <0.05 ). Conclusions The culture system of GT-T551 medium with 500 IU/mL IL-2 is more conducive to the proliferation of CIK cells. The cytotoxic effect reaches the peak when the effector-target ratio of CIK cells and 7721 cells is 80:1. [ABSTRACT FROM AUTHOR]

Avoiding immune surveillance and inducing a tumor-promoting inflammatory milieu found entry into the new generation of the hallmarks of cancer. Cancer cells hijack immune mechanisms which physiologically protect the body from the development of autoimmune diseases and excessive tissue damage during inflammation by downregulating immune responses. This is frequently achieved by upregulation of immune checkpoints. Therefore, the blocking of immune checkpoint ligand–receptor interactions can reinstall the immune systems capability to fight cancer cells as shown for CTLA4 and PD-1 inhibitors in a clinical setting. Newly described checkpoint antigens are currently under investigation in cancer immunotherapy. Preclinical data emphasize the immune checkpoint axis TIGIT–PVR/PVRL2 as very promising target. This axis includes additional receptors such as DNAM-1, CD96, and CD112R. In this review, we discuss the recent findings of the relevance of this complex receptor ligand system in hematologic and solid cancers. Emphasis is also laid on the discussion of potential combinations with other immunotherapeutic approaches. [ABSTRACT FROM AUTHOR]

Once aberrantly activated, the Wnt/β-catenin pathway may result in uncontrolled proliferation and eventually cancer. Efforts to counter and inhibit this pathway are mainly directed against β-catenin, as it serves a role on the cytoplasm and the nucleus. In addition, specially-generated lymphocytes are recruited for the purpose of treating liver cancer. Peripheral blood mononuclear lymphocytes are expanded by the timely addition of interferon γ, interleukin (IL)-1β, IL-2 and anti-cluster of differentiation 3 antibody. The resulting cells are called cytokine-induced killer (CIK) cells. The present study utilised these cells and combine them with drugs inhibiting the Wnt pathway in order to examine whether this resulted in an improvement in the killing ability of CIK cells against liver cancer cells. Drugs including ethacrynic acid (EA) and ciclopirox olamine (CPX) were determined to be suitable candidates, as determined by previous studies. Drugs were administered on their own and combined with CIK cells and then a cell viability assay was performed. These results suggest that EA-treated cells demonstrated apoptosis and were significantly affected compared with untreated cells. Unlike EA, CPX killed normal and cancerous cells even at low concentrations. Subsequent to combining EA with CIK cells, the potency of killing was increased and a greater number of cells died, which proves a synergistic action. In summary, EA may be used as an anti-hepatocellular carcinoma drug, while CPX possesses a high toxicity to cancerous as well as to normal cells. It was proposed that EA should be integrated into present therapeutic methods for cancer. [ABSTRACT FROM AUTHOR]

Background: Application of dendritic cells (DC) for cancer immunotherapy involves tumor-associated immunogenic antigens for effective therapeutic strategies. The present study investigated whether DC co-cultured with autologous cytokine-induced killer cells (CIK) could induce a more specific immune response against liver cancer stem cells (LCSC) generated from human hepatocellular carcinoma (HCC) cells in vitro and in vivo.Methods: Human DC and CIK were generated from peripheral blood mononuclear cells (PBMCs) taken from consenting liver cancer patients. Flow cytometry was used to determine the phenotypes of DC and CIK, and cell proliferation. The tumor growth and anti-tumor activity of these cells were further evaluated using a nude mouse tumor model.Results: We demonstrated that DC and CIK significantly enhanced the apoptosis ratio, depending on DC-CIK cell numbers, by increasing caspase-3 protein expression and reducing proliferating cell nuclear antigen (PCNA) protein expression against LCSC. The in vivo data indicated that DC-CIK exhibited significant LCSC cell-induced tumor growth inhibition in nude mice, which was most significant with LCSC antigen loaded DCs.Conclusions: The results showed, that DC-CIK cells could inhibit HCC and LCSC growths in vitro and in vivo and the most successful DC triggering of cell cytotoxic activity could be achieved by their LCSC antigen loading. [ABSTRACT FROM AUTHOR]

In the present study, the function and mechanism of cytokine-induced killer cells (CIK) combined with dendritic cells (DC-CIK) were examined in Lewis lung cancer (LLC) cells. Co-culture of CIK dendritic cells (DC) in vitro was used to investigate their proliferation and the antitumor effects on LLC cells. DC and CIK cells were collected from healthy human peripheral blood mononuclear cells and co-cultured as an experimental group, while LLC cells were cultured alone as a control group. Cell morphology was observed by an inverted microscope and an MTT assay was utilized to detect the proliferation of LLC cells. Expression of 14-3-3ζ and p-Bad were measured by western blot analysis. Compared with the control group, treatment of LLC cells with DC-CIK resulted in decreased cell adherence, reduced cell proliferation and abnormal morphological changes. Additionally, DC-CIK treatment of LLC cells resulted in the decreased expression of 14-3-3ζ and p-Bad protein in LLC cells, which may provide important information pertaining to the possible mechanism of DC-CIK-induced antitumor activity against LLC cells. The present study provides a theoretical and experimental basis for the clinical treatment of DC-CIK cell co-culture. [ABSTRACT FROM AUTHOR]

Primitive neuroectodermal tumor (PNET) rarely occurs as a primary renal neoplasm. Renal (r)PNET is a rare but aggressive neoplasm with poor prognosis; the majority of patients are diagnosed as advanced stage at presentation and face a worse prognosis than patients with localized disease. The present study describes the diagnosis and management of eight cases of rPNET at an advanced stage, who were treated at two institutions [Lingnan Hospital (branch of The Third Affiliated Hospital) and the Cancer Center of Sun Yat-sen University, Guangzhou], from December 2004 to January 2013. The clinical and pathological results of all patients were retrospectively obtained. Kaplan-Meier analysis was performed to estimate patient survival. The study cohort comprised five males and three females. Radical nephrectomy was performed in seven cases, while the remaining case only received needle biopsy of the tumor. Five cases received adjuvant chemotherapy, while three received no further treatment after surgery. Of note, one case received cytokine-induced killer (CIK) cell immunotherapy combined with surgery and chemotherapy. The overall median survival was 20 months with a 3-year survival rate of 25%. The overall survival of the four patients who received adjuvant chemotherapy following surgery was 36 months, compared with 10 months in the three patients without further treatment. The patient who received CIK cell immunotherapy survived for 20 months. Based on the observations of the present and previous studies, surgical excision and chemotherapy are recommended for treating rPNET at advanced stage. Furthermore, the present study was the first to report on CIK cell immunotherapy for a patient with rPNET, indicating that it may be a promising optional treatment. However, further studies are required to validate the benefit of CIK cells and to establish an appropriate immunotherapy protocol. [ABSTRACT FROM AUTHOR]

Background Prolonged immunosuppression or delayed T-cell recovery may favor Epstein-Barr virus (EBV) infection or reactivation after allogeneic hematopoietic stem cell transplantation (HSCT), which can lead to post-transplant lymphoproliferative disease (PTLD) and high-grade malignant B-cell lymphoma. Cytokine-induced killer (CIK) cells with dual specific anti-tumor and virus-specific cellular immunity may be applied in this context. Methods CIK cells with EBV-specificity were generated from peripheral blood mononuclear cells (PBMCs), expanded in the presence of interferon-γ, anti-CD3, interleukin (IL)-2 and IL-15 and were pulsed twice with EBV consensus peptide pool. CIK cells with EBV-specificity and conventional CIK cells were phenotypically and functionally analyzed. Additionally, CIK cells with EBV-specificity were applied to a patient with EBV-related PTLD rapidly progressing to highly aggressive B-cell lymphoma on a compassionate use basis after approval and agreement by the regulatory authorities. Results Pre-clinical analysis showed that generation of CIK cells with EBV-specificity was feasible. In vitro cytotoxicity analyses showed increased lysis of EBV-positive target cells, enhanced proliferative capacity and increased secretion of cytolytic and proinflammatory cytokines in the presence of EBV peptide-displaying target cells. In addition, 1 week after infusion of CIK cells with EBV-specificity, the patient's highly aggressive B-cell lymphoma persistently disappeared. CIK cells with EBV-specificity remained detectable for up to 32 days after infusion and infusion did not result in acute toxicity. Discussion The transfer of both anti-cancer potential and T-cell memory against EBV infection provided by EBV peptide-induced CIK cells might be considered a therapy for EBV-related PTLD. [ABSTRACT FROM AUTHOR]

Infusion of patient-derived CD19-specific chimeric antigen receptor (CAR) T cells engineered by viral vectors achieved complete remission and durable response in relapsed and refractory (r/r) B-lineage neoplasms. Here, we expand on those findings by providing a preclinical evaluation of allogeneic non-viral cytokine-induced killer (CIK) cells transfected with the Sleeping Beauty (SB) transposon CD19CAR (CARCIK-CD19). Specifically, thanks to a large-scale 18-day manufacturing process, it was possible to achieve stable CD19CAR expression (62.425 ± 6.399%) and efficient T-cell expansion (23.36 ± 3.00-fold). Frozen/thawed CARCIK-CD19 remained fully functional both in vitro and in an established patient-derived xenograft (PDX) of MLL–ENL rearranged acute lymphoblastic leukemia (ALL). CARCIK-CD19 showed a dose-dependent antitumor response and prolonged persistence in a PDX, bearing the feature of a Philadelphia-like ALL with PAX5/AUTS2 translocation, and in a survival model of lymphoma, achieving complete eradication of disseminated tumors. Finally, the infusion of CARCIK-CD19 proved to be safe and well tolerated in a biodistribution and toxicity model. The infused cells persisted in the hematopoietic and post-injection perfused organs until the end of the study and consisted of CD8+, CD56+, and CAR+ T cells. Overall, these findings provide important implications for non-viral technology and the proof-of-concept that donor-derived CARCIK-CD19 are indeed effective against relapsed ALL, a possibility that will be tested in Phase I/II clinical trials after allogeneic hematopoietic stem-cell transplantation. [ABSTRACT FROM AUTHOR]

Lung cancer is the most common type of cancer with the highest cancer-associated mortality rates worldwide, as well as in Vietnam. Numerous studies have demonstrated that higher numbers and higher rate of activity of infiltrating natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) in the tumor are closely correlated with positive prognosis, tumor size decrease and longer survival of lung cancer patients. In the present study, the effectiveness of BINKIT® kit in the ex vivo expansion of NK cells and CTLs in the peripheral blood of 7 patients aged between 30 and 84 years with metastatic lung cancer was evaluated. After 21 days of culture, the average number of CTLs (CD3+CD8+) increased by 742.3-fold in the CTL culture, accounting for 72.2% of the cultured cell population, and the mean cell viability was 95.7%. In the NK cell culture, the average number of NK cells (CD3-CD56+) increased by 637.5-fold, accounting for 84.3% of the cultured cell population, with an average viability of 94.7%. The percentage of active NK cells (CD3-CD56+ bright) was 82.1%, which increased by 408.9-fold. Notably, a close correlation was identified between the numbers of cytokine-induced killer (CD3+CD56+) and NK (CD3-CD56+) cells in the NK cell culture (P<0.05). In the two culture conditions (namely NK cell and CTL cultures), no clear correlation was identified between the rate of initial immune cells in the peripheral blood and the corresponding number following ex vivo expansion (P>0.05). These results revealed that the method of expansion and activation of NK cells and CTLs from peripheral blood was successfully applied using BINKIT, and reached the requirements for clinical applications in cancer treatment in Vietnam. [ABSTRACT FROM AUTHOR]

Toll-like receptor (TLR) 7/8 agonists have been applied in combination with chemo-, radio- or immunotherapy for lymphoma, and used as topical drugs for the treatment of viral skin lesions and skin tumors. In the present study, the role of an adenine analog, 9-(4-carboxyphenyl)-8-hydroxy-2-(2-me thoxyethoxy)-adenine [termed Gao Dong (GD)], a novel TLR7 agonist, in the activation of cytokine-induced killer/natural killer (CIK/NK) cells was determined. The results of the present study indicated that GD was able to activate CIK/NK cells. The proportion of GD-induced CD3+CD56+ CIK and CD3-CD56+ NK cells was ~4% higher respectively compared with the control. Notably, combination therapy with CIK/NK cells stimulated by GD, markedly suppressed the proliferation of the chronic myelogenous leukemia K562 cell line. Following GD treatment, the cytotoxicity improved by ~25 and 21% when the effector/target ratio was 20:1 and 10:1, respectively. The results of the present study suggested a novel protocol for CIK/NK cell proliferation and revealed that GD may serve as a potent innate and adaptive immunomodulator in immunocyte culture. [ABSTRACT FROM AUTHOR]

Immunotherapy has changed treatment practices for many hematologic malignancies. Even in the current era of targeted therapy, chemotherapy remains the backbone of treatment for many hematologic malignancies, especially in acute leukemias, where relapse remains the major cause of mortality. Application of novel immunotherapies in hematology attempts to harness the killing power of the immune system against leukemia and lymphoma. Cellular immunotherapy is evolving rapidly for high-risk hematologic disorders. Recent advances include chimeric antigen-receptor T cells, mesenchymal stromal/stem cells, dendritic cell tumor vaccines, cytokine-induced killer cells, and virus-specific T cells. The advantages of nontransplantation cellular immunotherapy include suitability for patients for whom transplantation has failed or is contraindicated, and a potentially less-toxic treatment alternative to transplantation for relapsed/refractory patients. This review examines those emerging cellular immunotherapies that are changing treatment paradigms for patients with hematologic malignancies. [ABSTRACT FROM AUTHOR]

Cytokine‑induced killer cells (CIKs) adoptive immunotherapy for efficient antitumor ability is used clinically, but details regarding the proteins associated with CIK activity remain unclear. In the current study, the cytotoxicity of CIKs on hepatoma was identified to be significantly downregulated by 1.61‑fold following gentamincin treatment. Further research revealed that a differentially expressed protein (P43) was significantly downregulated by 1.22‑fold using one‑dimensional gel electrophoresis analysis. Of these, the P43 was identified as human haptoglobin using liquid chromatography‑mass spectrometry. Western blotting demonstrated that the haptoglobin specifically reacted with rabbit anti‑human‑haptoglobin. Furthermore, western blotting results verified that the haptoglobin was significantly downregulated by 1.17‑fold compared with the control group. In addition, the expression of haptoglobin mRNA was significantly downregulated by 1.73‑fold following gentamincin treatment. Taken together, the results of the present study demonstrated that the expression of haptoglobin protein was associated with the activity of CIKs, and the results will be beneficial to the further investigation of CIK activity‑enhancement mechanism. [ABSTRACT FROM AUTHOR]

Background: Surgical resection combined with adjuvant chemotherapy is considered as the gold-standard treatment for advanced colorectal cancer patients. These patients have a poor 5-year survival rate of 5% or less. Furthermore, a large dose of chemotherapy can produce adverse side effects and severe toxicity. Therefore, this retrospective study aimed to evaluate the efficacy of dendritic cell-cytokine-induced killer (DC-CIK) cell infusion as an adjuvant therapy in patients with advanced colorectal cancer combined with first-line treatment. Methods: A total of 142 patients with stage III/IV colorectal carcinoma who had been treated with first-line therapy were included in this study. Among these patients, 71 patients received first-line treatment only (non-DC-CIK group), while the other 71 patients who had similar demographic and clinical characteristics received a DC-CIK cell infusion combined with first-line treatment (DC-CIK group). These patients were followed up until August 2014. Data were analyzed by Kaplan-Meier and Cox regression. Results: Our results showed that the 5-year overall survival (OS) rate for the DC-CIK group versus the non-DC-CIK group was 41.3 versus 19.4% (p = 0.001) and the 5-year progression-free survival (PFS) rate for the DC-CIK group versus the non- DC-CIK group was 57.4 versus 33.6% (p = 0.022). Conclusions: Our results showed that patients with advanced colorectal cancer might benefit from DC-CIK immunotherapy combined with first-line therapy by significantly prolonging 5-year OS and PFS. [ABSTRACT FROM AUTHOR]

Little progress has been made in the treatment of advanced cancer. Dendritic cells (DCs) plus cytokine-induced killer (CIK) cells have exhibited antitumor effects. Thus, the aim of the present study was to evaluate the clinical efficacy of DC-CIK cell treatment in patients with advanced cancer. A paired study including 57 patients treated with DC-CIK cells (DC-CIK group) and 33 patients treated with best supportive care alone (BSC group) was performed. The patients in the DC-CIK group were matched to those in the control group in terms of sex, age, tumor type and clinical stage. T-cell subsets were detected and overall survival (OS) was compared between the two groups. The results demonstrated that CD4+/CD25+ and CD8+/CD28- subsets significantly decreased following DC-CIK immunotherapy (P<0.05). The CD3+, CD3+/CD8+, CD8+/CD28+ and CD3+/CD56+ T-cell subsets were significantly increased in the DC-CIK group compared with the BSC group, while the CD8+/CD28- subset was significantly decreased. Univariate analysis demonstrated that a lower CD8+/CD28- and a higher CD8+/CD28+ ratio were associated with prolonged OS in advanced cancer patients. In addition, DC-CIK treatment administration, age (>60 vs. <60 years), clinical stage and the frequency of CIK treatment significantly affected the OS of patients in the DC-CIK group. A CD8+/CD28- ratio of <21.12 was found to decrease the hazard ratio (HR) of OS to 0.50 [95% confidence interval (CI): 0.29-0.87] and a CD8+/CD28+ ratio >9.04 was found to decrease the HR of OS to 0.45 (95% CI: 0.21-0.98). No serious side effects were observed in the DC-CIK group. Taken together, these data indicate that DC-CIK infusions were able to change the ratios of the T-cell subsets, which increased the T helper cell and cytotoxic T lymphocyte subsets, while it decreased regulatory T lymphocyte subsets. Thus, this method of immunotherapy was found to improve the imbalance in the immune system and prolong the OS in patients with advanced cancer. [ABSTRACT FROM AUTHOR]

Pseudomonas aeruginosa -mannose sensitive hemagglutinin (PA-MSHA) injection serves as immunological adjuvant in clinical treatment of cancer patients. In present study, we investigated whether PA-MSHA injection enhanced the anti-tumor efficacy of CIK cells. Twenty patients with malignancies were enrolled in this retrospective clinical trial. They were divided into two groups: 10 patients received PA-MSHA treated CIK cells transfusion combined with chemotherapy, and other patients accepted CIK cells and chemotherapy. The efficacy of PA-MSHA treated CIK cells was also observed in vitro and in vivo . With PA-MSHA treatment CIK cells exhibited enhanced proliferation but decreased expression of inhibitory cell surface markers such as Tim-3 and PD-1. Particularly in CIK cells, PA-MSHA promoted the extrusion of pro-inflammatory cytokines like IFN-γ. Of 10 patients with PA-MSHA treated CIK cells and chemotherapy, two patients reached partial remissions, 7 patients had stable disease and the other one had progressive disease. Some of these patients experienced fever after cell infusion. 8 patients with CIK cells showed stable disease and 2 patients had progressive disease. Moreover, the side effects were small in patients with CIK treatment. Our data indicated that PA-MSHA improves the functions of CIK cells and shed new light on developing more potent therapeutic approaches for malignancies. [ABSTRACT FROM AUTHOR]

Objective Cytokine-induced killer (CIK) cells have important therapeutic effects in adoptive cell transfer (ACT) for the treatment of various malignancies. In this study, we focused on in vitro expansion of CIK cells and their clinical efficacy in combination with chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). Methods A total of 64 patients with NSCLC (enrolled from 2011 to 2012), including 32 patients who received chemotherapy alone or with sequential radiotherapy (conventional treatment, control group) and 32 patients who received conventional treatment and sequential CIK infusion (study group), were retrospectively analyzed. The time to progression (TTP), overall survival (OS) and adverse effects were analyzed and the phenotype of lymphocytes in CIK population was also determined by flow cytometry. Results After in vitro expansion, the average percentage of CIK cells was 26.35%. During the 54-month follow up, the median OS and TTP were significantly longer in the study group than in the control group ( P = 0.0189 and P = 0.0129, respectively). The median OS of the ACT ≥ 4 cycles subgroup was significantly longer than that of the ACT < 4 cycles subgroup ( P = 0.0316). The percentage of CIK cells in patients who received ≥ 4 cycles of ACT was higher than that in patients treated with < 4 cycles of ACT ( P = 0.0376). Notably, CIK cells were difficult to expand in vitro in some patients after the first ACT cycle but became much easier as the treatment cycles increased monthly. Longer treatment interval negatively impacted the expansion of CIK cells. Conclusions Systematic immune levels can be increasingly boosted by reinfusion of ACT. Conventional treatment plus CIK cells is an effective therapeutic strategy to prevent progression and prolong survival of patients with advanced NSCLC. [ABSTRACT FROM AUTHOR]

Endometrial cancer is the most prevalent gynecological malignancy in the USA, and its treatment involves surgery, chemotherapy, and radiotherapy. Cytokine-induced killer (CIK) cell-based treatments have shown antitumor activity against several solid tumors. However, to the best of our knowledge, there are no reports yet of CIK immunotherapy in the treatment of endometrial cancer, and consequently, little is known about its efficacy and safety. Here, we report a case of an endometrial cancer patient receiving a combination treatment with CIK cells immunotherapy and chemotherapy. Assessment for clinical features was carried out after every two cycles of CIK immunotherapy and chemotherapy. No severe toxicity was observed after infusion of CIK cells. After 4 cycles of treatment, the patient achieved complete response and showed elevated Karnofsky Performance Status scores with an overall survival time of 13.6 months. The combination therapy improved the quality of life and prolonged patient survival time, which suggested that CIK cell therapy might be a potentially beneficial option for endometrial cancer. [ABSTRACT FROM AUTHOR]

Cytokine-Induced killer (CIK) cells are raising growing interest in cellular antitumor therapy, as they can be easily expanded with a straightforward and inexpensive protocol, and are safe requiring only GMP-grade cytokines to obtain very high amounts of cytotoxic cells. CIK cells do not need antigen-specific stimuli to be activated and proliferate, as they recognize and destroy tumor cells in an HLA-independent fashion through the engagement of NKG2D. In several preclinical studies and clinical trials, CIK cells showed a reduced alloreactivity compared to conventional T cells, even when challenged across HLA-barriers; only in a few patients, a mild GVHD occurred after treatment with allogeneic CIK cells. Additionally, their antitumor activity can be redirected and further improved with chimeric antigen receptors, clinical-grade monoclonal antibodies or immune checkpoint inhibitors. The evidence obtained from a growing body of literature support CIK cells as a very promising cell population for adoptive immunotherapy. In this review, all these aspects will be addressed with a particular emphasis on the role of the cytokines involved in CIK cell generation, expansion and functionalization. [ABSTRACT FROM AUTHOR]

Previous studies have reported that regulatory T cells (Tregs), which are physiologically engaged in the maintenance of immunological self-tolerance, have a critical role in the regulation of the antitumor immune response. Targeting Tregs has the potential to augment cancer vaccine approaches. The current study therefore aimed to evaluate the role of cytokine-induced killer (CIK) cell infusion in modulating Tregs in patients with non-small cell lung cancer (NSCLC). A total of 15 patients with advanced NSCLC were treated by an infusion of CIK cells derived from autologous peripheral blood mononuclear cells (PBMCs). By using flow cytometry and liquid chip analysis, subsets of T cells and natural killer (NK) cells in peripheral blood, and plasma cytokine profiles in the treated patients, were analyzed at 2 and 4 weeks after CIK cell infusion. Cytotoxicity of PBMCs (n=15) and NK cells (n=6) isolated from NSCLC patients was evaluated before and after CIK cell therapy. Progression-free survival (PFS) and overall survival (OS) were also assessed. Analysis of the immune cell populations before and after treatment showed a significant increase in NK cells (P<0.05) concomitant with a significant decrease in Tregs (P<0.01) at 2 weeks post-infusion of CIK cells compared with the baseline. NK group 2D receptor (NKG2D) expression on NK cells was also significantly increased at 2 weeks post-infusion compared with the baseline (P<0.05). There was a positive correlation between NKG2D expression and the infusion number of CIK cells (P<0.05). When evaluated at 2 weeks after CIK cell therapy, the cytotoxicity of PBMCs and isolated NK cells was significantly increased compared with the baseline (P<0.01 and P<0.05). Correspondingly, plasma cytokine profiles showed significant enhancement of the following antitumor cytokines: Interferon (IFN)-γ (P<0.05), IFN-γ-inducible protein 10 (P<0.01), tumor necrosis factor-a (P<0.001), granulocyte-macrophage colony-stimulating factor (P<0.01), monocyte chemotactic protein-3 (P<0.01) and interleukin-21 (P<0.05) at 2 weeks post-infusion, compared with the baseline. At the same time, the expression of transforming growth factor-β1, which is primarily produced by Tregs, was significantly decreased compared with the baseline (P<0.05). Median PFS and OS in the CIK cell treatment group were significantly increased compared with the control group (PFS, 9.98 vs. 5.44 months, P=0.038; OS, 24.17 vs. 20.19 months, P=0.048). No severe side-effects were observed during the treatment period. In conclusion, CIK cell therapy was able to suppress Tregs and enhance the antitumor immunity of NK cells in advanced NSCLC patients. Therefore, CIK cell treatment may improve PFS and OS in patients with advanced NSCLC. CIK cell infusion may have therapeutic value for patients with advanced NSCLC, as a treatment that can be combined with chemotherapy and radiotherapy. [ABSTRACT FROM AUTHOR]

Purpose: To systematically investigate the efficacy and safety of the combination of FOLFOX (oxaliplatin, 5-fluorouracil, and leucovorin) regimen and cocultured dendritic cells and cytokineinduced killer cells (DC-CIK) immunotherapy for the treatment of colorectal cancer (CRC). Methods: Publications 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. Results: Ten 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-ü (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). Conclusion: The combination of FOLFOX regimen and DC-CIK immunotherapy was safe and effective for CRC patients. [ABSTRACT FROM AUTHOR]

Background aims. Cervical cancer constitutes a major problem in women's health worldwide, but the efficacy of the standard therapy is unsatisfactory. Cytokine-induced killer (CIK) cells exhibit antitumor activity against a variety of malignancies in preclinical models and have proven safe and effective in clinical trials. However, current CIK therapy has limitations and needs to be improved to meet the clinical requirements. The aim of this study was to investigate whether suppressing the expression of cytokine signaling 1 (SOCS1) in dendritic cells (DCs) can shorten in vitro CIK culture time and improve its antitumor efficacy. Methods. DCs were pre-cultured for 3 days before infected with adenovirus-mediated-SOCSl short hairpin RNA (Ad-sh-SOCSl) and pulsed with CTL epitope peptides E7.The DCs infected by Ad-sh-SOCSl (gmDCs) and CIKs were then co-cultured for 5 or 9 days, and CIK proliferation and antitumor activity were evaluated both in vitro and in vivo. Results. Our data show that gmDCs significantly stimulated the expansion of co-cultured CIKs and increased the secretion of interferon-y and interleukin-12. Moreover, gmDCs-activated CIKs showed higher cytotoxic activity againstTC-1 cells expressing HPV16E6 and E7. Our in vivo study showed that the mice infused with gmDCs-activated CIKs on day 10 had an increased survival rate and prolonged survival time compared with the controls. Conclusions. Taken together, these results indicate that DCs modified by adenovirus-mediated SOCS1 silencing can promote CIKs expansion and enhance the efficacy of antitumor immunotherapy both in vitro and in vivo, which represents an effective therapeutic approach for cervical cancer and other tumors. [ABSTRACT FROM AUTHOR]