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Abstract Despite the favorable effects of immunotherapies in multiple types of cancers, its complete success in CNS malignancies remains challenging. Recently, a successful clinical trial of cytokine-induced killer (CIK) cell immunotherapy in patients with glioblastoma (GBM) has opened a new avenue for adoptive cellular immunotherapies in CNS malignancies. Prompt from these findings, herein, we investigated whether dendritic cells (DC) in combination with cytokine-induced killer cells (DC-CIK) could also provide an alternative and more effective way to improve the efficacy of GBM treatment. The analysis showed that DC-CIK cells exerted a significant cytotoxic effect on the glioblastoma cell lines, especially with the phenotype of stem-like cells (GSCs). In addition, the increased specific lysis of these cells subsequent to DC-CIK co-culture was confirmed with confocal fluorescence microscope. The direct interactions between tumor and effector cells were found to be highly effective in GBM organoids (GBOs). Moreover, a significant increase in apoptosis and elevated levels of IFN-γ (and not TNF-α) secretion were observed as a targeting mechanism of DC-CIK cells against GBM cell models. Overall, we provide important preliminary evidence that DC-CIK cells may have potential in the treatment of CNS malignancies, particularly glioblastoma.

Abstract Background Immunotherapy utilizing dendritic cells (DCs) and cytokine-induced killer (CIK) cells is a promising treatment approach for solid tumors. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of DC-CIK immunotherapy by assessing overall survival, progression-free survival, overall response rate, disease control rate, and adverse events in relevant randomized controlled trials. The results of this analysis will contribute to optimizing treatment strategies and improving cancer immunotherapy outcomes. Method This systematic review and meta-analysis adhered to PRISMA guidelines. A comprehensive search was conducted on multiple databases for RCTs studying the combination of DC-CIK immunotherapy for solid tumors. Inclusion criteria were RCTs comparing DC-CIK immunotherapy with control therapy and reporting OS, PFS, ORR, or DCR. Two authors independently performed study selection and data extraction, with disagreements resolved through consensus or consultation with a third reviewer. Extracted data included study characteristics, participant information, interventions, outcomes, and quality assessment. Statistical analysis was performed using Review Manager and Stata software. Heterogeneity was assessed using chi-square and I-squared statistics. Sensitivity analysis and assessment of publication bias were planned. Results A total of 1013 records were initially retrieved, and after a thorough screening process, 13 randomized controlled trials (RCTs) were included in the meta-analysis. These studies involved a total of 1443 patients, with 730 receiving DC-CIK immunotherapy and 713 in the control groups. The included studies covered various cancer types, with the majority conducted in mainland China. The meta-analysis showed that DC-CIK immunotherapy was associated with improved overall survival (OS) and progression-free survival (PFS) compared to control therapy. Furthermore, DC-CIK immunotherapy demonstrated higher overall response rate (ORR) and disease control rate (DCR) compared to non-DC-CIK therapy. Adverse events were reported in both groups, with fever being more common in the DC-CIK immunotherapy group and bone marrow suppression and gastrointestinal reactions more common in the control group. Sensitivity analyses confirmed the stability of the results, while publication bias was observed for PFS and fever. Conclusions DC-CIK immunotherapy shows promising efficacy and safety for solid tumors, improving survival rates and response rates. Further research is needed to optimize treatment regimens and identify predictive factors.

Extracellular vesicles (EVs) are nano-sized membrane particles secreted by various cell types that are involved in many important cellular processes. Recently, EVs originating from immune cells, such as dendritic cells, chimeric antigen receptor T cells, and natural killer cells, have attracted much attention because of their known direct and indirect antitumor activity. Here, we report the EVs released by cytokine-activated CD8+ T (caCD8) cells and its cytotoxicity against cancer cells. CaCD8 cells can release EVs following stimulation of CD8+ T cells with an anti-CD3 antibody and a cytokine cocktail ex vivo. The isolated vesicles have typical EV characteristics, such as an oval shape and a size distribution between 30 and 200 nm, as well as CD81 expression. Notably, caCD8-EVs displayed cytotoxicity against various cancer cells in vitro. Furthermore, mechanism analysis demonstrates that caCD8-EVs not only contain typical cytotoxic proteins (i.e. granzyme B and perforin), but also significantly enrich interferon γ (IFNγ) compared with caCD8 cells. EV-derived IFNγ participates in EV-induced apoptosis in cancer cells. Therefore, our data reveal antitumor effects of EVs secreted from caCD8 cells and the potential role of the EV-derived IFNγ. [ABSTRACT FROM AUTHOR]

Breast cancer remains a significant health challenge worldwide, with substantial efforts aimed at understanding its pathogenesis, biological characteristics, and clinical triggers. Recently, immunotherapy such as the cytokine-induced killer cells combined with other drug therapies has offered new hope for patients with advanced breast cancer. However, the specific pathogenesis of combination regimens involving cytokine-induced killer cells remains elusive. Besides, the combination of immunotherapy with cytokine-induced killer cells might represent a novel breakthrough. This review outlines the current status of cytokine-induced killer cell therapies and their combination strategies, especially the combination of chemotherapy with molecularly targeted treatments, for the management of breast cancer.

ABSTRACT 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.

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]

Abstract 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.

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]

Introduction: A multitude of findings from cell cultures and animal studies are available to support the anti-cancer properties of cannabidiol (CBD). Since CBD acts on multiple molecular targets, its clinical adaptation, especially in combination with cancer immunotherapy regimen remains a serious concern. Methods: Considering this, we extensively studied the effect of CBD on the cytokine-induced killer (CIK) cell immunotherapy approach using multiple nonsmall cell lung cancer (NSCLC) cells harboring diverse genotypes. Results: Our analysis showed that, a) The Transient Receptor Potential Cation Channel Subfamily V Member 2 (TRPV2) channel was intracellularly expressed both in NSCLC cells and CIK cells. b) A synergistic effect of CIK combined with CBD, resulted in a significant increase in tumor lysis and Interferon gamma (IFNg) production. c) CBD had a preference to elevate the CD25+CD69+ population and the CD62L_CD45RA+terminal effector memory (EMRA) population in NKTCIK cells, suggesting early-stage activation and effector memory differentiation in CD3+CD56+ CIK cells. Of interest, we observed that CBD enhanced the calcium influx, which was mediated by the TRPV2 channel and elevated phosphor-Extracellular signal-Regulated Kinase (p-ERK) expression directly in CIK cells, whereas ERK selective inhibitor FR180204 inhibited the increasing cytotoxic CIK ability induced by CBD. Further examinations revealed that CBD induced DNA double-strand breaks via upregulation of histone H2AX phosphorylation in NSCLC cells and the migration and invasion ability of NSCLC cells suppressed by CBD were rescued using the TRPV2 antagonist (Tranilast) in the absence of CIK cells. We further investigated the epigenetic effects of this synergy and found that adding CBD to CIK cells decreased the Long Interspersed Nuclear Element-1 (LINE-1) mRNA expression and the global DNA methylation level in NSCLC cells carrying KRAS mutation. We further investigated the epigenetic effects of this synergy and found that adding CBD to CIK cells decreased the Long Interspersed Nuclear Element-1 (LINE-1) mRNA expression and the global DNA methylation level in NSCLC cells carrying KRAS mutation. Conclusions: Taken together, CBD holds a great potential for treating NSCLC with CIK cell immunotherapy. In addition, we utilized NSCLC with different driver mutations to investigate the efficacy of CBD. Our findings might provide evidence for CBD-personized treatment with NSCLC patients. [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]

Impaired immunohomeostasis in diabetic wounds prolongs inflammation and cytokine dysfunction, thus, delaying or preventing wound-surface healing. Extensive clinical studies have been conducted on cytokine-induced killer (CIK) cells recently, as they can be easily proliferated using a straightforward, inexpensive protocol. Therefore, the function of CIK cells in regulating inflammatory environments has been drawing attention for clinical management. Throughout the current investigation, we discovered the regenerative capacity of these cells in the challenging environment of wounds that heal poorly due to diabetes. We demonstrated that the intravenous injection of CIK cells can re-establish a proregenerative inflammatory microenvironment, promote vascularization and, ultimately, accelerate skin healing in diabetic mice. The results indicated that CIK cell treatment affects macrophage polarization and restores the function of regenerative cells under hyperglycemic conditions. This novel cellular therapy offers a promising intervention for clinical applications through specific inflammatory regulation functions. [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]

Follicular CXCR5+ PD-1+ CD8 T cells (CD8 Tfc) arise in multiple models of systemic autoimmunity yet their functional contribution to disease remains in debate. Here we define the follicular localization and functional interactions of CD8 Tfc with B cells during autoimmune disease. The absence of functional T regulatory cells in autoimmunity allows for CD8 Tfc development that then expands with lymphoproliferation. CD8 Tfc are identifiable within the lymph nodes and spleen during systemic autoimmunity, but not during tissue-restricted autoimmune disease. Autoimmune CD8 Tfc cells are polyfunctional, producing helper cytokines IL-21, IL-4, and IFNγ while maintaining cytolytic proteins CD107a, granzyme B, and TNF. During autoimmune disease, IL-2-KO CD8 T cells infiltrate the B cell follicle and germinal center, including the dark zone, and in vitro induce activation-induced cytidine deaminase in naïve B cells via IL-4 secretion. CD8 Tfc represent a unique CD8 T cell population with a diverse effector cytokine repertoire that can contribute to pathogenic autoimmune B cell response.

Abstract 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.

Malignant neoplasms arising from the gastrointestinal (GI) tract are among the most common types of cancer with high mortality rates. Despite advances in treatment in a small subgroup harboring targetable mutations, the outcome remains poor, accounting for one in three cancer-related deaths observed globally. As a promising therapeutic option in various tumor types, immunotherapy with immune checkpoint inhibitors has also been evaluated in GI cancer, albeit with limited efficacy except for a small subgroup expressing microsatellite instability. In the quest for more effective treatment options, energetic efforts have been placed to evaluate the role of several immunotherapy approaches comprising of cancer vaccines, adoptive cell therapies and immune checkpoint inhibitors. In this review, we report our experience with a personalized dendritic cell cancer vaccine and cytokine-induced killer cell therapy in three patients with GI cancers and summarize current clinical data on combined immunotherapy strategies. [ABSTRACT FROM AUTHOR]

This study aimed to characterize the safety and efficacy of DC-CIK therapy in two patients with previously treated chronic lymphocytic leukemia or peritoneal cancer, respectively. Participants had received conventional chemotherapy treatment for their specific cancers, and in addition, 1–2 treatments of DC-CIK therapy were administered to subjects over the course of 1 year. Subject A received an initial dosage of 3 intravenous infusions of DC-CIK therapy on three successive days and a repeat dosage 6 months later. Subject B received an initial dosage of 3 intravenous infusions of DC-CIK therapy on three successive days and received further chemotherapy after approximately 1 year. No treatment-related adverse events were reported, and both patients experienced favorable outcomes from the treatment, including enhanced treatment response, increased chemotherapy tolerance, and prolonged survival in comparison to typical 5-year survival rates.

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]

The current study aimed to investigate the antitumor effects and potent mechanism of cytokine-induced killer (CIK) cells combined with irreversible electroporation (IRE) via Panc02 cell-bearing mouse model in vivo. CIK cells were isolated from the spleens of Panc02 pancreatic-cancer (PC) subcutaneous-xenograft model and the proportion of different lymphocytes was also determined. The antitumor effect of the combination of IRE and CIK cells in a PC subcutaneous-xenograft model was also investigated. The proportion of cells that were positive for CD3+CD8+ and the proportion of CD3+CD56+ cells were both significantly increased after 21 days of in vitro culture. Combined treatment of IRE and CIK cell significantly inhibited tumor growth and increased the survival rate of Panc02 cell–bearing mice. Furthermore, infiltration of lymphocytes into tumor tissue was significantly increased by this combination therapy compared with the untreated group or monotherapy group. In addition, IRE significantly enhanced the expression of chemokine receptors elicited by CIK cells. In conclusion, IRE combined with CIK cells showed superior antitumor efficacy in a PC xenograft model, which we attributed to the promotion of lymphocytic infiltration, as well as to upregulation of chemokine receptor expression and the regulators of CIK cell proliferation.

Background: The therapeutic efficacy of cytokine-induced killer (CIK) cells versus dendritic cells (DC) co-cultured with CIK cells (DC-CIK) in treating esophageal cancer (EC) remains unclear due to the absence of a direct comparison of these two regimens. This study evaluated the comparative efficacy and safety of CIK cells versus DC-CIK using network meta-analysis in treating EC.Material and methods: We identified eligible studies from previous meta-analyses, then conducted an updated search to retrieve additional trials between February 2020 and July 2021. The primary outcomes included overall survival (OS), objective response rate (ORR), and disease control rate (DCR), and the secondary outcomes included quality of life improved rate (QLIR) and adverse events (AEs). A network meta-analysis of 12 studies was conducted using ADDIS software.Results: Twelve studies were identified, including six comparing CIK or DC-CIK plus chemotherapy (CT) with CT alone. Immunotherapy plus CT significantly improved overall survival (OS) (odds ratio [OR] 4.10, 95% confidence interval [CI] 1.23–13.69), objective response rate (ORR) (OR 2.72, 95% CI 1.79–4.11), disease control rate (DCR) (OR 3.45, 95% CI 2.32–5.14), and quality of life improvement rate (QLIR) (OR 3.54, 95% CI 2.31–5.41). DC-CIK+CT decreased the risk of leukopenia compared with CT alone. However, no statistical difference was detected between CIK-CT and DC-CIK+CT.Conclusion: Based on the available evidence, we concluded that CIK cell treatment is superior to CT alone, but CIK-CT and DC-CIK+CT may be comparable in treating EC. However, comparing CIK-CT and DC-CIK+CT is only based on indirect evidence, so it is undoubtedly necessary to conduct studies to compare CIK-CT with DC-CIK+CT in EC patients directly.

Malignant neoplasms arising from the gastrointestinal (GI) tract are among the most common types of cancer with high mortality rates. Despite advances in treatment in a small subgroup harboring targetable mutations, the outcome remains poor, accounting for one in three cancer-related deaths observed globally. As a promising therapeutic option in various tumor types, immunotherapy with immune checkpoint inhibitors has also been evaluated in GI cancer, albeit with limited efficacy except for a small subgroup expressing microsatellite instability. In the quest for more effective treatment options, energetic efforts have been placed to evaluate the role of several immunotherapy approaches comprising of cancer vaccines, adoptive cell therapies and immune checkpoint inhibitors. In this review, we report our experience with a personalized dendritic cell cancer vaccine and cytokine-induced killer cell therapy in three patients with GI cancers and summarize current clinical data on combined immunotherapy strategies.

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]

Abstract 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.

Despite recent progress in treating advanced non-small cell lung cancer, clinical intervention in extensive-stage small-cell lung cancer (ES-SCLC) remains stagnant. The purpose of this study was to evaluate the clinical efficacy of cytokine-induced killer (CIK) cells combined with cytotoxic chemotherapy, followed by anti-programmed death 1 antibody (sintilimab) maintenance, in ES-SCLC patients. To explore a new method for safe treatment of ES-SCLC patients, thirteen ES-SCLC patients were enrolled between June 2019 and December 2021. All patients received first-line chemotherapy (etoposide plus platinum) combined with CIK cell therapy. Patients who reached a stable disease state or responded well to treatment received sintilimab maintenance treatment. The primary objective of this study was to determine the median overall survival (OS); the secondary objective was to assess the objective response rate (ORR), progression-free survival 1 and 2 (PFS1 was defined as the duration from the signing of informed consent to the date of tumor progression, or death, or the last follow-up. PFS2 was defined as the duration from the first day of sintilimab treatment to the date of tumor progression, death, or the last follow-up.), and adverse reactions. At a 24.1-month follow-up, the median OS was 11.8 (95% confidence interval [CI]: 10.6–13.0) months, median PFS1 was 5.5 (95% CI: 5.0–6.0) months, and the median PFS2 was 2.3 (95% CI: 0.5–4.1) months. The ORR was 76.9% (10/13), the disease control rate was 100% (13/13), and the 20-month survival rate was 41.7%. Eight participants exhibited grade 3 or 4 adverse events after combination therapy. During maintenance treatment with sintilimab, level 3 adverse events occurred in 1 patient (1/9). In conclusion, adding CIK cells to standard chemotherapy regimens, followed by maintenance therapy with sintilimab, may represent a new safe and effective treatment strategy.Clinical trial registrationClinicalTrials.gov (NCT03983759)

Cytokine-induced killer cells (CIK) in combination with dendritic cells (DCs) have shown favorable outcomes in renal cell carcinoma (RCC), yet some patients exhibit recurrence or no response to this therapy. In a broader perspective, enhancing the antitumor response of DC-CIK cellsmay help to address this issue. Considering this, herein, we investigated the effect of anti-CD40 and anti-CTLA-4 antibodies on the antitumor response of DC-CIK cells against RCC cell lines. Our analysis showed that, a) anti-CD40 antibody (G28.5) increased the CD3+CD56+ effector cells of CIK cells by promoting the maturation and activation of DCs, b) G28.5 also increased CTLA-4 expression in CIK cells via DCs, but the increase could be hindered by the CTLA-4 inhibitor (ipilimumab), c) adding ipilimumab was also able to significantly increase the proportion of CD3+CD56+ cells in DC-CIK cells, d) anti-CD40 antibodies predominated over anti-CTLA-4 antibodies for cytotoxicity, apoptotic effect and IFN-g secretion of DC-CIK cells against RCC cells, e) after ipilimumab treatment, the population of Tregs in CIK cells remained unaffected, but ipilimumab combined with G28.5 significantly reduced the expression of CD28 in CIK cells. Taken together, we suggest that the agonistic anti-CD40 antibody rather than CTLA-4 inhibitor may improve the antitumor response of DC-CIK cells, particularly in RCC. In addition, we pointed towards the yet to be known contribution of CD28 in the crosstalk between anti-CTLA-4 and CIK cells. [ABSTRACT FROM AUTHOR]

Background: Cancer heterogeneity poses a serious challenge concerning the toxicity and adverse effects of therapeutic inhibitors, especially when it comes to combinatorial therapies that involve multiple targeted inhibitors. In particular, in non-small cell lung cancer (NSCLC), a number of studies have reported synergistic effects of drug combinations in the preclinical models, while they were only partially successful in the clinical setup, suggesting those alternative clinical strategies (with genetic background and immune response) should be considered. Herein, we investigated the antitumor effect of cytokine-induced killer (CIK) cells in combination with ALK and PD-1 inhibitors in vitro on genetically variable NSCLC cell lines. Methods: We co-cultured the three genetically different NSCLC cell lines NCI-H2228 (EML4-ALK), A549 (KRAS mutation), and HCC-78 (ROS1 rearrangement) with and without nivolumab (PD-1 inhibitor) and crizotinib (ALK inhibitor). Additionally, we profiled the variability of surface expression multiple immune checkpoints, the concentration of absolute dead cells, intracellular granzyme B on CIK cells using flow cytometry as well as RT-qPCR. ELISA and Western blot were performed to verify the activation of CIK cells. Results: Our analysis showed that (a) nivolumab significantly weakened PD-1 surface expression on CIK cells without impacting other immune checkpoints or PD-1 mRNA expression, (b) this combination strategy showed an effective response on cell viability, IFN-γ production, and intracellular release of granzyme B in CD3+ CD56+ CIK cells, but solely in NCI-H2228, (c) the intrinsic expression of Fas ligand (FasL) as a T-cell activation marker in CIK cells was upregulated by this additive effect, and (d) nivolumab induced Foxp3 expression in CD4+CD25+ subpopulation of CIK cells significantly increased. Taken together, we could show that CIK cells in combination with crizotinib and nivolumab can enhance the anti-tumor immune response through FasL activation, leading to increased IFN-γ and granzyme B, but only in NCI-H2228 cells with EML4-ALK rearrangement. Therefore, we hypothesize that CIK therapy may be a potential alternative in NSCLC patients harboring EML4-ALK rearrangement, in addition, we support the idea that combination therapies offer significant potential when they are optimized on a patient-by-patient basis. [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]

Purpose: The purpose of the study was to evaluate the antitumor activity of CIK cells in vitro and investigate the clinical efficacy of cytokine-induced killer (CIK) therapy following operation of renal cell carcinoma patients in North China. Method: In vitro experiments, the secretion of IFN-γ and IL-2 in CIK cells were detected by ELISA and the degranulation was detected by flow cytometry. From January 1, 2012 to October 1, 2015, 202 patients were enrolled in the study and were followed up for at least 36 months. The information of 101 patients who received CIK treatment following nephrectomy and other 101 patients who only received nephrectomy was retrospectively collected. In addition, the correlation of CIK treatment to prognosis of patients following nephrectomy, including disease-free survival (DFS) and overall survival (OS), was analyzed by Kaplan-Meier analyses. COX proportional hazards analyses were used to investigate the benefited population. Results: In vitro, DC-CIK group exhibited the highest cytokines secretion and cytotoxicity followed by the CIK group. In addition, survival analysis showed that patients in North China who received CIK therapy has better prognosis compared to the control group. And the COX proportional hazards analyses demonstrated that in North China, patients with different characteristics can benefit from CIK treatment at the same. Conclusions: CIK immunotherapy is an effective and safety adjuvant for the patients with ccRCC following nephrectomy in North China.

Abstract Adoptive cell therapy (ACT) is an approach to cancer treatment that involves the use of antitumor immune cells to target residual disease in patients after completion of chemo/radiotherapy. ACT has several advantages compared with other approaches in cancer immunotherapy, including the ability to specifically expand effector cells in vitro before selection for adoptive transfer, as well as the opportunity for host manipulation in order to enhance the ability of transferred cells to recognize and kill established tumors. One of the main challenges to the success of ACT in cancer clinical trials is the identification and generation of antitumor effector cells with high avidity for tumor recognition. Natural killer (NK) cells, cytokine‐induced killers and natural killer T cells are key innate or innate‐like effector cells in cancer immunosurveillance that act at the interface between innate and adaptive immunity, to have a greater influence over immune responses to cancer. In this review, we discuss recent studies that highlight their potential in cancer therapy and summarize clinical trials using these effector immune cells in adoptive cellular therapy for the treatment of cancer.

Abstract 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.

BackgroundCancer heterogeneity poses a serious challenge concerning the toxicity and adverse effects of therapeutic inhibitors, especially when it comes to combinatorial therapies that involve multiple targeted inhibitors. In particular, in non-small cell lung cancer (NSCLC), a number of studies have reported synergistic effects of drug combinations in the preclinical models, while they were only partially successful in the clinical setup, suggesting those alternative clinical strategies (with genetic background and immune response) should be considered. Herein, we investigated the antitumor effect of cytokine-induced killer (CIK) cells in combination with ALK and PD-1 inhibitors in vitro on genetically variable NSCLC cell lines.MethodsWe co-cultured the three genetically different NSCLC cell lines NCI-H2228 (EML4-ALK), A549 (KRAS mutation), and HCC-78 (ROS1 rearrangement) with and without nivolumab (PD-1 inhibitor) and crizotinib (ALK inhibitor). Additionally, we profiled the variability of surface expression multiple immune checkpoints, the concentration of absolute dead cells, intracellular granzyme B on CIK cells using flow cytometry as well as RT-qPCR. ELISA and Western blot were performed to verify the activation of CIK cells.ResultsOur analysis showed that (a) nivolumab significantly weakened PD-1 surface expression on CIK cells without impacting other immune checkpoints or PD-1 mRNA expression, (b) this combination strategy showed an effective response on cell viability, IFN-γ production, and intracellular release of granzyme B in CD3+ CD56+ CIK cells, but solely in NCI-H2228, (c) the intrinsic expression of Fas ligand (FasL) as a T-cell activation marker in CIK cells was upregulated by this additive effect, and (d) nivolumab induced Foxp3 expression in CD4+CD25+ subpopulation of CIK cells significantly increased. Taken together, we could show that CIK cells in combination with crizotinib and nivolumab can enhance the anti-tumor immune response through FasL activation, leading to increased IFN-γ and granzyme B, but only in NCI-H2228 cells with EML4-ALK rearrangement. Therefore, we hypothesize that CIK therapy may be a potential alternative in NSCLC patients harboring EML4-ALK rearrangement, in addition, we support the idea that combination therapies offer significant potential when they are optimized on a patient-by-patient basis.

Background: This study tested the hypothesis that combined therapy with probiotics and cytokine-induced killer (CIK) cells was superior to merely one on suppressing the peritoneal carcinomatosis and liver metastasis of colorectal cancer (CRC) cells in nude mice. Methods and Results: The in vitro study revealed that in HCT 116/SW620 CRC cell lines, cell viability, proliferation, colony formation, migratory ability, wound healing, and protein expression of PD-L1 and FAK were significantly and comparably suppressed and that apoptosis was significantly and comparably increased by probiotics and CIK cells, and these effects were further significantly enhanced by combined probiotics + CIK cell therapy (all p<0.001). Nude mice were categorized into Groups 1 (SC), 2 (HCT 116), 3 (HCT 116 + probiotics), 4 (HCT 116 + CIK cells), and 5 (HCT 116 + probiotics + CIK cells). CRC cells were intraperitoneally implanted into Groups 2 to 5, and the animals were euthanized by Day 28. The results demonstrated that the abdominal dissemination of CRC cells, tumor numbers, tumor weights, liver weights, liver necrosis areas and the expression of γ-H2AX/PD-L1/FAK in harvested liver tumors were lowest in Group 1, highest in Group 2, and significantly and progressively decreased in Groups 3 to 5 (all p<0.0001). The protein expression levels of apoptotic and DNA damage biomarkers (Bax/c-caspase 3/c-PARP/γ-H2AX), a metastatic biomarker (FAK) and three tumor proliferation and survival signaling biomarkers (JAK-STAT1, PI3K/Akt/m-TOR and Ras/Raf/MEK/ERK) exhibited identical patterns to that of a tumor immune escape biomarker (PD-L1) among the groups (all p<0.0001). Conclusion: The combination of probiotics and CIK cells was superior to either therapy alone in suppressing CRC cell growth, proliferation, liver metastasis and survival, mainly through downregulating cell proliferation and survival signaling pathways., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Extracellular vesicles (EVs) are nano-sized membrane particles secreted by various cell types that are involved in many important cellular processes. Recently, EVs originating from immune cells, such as dendritic cells, chimeric antigen receptor T cells, and natural killer cells, have attracted much attention because of their known direct and indirect antitumor activity. Here, we report the EVs released by cytokine-activated CD8+ T (caCD8) cells and its cytotoxicity against cancer cells. CaCD8 cells can release EVs following stimulation of CD8+ T cells with an anti-CD3 antibody and a cytokine cocktail ex vivo. The isolated vesicles have typical EV characteristics, such as an oval shape and a size distribution between 30 and 200 nm, as well as CD81 expression. Notably, caCD8-EVs displayed cytotoxicity against various cancer cells in vitro. Furthermore, mechanism analysis demonstrates that caCD8-EVs not only contain typical cytotoxic proteins (i.e. granzyme B and perforin), but also significantly enrich interferon γ (IFNγ) compared with caCD8 cells. EV-derived IFNγ participates in EV-induced apoptosis in cancer cells. Therefore, our data reveal antitumor effects of EVs secreted from caCD8 cells and the potential role of the EV-derived IFNγ., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Abstract 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

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]