Vaccine therapy with dendritic cells transfected with Il13ra2 mRNA for glioma in mice

2010 ◽  
Vol 113 (2) ◽  
pp. 270-279 ◽  
Author(s):  
Makoto Saka ◽  
Takayuki Amano ◽  
Koji Kajiwara ◽  
Koichi Yoshikawa ◽  
Makoto Ideguchi ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Therapeutic Potential ◽  
Immunohistochemical Analysis ◽  
Antitumor Effects ◽  
Histocompatibility Complex ◽  
Lysosomal Sorting ◽  
Glioma Model ◽  
Vaccination Therapy ◽  
Mouse Glioma

Object The Il13ra2 gene is often overexpressed in brain tumors, making Il13ra2 one of the vaccine targets for immunotherapy of glioma. In this study, using a mouse glioma model, the authors tested the hypothesis that vaccination using dendritic cells transfected with Il13ra2 mRNA induces strong immunological antitumor effects. Methods A plasmid was constructed for transduction of the mRNAs transcribed in vitro into dendritic cells. This was done to transport the intracellular protein efficiently into major histocompatibility complex class II compartments by adding a late endosomal/lysosomal sorting signal to the Il13ra2 gene. The dendritic cells transfected with this Il13ra2 mRNA were injected intraperitoneally into the mouse glioma model at 3 and 10 days after tumor cell implantation. The antitumor effects were estimated based on the survival rate, results of histological analysis, and immunohistochemical findings for immune cells. Results The group treated by vaccination therapy with dendritic cells transfected with Il13ra2 mRNA survived significantly longer than did the control groups. Immunohistochemical analysis revealed that greater numbers of T lymphocytes containing CD4+ and CD8+ T cells were found in the group vaccinated with dendritic cells transfected with Il13ra2 mRNA. Conclusions These results demonstrate the therapeutic potential of vaccination with dendritic cells transfected with Il13ra2 mRNA for the treatment of malignant glioma.

Antitumor effects of vaccination with dendritic cells transfected with modified receptor for hyaluronan-mediated motility mRNA in a mouse glioma model

2007 ◽  
Vol 106 (4) ◽  
pp. 638-645 ◽  
Author(s):  
Takayuki Amano ◽  
Koji Kajiwara ◽  
Koichi Yoshikawa ◽  
Jun Morioka ◽  
Sadahiro Nomura ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Therapeutic Potential ◽  
Immunohistochemical Analysis ◽  
Antitumor Effects ◽  
Serological Screening ◽  
Lysosomal Sorting ◽  
Glioma Model ◽  
Vaccination Therapy ◽  
Mouse Glioma

Object The receptor for hyaluronan-mediated motility (RHAMM) is frequently overexpressed in brain tumors and was recently identified as an immunogenic antigen by using serological screening of cDNA expression libraries. In this study, which was conducted using a mouse glioma model, the authors tested the hypothesis that vaccination with dendritic cells transfected with RHAMM mRNA induces strong immunological antitumor effects. Methods The authors constructed a plasmid for transduction of the mRNAs transcribed in vitro into dendritic cells, which were then used to transport the intracellular protein RHAMM efficiently into major histocompatibility complex class II compartments by adding a late endosomal–lysosomal sorting signal to the RHAMM gene. The dendritic cells transfected with this RHAMM mRNA were injected intraperitoneally into the mouse glioma model 3 and 10 days after tumor cell implantation. The antitumor effects of the vaccine were estimated by the survival rate, histological analysis, and immunohistochemical findings for immune cells. Mice in the group treated by vaccination therapy with dendritic cells transfected with RHAMM mRNA survived significantly longer than those in the control groups. Immunohistochemical analysis revealed that greater numbers of T lymphocytes containing T cells activated by CD4+, CD8+, and CD25+ were found in the group vaccinated with dendritic cells transfected with RHAMM mRNA. Conclusions These results demonstrate the therapeutic potential of vaccination with dendritic cells transfected with RHAMM mRNA for the treatment of malignant glioma.

scholarly journals Tumor cytotoxicity and immunogenicity of a novel V-jet neon plasma source compared to the kINPen

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lea Miebach ◽  
Eric Freund ◽  
Stefan Horn ◽  
Felix Niessner ◽  
Sanjeev Kumar Sagwal ◽  
...  
Keyword(s):  
Cell Death ◽  
Dendritic Cells ◽  
Cancer Cells ◽  
Treatment Time ◽  
Plasma Source ◽  
In Vivo Model ◽  
Antitumor Effects ◽  
Plasma Device

AbstractRecent research indicated the potential of cold physical plasma in cancer therapy. The plethora of plasma-derived reactive oxygen and nitrogen species (ROS/RNS) mediate diverse antitumor effects after eliciting oxidative stress in cancer cells. We aimed at exploiting this principle using a newly designed dual-jet neon plasma source (Vjet) to treat colorectal cancer cells. A treatment time-dependent ROS/RNS generation induced oxidation, growth retardation, and cell death within 3D tumor spheroids were found. In TUM-CAM, a semi in vivo model, the Vjet markedly reduced vascularized tumors' growth, but an increase of tumor cell immunogenicity or uptake by dendritic cells was not observed. By comparison, the argon-driven single jet kINPen, known to mediate anticancer effects in vitro, in vivo, and in patients, generated less ROS/RNS and terminal cell death in spheroids. In the TUM-CAM model, however, the kINPen was equivalently effective and induced a stronger expression of immunogenic cancer cell death (ICD) markers, leading to increased phagocytosis of kINPen but not Vjet plasma-treated tumor cells by dendritic cells. Moreover, the Vjet was characterized according to the requirements of the DIN-SPEC 91315. Our results highlight the plasma device-specific action on cancer cells for evaluating optimal discharges for plasma cancer treatment.

scholarly journals Endogenous dendritic cells mediate the effects of intravenously injected therapeutic immunosuppressive dendritic cells in transplantation

Blood ◽  
2010 ◽  
Vol 116 (15) ◽  
pp. 2694-2705 ◽  
Author(s):  
Sherrie J. Divito ◽  
Zhiliang Wang ◽  
William J. Shufesky ◽  
Quan Liu ◽  
Olga A. Tkacheva ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Indirect Pathway ◽  
Allograft Survival ◽  
Complex Molecules ◽  
Cell Responses ◽  
Histocompatibility Complex

Abstract The prevailing idea regarding the mechanism(s) by which therapeutic immunosuppressive dendritic cells (DCs) restrain alloimmunity is based on the concept that they interact directly with antidonor T cells, inducing anergy, deletion, and/or regulation. However, this idea has not been tested in vivo. Using prototypic in vitro–generated maturation-resistant (MR) DCs, we demonstrate that once MR-DCs carrying donor antigen (Ag) are administered intravenously, they decrease the direct and indirect pathway T-cell responses and prolong heart allograft survival but fail to directly regulate T cells in vivo. Rather, injected MR-DCs are short-lived and reprocessed by recipient DCs for presentation to indirect pathway CD4+ T cells, resulting in abortive activation and deletion without detrimental effect on the number of indirect CD4+ FoxP3+ T cells, thus increasing the regulatory to effector T cell relative percentage. The effect on the antidonor response was independent of the method used to generate therapeutic DCs or their viability; and in accordance with the idea that recipient Ag-presenting cells mediate the effects of therapeutic DCs in transplantation, prolongation of allograft survival was achieved using donor apoptotic MR-DCs or those lacking surface major histocompatibility complex molecules. We therefore conclude that therapeutic DCs function as Ag-transporting cells rather than Ag-presenting cells to prolong allograft survival.

scholarly journals Cannabinoids in cancer treatment: Therapeutic potential and legislation

2019 ◽  
Vol 19 (1) ◽  
pp. 14-23 ◽  
Author(s):  
Barbara Dariš ◽  
Mojca Tancer Verboten ◽  
Željko Knez ◽  
Polonca Ferk
Keyword(s):  
Cancer Treatment ◽  
Cancer Patients ◽  
Cannabis Sativa ◽  
Therapeutic Potential ◽  
Herbal Remedy ◽  
Synthetic Cannabinoids ◽  
Cancer Type ◽  
Antitumor Effects ◽  
The Eu

The plant Cannabis sativa L. has been used as an herbal remedy for centuries and is the most important source of phytocannabinoids. The endocannabinoid system (ECS) consists of receptors, endogenous ligands (endocannabinoids) and metabolizing enzymes, and plays an important role in different physiological and pathological processes. Phytocannabinoids and synthetic cannabinoids can interact with the components of ECS or other cellular pathways and thus affect the development/progression of diseases, including cancer. In cancer patients, cannabinoids have primarily been used as a part of palliative care to alleviate pain, relieve nausea and stimulate appetite. In addition, numerous cell culture and animal studies showed antitumor effects of cannabinoids in various cancer types. Here we reviewed the literature on anticancer effects of plant-derived and synthetic cannabinoids, to better understand their mechanisms of action and role in cancer treatment. We also reviewed the current legislative updates on the use of cannabinoids for medical and therapeutic purposes, primarily in the EU countries. In vitro and in vivo cancer models show that cannabinoids can effectively modulate tumor growth, however, the antitumor effects appear to be largely dependent on cancer type and drug dose/concentration. Understanding how cannabinoids are able to regulate essential cellular processes involved in tumorigenesis, such as progression through the cell cycle, cell proliferation and cell death, as well as the interactions between cannabinoids and the immune system, are crucial for improving existing and developing new therapeutic approaches for cancer patients. The national legislation of the EU Member States defines the legal boundaries of permissible use of cannabinoids for medical and therapeutic purposes, however, these legislative guidelines may not be aligned with the current scientific knowledge.

scholarly journals Downregulation of PD-L1 via FKBP5 by celecoxib augments antitumor effects of PD-1 blockade in a malignant glioma model

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Izumi Yamaguchi ◽  
Kohei Nakajima ◽  
Kenji Shono ◽  
Yoshifumi Mizobuchi ◽  
Toshitaka Fujihara ◽  
...  
Keyword(s):  
Antibody Therapy ◽  
High Expression ◽  
Antibody Treatment ◽  
Antitumor Effects ◽  
Fk506 Binding Protein ◽  
Cox 2 ◽  
Glioma Model ◽  
Human Gbm ◽  
Post Transcriptional Regulation

Abstract Background Antitumor therapies targeting programmed cell death-1 (PD-1) or its ligand-1 (PD-L1) are used in various cancers. However, in glioblastoma (GBM), the expression of PD-L1 varies between patients, and the relationship between this variation and the efficacy of anti-PD-1 antibody therapy remains unclear. High expression levels of PD-L1 affect the proliferation and invasiveness of GBM cells. As COX-2 modulates PD-L1 expression in cancer cells, we tested the hypothesis that the COX-2 inhibitor celecoxib potentiates anti-PD-1 antibody treatment via the downregulation of PD-L1. Methods Six-week-old male C57BL/6 mice injected with murine glioma stem cells (GSCs) were randomly divided into four groups treated with vehicle, celecoxib, anti-PD-1 antibody, or celecoxib plus anti-PD-1 antibody and the antitumor effects of these treatments were assessed. To verify the mechanisms underlying these effects, murine GSCs and human GBM cells were studied in vitro. Results Compared with that with each single treatment, the combination of celecoxib and anti-PD-1 antibody treatment significantly decreased tumor volume and prolonged survival. The high expression of PD-L1 was decreased by celecoxib in the glioma model injected with murine GSCs, cultured murine GSCs, and cultured human GBM cells. This reduction was associated with post-transcriptional regulation of the co-chaperone FK506-binding protein 5 (FKBP5). Conclusions Combination therapy with anti-PD-1 antibody plus celecoxib might be a promising therapeutic strategy to target PD-L1 in glioblastoma. The downregulation of highly-expressed PD-L1 via FKBP5, induced by celecoxib, could play a role in its antitumor effects.

Phenotypic and Functional Effects of Perifosine on Dendritic Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4803-4803
Author(s):  
Weihua Song ◽  
Teru Hideshima ◽  
Yu-Tzu Tai ◽  
Kenneth C. Anderson ◽  
Nikhil C. Munshi
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Annexin V ◽  
Antitumor Agent ◽  
Dependent Manner ◽  
Immune Functions ◽  
Akt Inhibitor ◽  
Antitumor Effects

Abstract Perifosine is a synthetic novel alkylphospholipid, a new class of antitumor agent which targets cell membranes and inhibits Akt activation. Perifosine inhibits multiple myeloma (MM) cell growth in vitro and in vivo mouse model. Currently perifosine is under the evaluation of phase II clinical trail in MM. Although perifosine has shown significant direct antitumor effects, its effect on immune system has not yet been clarified. The objective of this study is to evaluate the effects of perifosine on the activity of antigen presenting cells (APCs). Monocyte-derived dendritic cells (DCs) from normal human donors were used as the APCs, and mature DCs were obtained by the treatment of TNF-α and IL-1β. Perifosine was used at the concentrations of 2.5 uM, 5 uM and 10 uM for the treatment with DCs. We first evaluated the effect of perifosine on the survival of DCs. We observed that the perifosine treatment up to 48 hours had no effect on viability (>90%) of DCs, assessed by annexin V and PI staining. Alteration of phenotype by perifosine on DCs was further examined by flow cytometry. Our results demonstrated that with dose-dependent manner, perifosine led to a significant down-regulation of surface antigens on immature DCs at 24 and 48 hours, which associated to costimulation (CD40, CD80 and CD86), antigen presentation (HLA-ABC, HLA-DPQR) and maturation (CD83). However, we did not observed significant effect of perifosine on above surface markers on mature DCs. Since DCs play a crucial role on the regulation of Th1/Th2 immune responses by the production of IL-12, we next evaluated IL-12 secretion by DCs with and without perifosine treatment. Importantly, treatment with perifosine significantly decreased LPS-induced-IL-12 production, compared to untreated DCs (untrt vs. trt = 192.29 vs. 166.23 pg/ml (2.5uM), 111.19 pg/ml (5uM) and 44.886 pg/ml (10uM)) at 24 hours. To assess the effect of perifosine on DCs function on the regulation of T cell responses, we stimulated allogenic T cells with mature DCs with or without the pre-treatment of perifosine. The proliferation assay by 3H-TdR incorporation and IFN-γ production by ELISA indicated perifosine-treated DCs had no significant effect on the regulation of T cells function. Taken together, these results showed that DCs function are influenced by the treatment of perifosine. Our pre-clinical data therefore indicates the need to monitor immune functions in patients under the Akt inhibitor treatment.

scholarly journals Dendritic Cells Pulsed with Intact Streptococcus pneumoniae Elicit both Protein- and Polysaccharide-specific Immunoglobulin Isotype Responses In Vivo through Distinct Mechanisms

2001 ◽  
Vol 195 (1) ◽  
pp. 1-14 ◽  
Author(s):  
Jesus Colino ◽  
Yi Shen ◽  
Clifford M. Snapper
Keyword(s):  
Dendritic Cells ◽  
Streptococcus Pneumoniae ◽  
Myeloid Dendritic Cells ◽  
Bacterial Proteins ◽  
Histocompatibility Complex ◽  
Tnf Α ◽  
Necrosis Factor ◽  
Igg1 Isotype

Immature bone marrow–derived myeloid dendritic cells (BMDCs) are induced to undergo phenotypic maturation and secretion of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-12, and IL-10 when pulsed in vitro with intact Streptococcus pneumoniae. After transfer to naive mice, pulsed BMDCs induce immunoglobulin (Ig) isotype responses specific for both protein and polysaccharide pneumococcal antigens, having in common the requirement for viable BMDCs, T cells, and B7-dependent costimulation in the recipient mice. Whereas primary Ig isotype responses to bacterial proteins uniformly require BMDC expression of major histocompatibility complex class II, CD40, and B7, and the secretion of IL-6, but not IL-12, similar requirements for antipolysaccharide Ig responses were only observed for the IgG1 isotype.

scholarly journals Anti-EphA2 Antibodies with Distinct In Vitro Properties Have Equal In Vivo Efficacy in Pancreatic Cancer

2009 ◽  
Vol 2009 ◽  
pp. 1-10 ◽  
Author(s):  
Helenia Ansuini ◽  
Annalisa Meola ◽  
Zeynep Gunes ◽  
Valentina Paradisi ◽  
Monica Pezzanera ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Monoclonal Antibodies ◽  
Therapeutic Potential ◽  
Tumor Cell Line ◽  
Immunohistochemical Analysis ◽  
Receptor Activation ◽  
Rapid Identification ◽  
Antibody Treatment

The EphA2 receptor tyrosine kinase is overexpressed in a variety of human epithelial cancers and is a determinant of malignant cellular behavior in pancreatic adenocarcinoma cells. Moreover, it is expressed in tumor endothelium and its activation promotes angiogenesis. To better clarify the therapeutic potential of monoclonal antibodies (mAbs) directed to the EphA2 receptor, we generated a large number of mAbs by differential screening of phage-Ab libraries by oligonucleotide microarray technology and implemented a strategy for the rapid identification of antibodies with the desired properties. We selected two high-affinity and highly specific EphA2 monoclonal antibodies with different in vitro properties on the human pancreatic tumor cell line MiaPaCa2. One is a potent EphA2-agonistic antibody, IgG25, that promotes receptor endocytosis and subsequent degradation, and the second is a ligand antagonist, IgG28, that blocks the binding to ephrin A1 and is cross-reactive with the mouse EphA2 receptor. We measured the effect of antibody treatment on the growth of MiaPaCa2 cells orthotopically transplanted in nude mice. Both IgG25 and IgG28 had strong antitumor and antimetastatic efficacy. In vivo treatment with IgG25 determined the reduction of the EphA2 protein levels in the tumor and the phosphorylation of FAK on Tyr576 while administration of IgG28 caused a decrease in tumor vascularization as measured by immunohistochemical analysis of CD31 in tumor sections. These data show that in a pancreatic cancer model comparable therapeutic efficacy is obtained either by promoting receptor degradation or by blocking receptor activation.

Deficient MHC class I cross-presentation of soluble antigen by murine neonatal dendritic cells

Blood ◽  
2004 ◽  
Vol 103 (11) ◽  
pp. 4240-4242 ◽  
Author(s):  
Tobias R. Kollmann ◽  
Sing Sing Way ◽  
Heidi L. Harowicz ◽  
Adeline M. Hajjar ◽  
Christopher B. Wilson
Keyword(s):  
Dendritic Cells ◽  
Mhc Class I ◽  
T Cell Response ◽  
Class I ◽  
Soluble Antigen ◽  
In Vitro System ◽  
Cross Presentation ◽  
Histocompatibility Complex ◽  
Large Numbers

Abstract Neonates respond suboptimally to many vaccines. The reasons for this defect are unclear, but suboptimal antigen presentation by dendritic cells has been suggested as one possibility. In this report we describe an in vitro system that allows the generation of large numbers of resting murine neonatal dendritic cells facilitating their study. Using this system, we show a clear reduction in the ability of neonatal dendritic cells to present soluble ovalbumin, while the capacity to present ovalbumin peptide is intact. This suggests a specific defect in cross-presentation of exogenous antigen via the major histocompatibility complex (MHC) class I pathway. Deficient cross-presentation may contribute to the suboptimal CD8 T-cell response to vaccines in neonates. (Blood. 2004;103:4240-4242)

scholarly journals Engineered adipose-derived stem cells with IGF-1-modified mRNA ameliorates osteoarthritis development

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Haoyu Wu ◽  
Zhi Peng ◽  
Ying Xu ◽  
Zixuan Sheng ◽  
Yanshan Liu ◽  
...  
Keyword(s):  
Stem Cells ◽  
High Efficiency ◽  
Therapeutic Potential ◽  
Immunohistochemical Analysis ◽  
Fluorescent Labeling ◽  
Knee Joints ◽  
Adipose Derived Stem Cells ◽  
Promising Alternative

Abstract Background Osteoarthritis (OA), a prevalent degenerative disease characterized by degradation of extracellular matrix (ECM), still lacks effective disease-modifying therapy. Mesenchymal stem cells (MSCs) transplantation has been regarded as the most promising approach for OA treatment while engrafting cells alone might not be adequate for effective regeneration. Genetic modification has been used to optimize MSC-based therapy; however, there are still significant limitations that prevent the clinical translation of this therapy including low efficacy and safety concerns. Recently, chemically modified mRNA (modRNA) represents a promising alternative for the gene-enhanced MSC therapy. In this regard, we hypothesized that adipose derived stem cells (ADSCs) engineered with modRNA encoding insulin-like growth factor 1 (IGF-1) were superior to native ADSCs on ameliorating OA development. Methods Mouse ADSCs were acquired from adipose tissue and transfected with modRNAs. First, the kinetics and efficacy of modRNA-mediated gene transfer in mouse ADSCs were analyzed in vitro. Next, we applied an indirect co-culture system to analyze the pro-anabolic potential of IGF-1 modRNA engineered ADSCs (named as IGF-1-ADSCs) on chondrocytes. Finally, we evaluated the cell retention and chondroprotective effect of IGF-1-ADSCs in vivo using fluorescent labeling, histology and immunohistochemistry. Results modRNA transfected mouse ADSCs with high efficiency (85 ± 5%) and the IGF-1 modRNA-transfected ADSCs facilitated burst-like production of bio-functional IGF-1 protein. In vitro, IGF-1-ADSCs induced increased anabolic markers expression of chondrocytes in inflammation environment compared to untreated ADSCs. In a murine OA model, histological and immunohistochemical analysis of knee joints harvested at 4 weeks and 8 weeks after OA induction suggested IGF-1-ADSCs had superior therapeutic effect over native ADSCs demonstrated by lower histological OARSI score and decreased loss of cartilage ECM. Conclusions These findings collectively supported the therapeutic potential of IGF-1-ADSCs for clinical OA management and cartilage repair.

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