scholarly journals Intravesical High Dose BCG Tokyo and Low Dose BCG Tokyo with GMCSF+IFN α Induce Systemic Immunity in a Murine Orthotopic Bladder Cancer Model

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1766
Author(s):  
Sin Mun Tham ◽  
Juwita N. Rahmat ◽  
Edmund Chiong ◽  
Qinghui Wu ◽  
Kesavan Esuvaranathan ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Bladder Cancer ◽  
Low Dose ◽  
Bladder Cancer Cell Line ◽  
High Dose ◽  
Cytokine Gene ◽  
Systemic Immunity ◽  
Bcg Therapy ◽  
Cytokine Gene Therapy

This study evaluates a short therapy schedule for bladder cancer using BCG Tokyo. BCG Tokyo was evaluated in vitro using bone marrow derived dendritic cells, neutrophils, RAW macrophages and the murine bladder cancer cell line, MB49PSA, and compared to other BCG strains. BCG Tokyo > BCG TICE at inducing cytokine production. In vivo, high dose (1 × 107 colony forming units (cfu)) and low dose (1 × 106 cfu) BCG Tokyo with and without cytokine genes (GMCSF + IFNα) were evaluated in C57BL/6J mice (n = 12–16 per group) with orthotopically implanted MB49PSA cells. Mice were treated with four instillations of cytokine gene therapy and BCG therapy. Both high dose BCG alone and low dose BCG combined with cytokine gene therapy were similarly effective. In the second part the responsive groups, mice (n = 27) were monitored by urinary PSA analysis for a further 7 weeks after therapy cessation. More mice were cured at day 84 than at day 42 confirming activation of the immune system. Cured mice resisted the re-challenge with subcutaneous tumors unlike naïve, age matched mice. Antigen specific T cells recognizing BCG, HY and PSA were identified. Thus, fewer intravesical instillations, with high dose BCG Tokyo or low dose BCG Tokyo with GMCSF + IFNα gene therapy, can induce effective systemic immunity.

scholarly journals Gmcsf and Ifnα gene therapy improves the response to BCG immunotherapy in a murine model of bladder cancer

2020 ◽  
Vol 16 (17) ◽  
pp. 1179-1188
Author(s):  
Sin Mun Tham ◽  
Ratha Mahendran ◽  
Edmund Chiong ◽  
Qing Hui Wu ◽  
Kesavan Esuvaranathan
Keyword(s):  
Gene Therapy ◽  
Immune Cell ◽  
Combined Therapy ◽  
Cytokine Gene ◽  
Cell Recruitment ◽  
Bcg Therapy ◽  
Cytokine Gene Therapy ◽  
Tumor Environment ◽  
Mrna Analysis ◽  
Immune Cell Recruitment

Aim: To develop a strategy to improve response to bacillus Calmette-Gueri (BCG) using cytokine gene therapy ( Gmcsf + Ifnα). Materials & methods: MB49-PSA tumor-bearing C57BL/6N mice were assigned into four groups: control; Gmcsf + Ifnα therapy; BCG therapy or combined therapy ( Gmcsf + Ifnα and BCG). In schedule 1, cytokine gene therapy was delivered before BCG therapy (eight instillations). In schedule 2, cytokine gene and BCG therapy were instilled alternatively (eight instillations). Tumors were analyzed by immunohistochemistry and mRNA analysis and urinary immune cells by flow cytometry. Results: Combined therapy in schedule 2 reduced tumor growth, increased immune cell recruitment and was associated with reduced inflammation when compared with BCG therapy. Conclusion: Alternating cytokine gene delivery with BCG therapy modulates the tumor environment increasing receptivity to BCG.

Low-Dose Vaccinia Virus-Mediated Cytokine Gene Therapy of Glioma

2001 ◽  
Vol 24 (1) ◽  
pp. 46-57 ◽  
Author(s):  
Bing Chen ◽  
Tatyana M. Timiryasova ◽  
Peyman Haghighat ◽  
Melba L. Andres ◽  
Eric H. Kajioka ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Vaccinia Virus ◽  
Low Dose ◽  
Cytokine Gene ◽  
Cytokine Gene Therapy

scholarly journals Newly Developed Recombinant Antithrombin Protects the Endothelial Glycocalyx in an Endotoxin-Induced Rat Model of Sepsis

2020 ◽  
Vol 22 (1) ◽  
pp. 176
Author(s):  
Toshiaki Iba ◽  
Jerrold H. Levy ◽  
Koichiro Aihara ◽  
Katsuhiko Kadota ◽  
Hiroshi Tanaka ◽  
...  
Keyword(s):  
Dose Group ◽  
Low Dose ◽  
Leukocyte Adhesion ◽  
Endothelial Glycocalyx ◽  
High Dose Group ◽  
Control Group ◽  
High Dose ◽  
Protective Effects ◽  
Circulating Levels

(1) Background: The endothelial glycocalyx is a primary target during the early phase of sepsis. We previously reported a newly developed recombinant non-fucosylated antithrombin has protective effects in vitro. We further evaluated the effects of this recombinant antithrombin on the glycocalyx damage in an animal model of sepsis. (2) Methods: Following endotoxin injection, in Wistar rats, circulating levels of hyaluronan, syndecan-1 and other biomarkers were evaluated in low-dose or high-dose recombinant antithrombin-treated animals and a control group (n = 7 per group). Leukocyte adhesion and blood flow were evaluated with intravital microscopy. The glycocalyx was also examined using side-stream dark-field imaging. (3) Results: The activation of coagulation was inhibited by recombinant antithrombin, leukocyte adhesion was significantly decreased, and flow was better maintained in the high-dose group (both p < 0.05). Circulating levels of syndecan-1 (p < 0.01, high-dose group) and hyaluronan (p < 0.05, low-dose group; p < 0.01, high-dose group) were significantly reduced by recombinant antithrombin treatment. Increases in lactate and decreases in albumin levels were significantly attenuated in the high-dose group (p < 0.05, respectively). The glycocalyx thickness was reduced over time in control animals, but the derangement was attenuated and microvascular perfusion was better maintained in the high-dose group recombinant antithrombin group (p < 0.05). (4) Conclusions: Recombinant antithrombin maintained vascular integrity and the microcirculation by preserving the glycocalyx in this sepsis model, effects that were more prominent with high-dose therapy.

scholarly journals Peptide-guided JC polyomavirus-like particles specifically target bladder cancer cells for gene therapy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Wei-Hong Lai ◽  
Chiung-Yao Fang ◽  
Ming-Chieh Chou ◽  
Mien-Chun Lin ◽  
Cheng-Huang Shen ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Bladder Cancer ◽  
Cancer Cells ◽  
Suicide Gene ◽  
Transduction Efficiency ◽  
Ligand Molecule ◽  
Jc Polyomavirus ◽  
Exogenous Dna ◽  
Bladder Cancer Cells

AbstractThe ultimate goal of gene delivery vectors is to establish specific and effective treatments for human diseases. We previously demonstrated that human JC polyomavirus (JCPyV) virus-like particles (VLPs) can package and deliver exogenous DNA into susceptible cells for gene expression. For tissue-specific targeting in this study, JCPyV VLPs were conjugated with a specific peptide for bladder cancer (SPB) that specifically binds to bladder cancer cells. The suicide gene thymidine kinase was packaged and delivered by SPB-conjugated VLPs (VLP-SPBs). Expression of the suicide gene was detected only in human bladder cancer cells and not in lung cancer or neuroblastoma cells susceptible to JCPyV VLP infection in vitro and in vivo, demonstrating the target specificity of VLP-SPBs. The gene transduction efficiency of VLP-SPBs was approximately 100 times greater than that of VLPs without the conjugated peptide. JCPyV VLPs can be specifically guided to target particular cell types when tagged with a ligand molecule that binds to a cell surface marker, thereby improving gene therapy.

scholarly journals In VitroActivities of Daptomycin-, Vancomycin-, and Teicoplanin-Loaded Polymethylmethacrylate against Methicillin-Susceptible, Methicillin-Resistant, and Vancomycin-Intermediate Strains of Staphylococcus aureus

2011 ◽  
Vol 55 (12) ◽  
pp. 5480-5484 ◽  
Author(s):  
Yuhan Chang ◽  
Wen-Chien Chen ◽  
Pang-Hsin Hsieh ◽  
Dave W. Chen ◽  
Mel S. Lee ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
High Performance ◽  
Low Dose ◽  
Antibacterial Activities ◽  
High Dose ◽  
Bone Cements ◽  
Antibacterial Effects ◽  
Methicillin Resistant ◽  
Content Type

ABSTRACTThe objective of this study was to evaluate the antibacterial effects of polymethylmethacrylate (PMMA) bone cements loaded with daptomycin, vancomycin, and teicoplanin against methicillin-susceptibleStaphylococcus aureus(MSSA), methicillin-resistantStaphylococcus aureus(MRSA), and vancomycin-intermediateStaphylococcus aureus(VISA) strains. Standardized cement specimens made from 40 g PMMA loaded with 1 g (low-dose), 4 g (middle-dose) or 8 g (high-dose) antibiotics were tested for elution characteristics and antibacterial activities. The patterns of release of antibiotics from the cement specimens were evaluated usingin vitrobroth elution assay with high-performance liquid chromatography. The activities of broth elution fluid against differentStaphylococcus aureusstrains (MSSA, MRSA, and VISA) were then determined. The antibacterial activities of all the tested antibiotics were maintained after being mixed with PMMA. The cements loaded with higher dosages of antibiotics showed longer elution periods. Regardless of the antibiotic loading dose, the teicoplanin-loaded cements showed better elution efficacy and provided longer inhibitory periods against MSSA, MRSA, and VISA than cements loaded with the same dose of vancomycin or daptomycin. Regarding the choice of antibiotics for cement loading in the treatment ofStaphylococcus aureusinfection, teicoplanin was superior in terms of antibacterial effects.

Establishment and characterization of a rectal cancer model in mice: application to cytokine gene therapy

2002 ◽  
Vol 17 (6) ◽  
pp. 388-395 ◽  
Author(s):  
Yun Chen ◽  
King-Jen Chang ◽  
Lih-Hwa Hwang ◽  
Chiung-Nien Chen ◽  
Sheng-Hong Tseng
Keyword(s):  
Gene Therapy ◽  
Rectal Cancer ◽  
Cytokine Gene ◽  
Cancer Model ◽  
Cytokine Gene Therapy

IL-2 cytokine gene therapy of epithelial ovarian cancer

1999 ◽  
Vol 93 (4) ◽  
pp. S82-S83
Author(s):  
A ALHENDY ◽  
A MAGLIOCCO ◽  
T ALTEWEGERI ◽  
M ALHENDY ◽  
J CHEDRESE
Keyword(s):  
Ovarian Cancer ◽  
Gene Therapy ◽  
Epithelial Ovarian Cancer ◽  
Cytokine Gene ◽  
Cytokine Gene Therapy

scholarly journals 735 Identification of a small molecule that prevents T cell exhaustion using machine learning algorithms paired with high-resolution single cell RNAseq

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A766-A766
Author(s):  
Isabelle Le Mercier ◽  
Sunny Sun ◽  
Dongmei Xiao ◽  
Laura Isacco ◽  
Daniel Treacy ◽  
...  
Keyword(s):  
T Cell ◽  
Low Dose ◽  
Machine Learning Algorithms ◽  
High Dose ◽  
T Cell Exhaustion ◽  
Tcr Signaling ◽  
Compound A ◽  
Cell Exhaustion

BackgroundT cell responses are tightly regulated and require a constant balance of signals during the different stages of their activation, expansion, and differentiation. As a result of chronic antigen exposure, T cells become exhausted in solid tumors, preventing them from controlling tumor growth.MethodsWe identified a transcriptional signature associated with T cell exhaustion in patients with melanoma and used our proprietary machine learning algorithms to predict molecules that would prevent T cell exhaustion and improve T cell function. Among the predictions, an orally available small molecule, Compound A, was highly predicted.ResultsCompound A was tested in an in vitro T cell Exhaustion assay and shown to prevent loss of proliferation and expression of immune checkpoint receptors. Transcriptionally, Compound A-treated cells looked indistinguishable from conventionally expanded, non-exhausted T cells. However, when assessed in a classical T cell activation assay, Compound A demonstrated dose dependent activity. At low dose, Compound A was immuno-stimulatory, allowing cells to divide further by preventing activation induced cell death. At higher doses, Compound A demonstrated immuno-suppressive activity preventing early CD69 upregulation and T cell proliferation. All together, these observations suggest that Compound A prevented exhaustion with a mechanism of action involving TCR signaling inhibition. While cessation of TCR signaling or rest has been recently associated with improved CAR-T efficacy by preventing or reversing exhaustion during the in vitro manufacturing phase, it is unclear if that mechanism would translate in vivo.Compound A was evaluated in the CT26 and MC38 syngeneic mouse models alongside anti-PD1. At low dose Compound A closely recapitulated anti-PD1 mediated cell behavior changes by scRNA-seq and flow cytometry in CT26 mice. At high dose, Compound A led to the accumulation of naive cells in the tumor microenvironment (TME) confirming the proposed mechanism of action. Low dose treatment was ineffective in MC38 mouse model but a pulsed treatment at high dose also recapitulated anti-PD1 activity in most animals. Importantly, we identified a new T cell population responding to anti-PD1 that was particularly increased in the MC38 mouse model; Compound A treatment also impacted this population.ConclusionsThese data confirm that mild TCR inhibition either suboptimal or fractionated can prevent exhaustion in vivo. However, this approach has a very limited window of activity between immuno-modulatory and immuno-suppressive effects, thereby limiting potential clinical benefit. Finally, these results demonstrate that our approach and platform was able to predict molecules that would prevent T cell exhaustion in vivo.

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