scholarly journals Synergistic antitumor effect with indoleamine 2,3-dioxygenase inhibition and temozolomide in a murine glioma model

2016 ◽  
Vol 124 (6) ◽  
pp. 1594-1601 ◽  
Author(s):  
Mitsuto Hanihara ◽  
Tomoyuki Kawataki ◽  
Kyoko Oh-Oka ◽  
Kentaro Mitsuka ◽  
Atsuhito Nakao ◽  
...  
Keyword(s):  
Oral Administration ◽  
Antitumor Effect ◽  
Therapeutic Potential ◽  
Orthotopic Model ◽  
Antitumor Effects ◽  
Secondary Glioblastoma ◽  
Indoleamine 2,3 Dioxygenase ◽  
Key Enzyme ◽  
Glioma Model ◽  
Murine Glioma

OBJECT Indoleamine 2,3-dioxygenase (IDO), a key enzyme of tryptophan (Trp) metabolism, is involved in tumor-derived immune suppression through depletion of Trp and accumulation of the metabolite kynurenine, resulting in inactivation of natural killer cells and generation of regulatory T cells (Tregs). It has been reported that high expression of IDO in cancer cells is associated with suppression of the antitumor immune response and is consistent with a poor prognosis. Thus, IDO may be a therapeutic target for malignant cancer. The authors have recently shown that IDO expression is markedly increased in human glioblastoma and secondary glioblastoma with malignant change, suggesting that IDO targeting may also have therapeutic potential for patients with glioma. The aim of this study was to investigate the antitumor effect of IDO inhibition and to examine the synergistic function of IDO inhibitor and temozolomide (TMZ) in a murine glioma model. METHODS Murine glioma GL261 cells and human glioma U87 cells were included in this study. The authors used 3 mouse models to study glioma cell growth: 1) a subcutaneous ectopic model, 2) a syngeneic intracranial orthotopic model, and 3) an allogenic intracranial orthotopic model. IDO inhibition was achieved via knockdown of IDO in GL261 cells using short hairpin RNA (shRNA) and through oral administration of the IDO inhibitor, 1-methyl-l-tryptophan (1-MT). Tumor volume in the subcutaneous model and survival time in the intracranial model were evaluated. RESULTS In the subcutaneous model, oral administration of 1-MT significantly suppressed tumor growth, and synergistic antitumor effects of 1-MT and TMZ were observed (p < 0.01). Mice containing intracranially inoculated IDO knockdown cells had a significantly longer survival period as compared with control mice (p < 0.01). CONCLUSIONS These results suggest that IDO expression is implicated in immunosuppression and tumor progression in glioma cells. Therefore, combining IDO inhibition with standard TMZ treatment could be an encouraging therapeutic strategy for patients with malignant glioma.

scholarly journals Local tumor irradiation augments the antitumor effect of cytokine-producing autologous cancer cell vaccines in a murine glioma model

2002 ◽  
Vol 9 (1) ◽  
pp. 44-52 ◽  
Author(s):  
Katalin Lumniczky ◽  
Szilvia Desaknai ◽  
Laszlo Mangel ◽  
Bela Szende ◽  
Hirofumi Hamada ◽  
...  
Keyword(s):  
Cancer Cell ◽  
Antitumor Effect ◽  
Local Tumor ◽  
Tumor Irradiation ◽  
Glioma Model ◽  
Murine 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.

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 HSV-TK–engineered donor lymphocytes after allogeneic stem-cell transplantation

Blood ◽  
2007 ◽  
Vol 109 (11) ◽  
pp. 4698-4707 ◽  
Author(s):  
Fabio Ciceri ◽  
Chiara Bonini ◽  
Sarah Marktel ◽  
Elisabetta Zappone ◽  
Paolo Servida ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Antitumor Effect ◽  
Therapeutic Potential ◽  
Selective Treatment ◽  
Antitumor Effects ◽  
Hematopoietic Stem ◽  
Donor Lymphocytes

Abstract The extensive exploitation of the antitumor effect of donor lymphocytes infused after allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is limited by the risk of graft-versus-host disease (GvHD). To overcome this limitation, we investigated the therapeutic potential of donor lymphocytes engineered with the suicide gene thymidine kinase of herpes simplex virus (TK) in 23 patients experiencing recurrence of hematologic malignancies after allo-HSCT. Long-term follow-up of infused patients included analysis of engraftment of genetically engineered lymphocytes, in vivo assessment of antitumor effect, and control of GvHD by ganciclovir. All 17 patients evaluable for engraftment and graft-versus-leukemia (GvL) had circulating TK+ cells detectable beginning at a median time of 18 days. Eleven patients (65%) experienced a substantial clinical benefit resulting in 6 (35%) complete remissions and 5 (29%) partial responses. The antitumor effect tightly correlated with the in vivo expansion of TK+ cells. Seven patients received ganciclovir, resulting in elimination of TK+ cells and effective and selective treatment of GvHD. Immunization against HSV-TK was observed in 7 patients but did not preclude an effective GvL. These data validate the feasibility, safety, and efficacy of TK+ cells in the context of allografting and represent the basis for a broader application of this technology.

Local production of TGF β1 inhibits cerebral edema, enhances TNF-α induced apoptosis and improves survival in a murine glioma model

1998 ◽  
Vol 86 (1) ◽  
pp. 46-52 ◽  
Author(s):  
David M Ashley ◽  
John H Sampson ◽  
Gary E Archer ◽  
Laura P Hale ◽  
Darell D Bigner
Keyword(s):  
Cerebral Edema ◽  
Local Production ◽  
Tnf Α ◽  
Glioma Model ◽  
Induced Apoptosis ◽  
Tgf Β1 ◽  
Murine Glioma

scholarly journals DDEL-13. FOCUSED ULTRASOUND MEDIATED BLOOD BRAIN BARRIER DISRUPTION IN A MURINE MODEL OF PONTINE GLIOMA: A SAFETY AND FEASIBILITY STUDY

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii286-iii286
Author(s):  
Zachary Englander ◽  
Hong-Jian Wei ◽  
Antonios Pouliopoulos ◽  
Pavan Upadhyayula ◽  
Chia-Ing Jan ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Focused Ultrasound ◽  
Brain Barrier ◽  
Center Frequency ◽  
Single Element ◽  
Pontine Glioma ◽  
Orthotopic Model ◽  
Function Generator ◽  
Blood Brain ◽  
Glioma Model

Abstract BACKGROUND Drug delivery remains a major obstacle in DIPG, as the blood brain barrier (BBB) limits the penetration of systemic therapies to the brainstem. Focused ultrasound (FUS) is an exciting new technology that, when combined with microbubbles, can open the BBB permitting the entry of drugs across the cerebrovasculature. Given that the utility of FUS in brainstem tumors remains unknown, the purpose of our study was to determine the safety and feasibility of this technique in a murine pontine glioma model. METHODS A syngeneic orthotopic model was established by stereotactic injection of PDGF-B+PTEN-/-p53-/- murine glioma cells (10,000/1ul) into the pons of B6 albino mice. A single-element, spherical-segment FUS transducer (center frequency=1.5MHz) driven by a function generator through a power amplifier (acoustic pressure=0.7MPa) was used with concurrent intravenous microbubble injection (FUS+MB) to sonicate the tumor on post-injection day 14. BBB opening was confirmed with gadolinium-enhanced MRI and Evans blue. Kondziela inverted screen (KIS) testing was completed to measure motor function. Mice were either immediately sacrificed for histopathological assessment or serially monitored for survival. RESULTS In mice treated with FUS (n=11), there was no measured deficit in KIS testing. Additionally, the degree of intra-tumoral hemorrhage and inflammation on H&E in control (n=5) and treated mice (n=5) was similar. Lastly, there was no difference in survival between the groups (control, n=6, median=26 days; FUS, n=6, median=25 days, p&gt;0.05). CONCLUSION FUS+MB is a safe and feasible technique to open the BBB in a preclinical pontine glioma model.

Abstract 1696: Compound RVX-208 Modulates HDL-C Levels and Function in Non-human Primates and in Early (phase I) Human Trials

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Larbi Krimbou ◽  
Ravi Jahagirdar ◽  
Dana Bailey ◽  
Anouar Hafiane ◽  
Isabelle Ruel ◽  
...  
Keyword(s):  
Oral Administration ◽  
Healthy Volunteers ◽  
Size Distribution ◽  
Cholesterol Efflux ◽  
Oral Absorption ◽  
Therapeutic Potential ◽  
Human Study ◽  
Treated Group ◽  
Atherosclerotic Cardiovascular Disease ◽  
Hdl Function

The novel compound RVX-208 is a small molecule that upregulates the gene expression of apoA-I and raises HDL-C in non-human primates. Here, we examined the effects of oral administration of RVX-208 on serum apoA-I and HDL-C levels , HDL size distribution, and HDL function. African green monkeys received RVX-208 (7.5, 15 and 30 mg/kg; twice daily and 60 mg/kg; once daily) or vehicle control for 28, 42, and 63 days. We report that RVX-208 chronic treatment resulted in a highly significant increase in the average of serum apoA-I and HDL-C levels (57% and 92%, respectively). Interestingly, RVX-208 treatment modified the distribution of HDL particle size causing a significant increase in preβ1-LpA-I and larger α1-LpA-I species. The ability of serum to promote cholesterol efflux via ABCA1, ABCG1 or SR-BI-dependent pathways in a cell culture model was significantly increased by RVX-208. The phase Ia safety and pharmacokinetic human study comprised of a total of 80 subjects. In the multiple ascending dose arm, 24 participants were randomly assigned to 3 cohorts of 8 healthy volunteers (6 active and 2 placebo), and received oral administration of RVX-208 at 2, 3 and 8 mg/kg per day or placebo for 7 days. The compound was well tolerated and had good oral absorption meeting the objectives of safety and pharmacokinetics. ApoA-I, HDL-C, HDL size distribution and ABCA1-dependent cholesterol efflux were assessed at days 1 (predose) and 7. The percent change from baseline to day 7 for apoA-I was 11% higher (P = 0.03) in the RVX-208 treated participants compared to placebo. Interestingly, preβ1-LpA-I change was 30% (P = 0.02) higher in the actively treated group and was found to strongly correlate with increased apoA-I levels (R2 = 0.72). Furthermore, ABCA1-dependent cholesterol efflux change was 10% higher (P = 0.03) and was found to correlate with increased preβ1-LpA-I . Taken together, these pharmacodynamic data from human healthy volunteers show consistent trends in apoA-I production and HDL functionality, supporting the findings in the African green monkey. Further investigation of the effect of RVX-208 on the HDL metabolic pathway is ongoing in humans and animals to establish the mechanisms of action and therapeutic potential in treating atherosclerotic cardiovascular disease.

scholarly journals Local Application of Autologous Platelet-Rich Fibrin Patch (PRF-P) Suppresses Regulatory T Cell Recruitment in a Murine Glioma Model

2018 ◽  
Vol 56 (7) ◽  
pp. 5032-5040 ◽  
Author(s):  
Wojciech K. Panek ◽  
Katarzyna C. Pituch ◽  
Jason Miska ◽  
Julius W. Kim ◽  
Aida Rashidi ◽  
...  
Keyword(s):  
T Cell ◽  
Regulatory T Cell ◽  
Local Application ◽  
Cell Recruitment ◽  
Platelet Rich Fibrin ◽  
Glioma Model ◽  
Autologous Platelet ◽  
Murine Glioma

scholarly journals Heparan Sulfate Mimetics in Cancer Therapy: The Challenge to Define Structural Determinants and the Relevance of Targets for Optimal Activity

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2915 ◽  
Author(s):  
Cinzia Lanzi ◽  
Giuliana Cassinelli
Keyword(s):  
Heparan Sulfate ◽  
Therapeutic Potential ◽  
Anticoagulant Activity ◽  
Growth Factor Receptor ◽  
Biological Behavior ◽  
Antitumor Action ◽  
Structural Determinants ◽  
Antitumor Effects ◽  
Combination Treatments ◽  
Heparin Derivatives

Beyond anticoagulation, the therapeutic potential of heparin derivatives and heparan sulfate (HS) mimetics (functionally defined HS mimetics) in oncology is related to their ability to bind and modulate the function of a vast array of HS-binding proteins with pivotal roles in cancer growth and progression. The definition of structural/functional determinants and the introduction of chemical modifications enabled heparin derivatives to be identified with greatly reduced or absent anticoagulant activity, but conserved/enhanced anticancer activity. These studies paved the way for the disclosure of structural requirements for the inhibitory effects of HS mimetics on heparanase, selectins, and growth factor receptor signaling, as well as for the limitation of side effects. Actually, HS mimetics affect the tumor biological behavior via a multi-target mechanism of action based on their effects on tumor cells and various components of the tumor microenvironment. Emerging evidence indicates that immunomodulation can participate in the antitumor activity of these agents. Significant ability to enhance the antitumor effects of combination treatments with standard therapies was shown in several tumor models. While the first HS mimetics are undergoing early clinical evaluation, an improved understanding of the molecular contexts favoring the antitumor action in certain malignancies or subgroups is needed to fully exploit their potential.

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