scholarly journals Multiple Treatment Cycles of Neural Stem Cell Delivered Oncolytic Adenovirus for the Treatment of Glioblastoma

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6320
Author(s):  
Jennifer Batalla-Covello ◽  
Hoi Wa Ngai ◽  
Linda Flores ◽  
Marisa McDonald ◽  
Caitlyn Hyde ◽  
...  
Keyword(s):  
High Grade Glioma ◽  
Oncolytic Adenovirus ◽  
Human Trial ◽  
Multiple Treatment ◽  
Intracerebral Administration ◽  
Therapeutic Benefits ◽  
Viral Particles ◽  
Rapid Clearance ◽  
Immunocompetent Mice ◽  
Higher Doses

Tumor tropic neural stem cells (NSCs) can improve the anti-tumor efficacy of oncovirotherapy agents by protecting them from rapid clearance by the immune system and delivering them to multiple distant tumor sites. We recently completed a first-in-human trial assessing the safety of a single intracerebral dose of NSC-delivered CRAd-Survivin-pk7 (NSC.CRAd-S-pk7) combined with radiation and chemotherapy in newly diagnosed high-grade glioma patients. The maximum feasible dose was determined to be 150 million NSC.CRAd-Sp-k7 (1.875 × 1011 viral particles). Higher doses were not assessed due to volume limitations for intracerebral administration and the inability to further concentrate the study agent. It is possible that therapeutic efficacy could be maximized by administering even higher doses. Here, we report IND-enabling studies in which an improvement in treatment efficacy is achieved in immunocompetent mice by administering multiple treatment cycles intracerebrally. The results imply that pre-existing immunity does not preclude therapeutic benefits attainable by administering multiple rounds of an oncolytic adenovirus directly into the brain.

Intratumoral injection of oncolytic adenovirus H101 in combination with vinorelbine/cisplatin chemotherapy in patients with advanced non-small cell lung cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17082-17082
Author(s):  
C. Zhou ◽  
Y. Xu ◽  
J. Ni ◽  
S. Zhou ◽  
J. Xu
Keyword(s):  
Advanced Nsclc ◽  
Survival Rates ◽  
Intratumoral Injection ◽  
Oncolytic Adenovirus ◽  
Time To Progression ◽  
Minor Response ◽  
Viral Particles ◽  
New Strategy ◽  
Nsclc Patients ◽  
First Time

17082 Background: Chemotherapy is main treatment for advanced NSCLC. But its efficacy is quite small with improvement of 1–2 months in median survival. New strategy against NSCLC is needed. Oncolytic adenovirus H101 is found to be effective against NSCLC. This trial is desigened to investigate efficacy and toxicity of intratumoral injection of H101 in combination with chemotherapy in the treatment of NSCLC. Methods: The NSCLC patients confirmed cytologically or pathologically were randomized to intratumoral injection of adenovirus H101 (1.5 × 1012 viral particles) plus NP chemotherapy (arm A) or NP chemotherapy (arm B). Objetive response was evaluated every two cycles and time to progression (TTP) and overall survival were followed up. Results: Out of 18 evaluable patients in Arm A, 4 patients showed partial response (PR),3 minor response(MR), 7 stable disease (SD) and 4 disease progression (PD), while in Arm B 16 evaluable patients showed 3 PR, 4 MR, 3 SD and 6 PD. At the first time of response evaluation, there was 1 PD in Arm A,but in Arm B there were 5 of PD. Failure rate in Arm B was significantly higher than in Arm B. Survival curves between the two arms were similar. Six month, 9 month and 1 year survival rates were slightly higher in Arm B and median TTP was also prolonged in Arm A. Except non-infectious fever, Arm A was similar in other toxicities to Arm B. there was only 2 patients developing mild pneumothorax. Conclusions: Intratumoral injection of H101 1.5 × 1012 viral particles in combination with NP chemotherapy was feasible, effective and safe in treatment of advanced NSCLC. No significant financial relationships to disclose.

Comparison of Listeria monocytogenes Virulence in a Mouse Model

2006 ◽  
Vol 69 (4) ◽  
pp. 842-846 ◽  
Author(s):  
KAZUE TAKEUCHI ◽  
NUTAN MYTLE ◽  
SONYA LAMBERT ◽  
MARGARET COLEMAN ◽  
MICHAEL P. DOYLE ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Mouse Model ◽  
Foodborne Pathogen ◽  
Strain Differences ◽  
Additional Food ◽  
Different Strains ◽  
Immunocompetent Mice ◽  
Immunocompromised Mice ◽  
Higher Doses ◽  
Major Data

Listeriosis results from exposure to the foodborne pathogen Listeria monocytogenes. Although many different strains of L. monocytogenes are isolated from food, no definitive tests currently predict which isolates are most virulent. The objectives of this study were to address two major data gaps for risk assessors, variability among L. monocytogenes strains in pathogenicity and virulence. Strains used in our monkey clinical trial or additional food isolates were evaluated for their virulence and infectivity in mice. All strains were equally pathogenic to immunocompromised mice, causing deaths to 50% of the population 3 days after exposure to doses ranging from 2 to 3 log CFU. Doses resulting in 50% deaths on the fifth day after administration were 1 to 2 log lower than those on the third day, indicating that the full course of pathogenicity exceeds the 3-day endpoint in immunocompromised mice. Three strains were chosen for further testing for their virulence and infectivity in liver and spleen in normal (immunocompetent) mice. Virulence was not significantly different (P > 0.05) among the three strains, all resulting in deaths to 50% of mice at 5 to 7 log CFU by 5 days after administration. All strains were equally infective in liver or spleen, with higher numbers of L. monocytogenes directly correlated with higher doses of administration. In addition, there was no preference of organs by any strains. The lack of strain differences may reflect the limitation of the mouse model and suggests the importance of using various models to evaluate the pathogenicity and virulence of L. monocytogenes strains.

CGTG-102 (Ad5/3-D24-GMCSF), a novel oncolytic adenovirus, in patients with refractory solid tumors: Experience from an advanced therapy access program.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13035-e13035
Author(s):  
Mikael Von Euler ◽  
Anna Kanerva ◽  
Petri Nokisalmi ◽  
Anniina Koski ◽  
Iulia Diaconu ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Oncolytic Adenovirus ◽  
Eligibility Criteria ◽  
Minor Response ◽  
Preclinical Testing ◽  
Viral Particles ◽  
Advanced Therapy ◽  
Wide Range ◽  
Major Organ ◽  
Tumor Types

e13035 Background: Following preclinical testing CGTG-102, a 5/3 chimeric oncolytic adenovirus armed with human GMCSF, has been used to treat 115 refractory cancer patients. Methods: Eligibility criteria included refractory advanced solid tumors, no major organ deficiencies and written informed consent. Patients were treated with either a single treatment or serial treatments with one or more viruses. Intra tumoral administration was performed under ultrasound guidance. The initial dose, 8 x 1010 Viral Particles (VP), was based on published safety results and preclinical testing and escalated in later patients. A routinely tolerated dose of 3 x 1011 VP was deemed optimal and is the target dose for clinical development. To reduce regulatory T-cells, low-dose cyclophosphamide 50 mg/day was given. Adverse Reactions (AR) were scored according to CTCAE 3.0. Imaging was done by CT before and ~2 months after treatment. Response was scored according to RECIST 1.1, including injected and non-injected lesions. Decrease not fulfilling PR was scored as minor response (MR). Results: The most common ARs were pain (82%), fever (81%), fatigue (79%), nausea (54%) and hemoglobin decrease (48%). Pain is mostly tumor pain or pain in the injected tumor, which may be causally related to the MOA of the therapy. Most ARs were G1 or G2; 6 were G4: 2 Hb decrease, 2 pulmonary embolism and single reports of thrombocytopenia and pericardial effusion, most probably due to the underlying disease.Imaging was performed when clinically useful. 65/115 are evaluable by imaging: 3% PR, 11% MR, 40% SD and 46% PD. Best results were obtained in Breast Cancer, Melanoma, Soft Tissue Sarcoma, Mesothelioma and Ovarian Cancer. Median survival in this heavily pre-treated refractory population is 164d, 95% CI 122d – 206d. Mean survival is 281d reflecting that approx. 30% survive more than 300d and 15% up to 600d. A wide range of samples are being analyzed to further characterize the viral and immunological aspects of the therapy. Conclusions: CGTG-102 is a novel oncolytic adenovirus with good safety profile and encouraging signs of efficacy. Formal clinical studies are underway in several tumor types in both US and EU.

Comparison of Multiple Treatment Planning Techniques for High-Grade Glioma Tumors Near to Critical Organs

2018 ◽  
Vol 41 (9) ◽  
pp. 514-519 ◽  
Author(s):  
Hande Bas Ayata ◽  
Cemile Ceylan ◽  
Ayhan Kılıç ◽  
Metin Güden ◽  
Kayıhan Engin
Keyword(s):  
Treatment Planning ◽  
High Grade Glioma ◽  
High Grade ◽  
Planning Techniques ◽  
Multiple Treatment ◽  
Glioma Tumors

scholarly journals Efficacy of HER2 retargeted herpes simplex virus as therapy for high-grade glioma in immunocompetent mice

2012 ◽  
Vol 19 (11) ◽  
pp. 788-795 ◽  
Author(s):  
E Reisoli ◽  
E Gambini ◽  
I Appolloni ◽  
V Gatta ◽  
M Barilari ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
High Grade Glioma ◽  
High Grade ◽  
Immunocompetent Mice ◽  
Simplex Virus

Emergence of Ad-Mediated Combination Therapy Against Cancer: What to Expect?

2018 ◽  
Vol 18 (2) ◽  
pp. 139-152 ◽  
Author(s):  
JinWoo Hong ◽  
Chae-Ok Yun
Keyword(s):  
Combination Therapy ◽  
Malignant Tumors ◽  
Treatment Modalities ◽  
Preclinical Models ◽  
Promising Alternative ◽  
The Past ◽  
Novel Treatment ◽  
Viral Particles ◽  
Rapid Clearance ◽  
Therapeutic Profile

Novel treatment modalities are rapidly advancing toward clinical use as many malignant cancers still remain incurable. Adenovirus (Ad) in particular has been extensively researched as a promising alternative to conventional cancer therapy in the past decades. Although Ad has demonstrated promising therapeutic outcome and cancer specificity in preclinical models, its therapeutic efficacy in clinical trials is still insufficient due to several drawbacks such as rapid clearance of viral particles by host immune response, induction of acute inflammatory response, and hepatotoxicity. In this regard, combination of Ad with other cancer treatment modalities, such as chemotherapy, radiotherapy, or immunotherapy, can be an effective strategy to overcome the limitations of Ad. Cancerspecific and effective expression of multifunctional therapeutic genes by Ad can enhance the therapeutic profile of other treatment modalities, making it a logical candidate for combination therapy to combat malignant tumors.

scholarly journals Modeling the oxidative consumption of curcumin from controlled released poly(beta-amino ester) microparticles in the presence of a free radical generating system

2019 ◽  
Vol 6 (4) ◽  
pp. 201-210 ◽  
Author(s):  
Carolyn T Jordan ◽  
J Zach Hilt ◽  
Thomas D Dziubla
Keyword(s):  
Therapeutic Potential ◽  
Clinical Success ◽  
Amino Ester ◽  
Therapeutic Benefits ◽  
Consumption Rates ◽  
Rapid Clearance ◽  
Drug Modeling ◽  
First Time ◽  
Kinetics Of ◽  
Poor Stability

AbstractDespite the promise of its therapeutic benefits, curcumin as a free molecule has failed to demonstrate significant clinical success. Arguably, its inherently poor stability and rapid clearance is a significant reason for these negative outcomes. The incorporation of curcumin into the backbone of a crosslinked hydrogel that utilizes poly(beta-amino ester) (PBAE) chemistry can provide a tunable protective network with the ability to release at a controlled rate while improving its therapeutic potential. Kinetics of curcumin conjugated PBAE microparticles controlled release delivery system in the presence of oxidative environments was studied for the first time, where consumption rates of active curcumin and release products were obtained. The constituent amount of curcumin present in solution was improved by incorporating the active into the network in comparison to curcumin as a free drug. Modeling curcumin conjugated PBAE microparticles will provide a design platform to improve translation and overall success in delivering a therapeutic agent that matches levels of oxidative stress.

scholarly journals Favipiravir Inhibits Mayaro Virus Infection in Mice

Viruses ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2213
Author(s):  
Michèle Bengue ◽  
Ai-rada Pintong ◽  
Florian Liegeois ◽  
Antoine Nougairède ◽  
Rodolphe Hamel ◽  
...  
Keyword(s):  
Antiviral Treatment ◽  
Antiviral Drug ◽  
Viral Rna ◽  
In Vivo Model ◽  
Blood Levels ◽  
Viral Particles ◽  
Mayaro Virus ◽  
Immunocompetent Mice

Mayaro virus (MAYV) is an emergent alphavirus that causes MAYV fever. It is often associated with debilitating symptoms, particularly arthralgia and myalgia. MAYV infection is becoming a considerable health issue that, unfortunately, lacks a specific antiviral treatment. Favipiravir, a broad-spectrum antiviral drug, has recently been shown to exert anti-MAYV activity in vitro. In the present study, the potential of Favipiravir to inhibit MAYV replication in an in vivo model was evaluated. Immunocompetent mice were orally administrated 300 mg/kg/dose of Favipiravir at pre-, concurrent-, or post-MAYV infection. The results showed a significant reduction in infectious viral particles and viral RNA transcripts in the tissues and blood of the pre- and concurrently treated infected mice. A significant reduction in the presence of both viral RNA transcript and infectious viral particles in the tissue and blood of pre- and concurrently treated infected mice was observed. By contrast, Favipiravir treatment post-MAYV infection did not result in a reduction in viral replication. Interestingly, Favipiravir strongly decreased the blood levels of the liver disease markers aspartate- and alanine aminotransferase in the pre- and concurrently treated MAYV-infected mice. Taken together, these results suggest that Favipiravir is a potent antiviral drug when administered in a timely manner.

scholarly journals Optimization of Early Steps in Oncolytic Adenovirus ONCOS-401 Production in T-175 and HYPERFlasks

2019 ◽  
Vol 20 (3) ◽  
pp. 621 ◽  
Author(s):  
Lukasz Kuryk ◽  
Anne-Sophie Møller ◽  
Antti Vuolanto ◽  
Sari Pesonen ◽  
Mariangela Garofalo ◽  
...  
Keyword(s):  
Scale Up ◽  
A549 Cells ◽  
Oncolytic Adenovirus ◽  
Oncolytic Viruses ◽  
Oncolytic Adenoviruses ◽  
Combination Strategies ◽  
Viral Particles ◽  
Advanced Therapy ◽  
Viral Yield ◽  
Harvesting Method

Oncolytic adenoviruses can trigger lysis of tumor cells, induce an antitumor immune response, bypass classical chemotherapeutic resistance strategies of tumors, and provide opportunities for combination strategies. A major challenge is the development of scalable production methods for viral seed stocks and sufficient quantities of clinical grade viruses. Because of promising clinical signals in a compassionate use program (Advanced Therapy Access Program) which supported further development, we chose the oncolytic adenovirus ONCOS-401 as a testbed for a new approach to scale up. We found that the best viral production conditions in both T-175 flasks and HYPERFlasks included A549 cells grown to 220,000 cells/cm2 (80% confluency), with ONCOS-401 infection at 30 multiplicity of infection (MOI), and an incubation period of 66 h. The Lysis A harvesting method with benzonase provided the highest viral yield from both T-175 and HYPERFlasks (10,887 ± 100 and 14,559 ± 802 infectious viral particles/cell, respectively). T-175 flasks and HYPERFlasks produced up to 2.1 × 109 ± 0.2 and 1.75 × 109 ± 0.08 infectious particles of ONCOS-401 per cm2 of surface area, respectively. Our findings suggest a suitable stepwise process that can be applied to optimizing the initial production of other oncolytic viruses.

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