ArticleHuman gene therapy methods2016
Preclinical Efficacy and Safety Profile of Allometrically Scaled Doses of Doxycycline Used to Turn "On" Therapeutic Transgene Expression from High-Capacity Adenoviral Vectors in a Glioma Model.
Article in Human gene therapy methods, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
6 citing papers in PubMed, 8 citations in OpenAlex.
- Cell and gene therapy in neuro-oncology.Handbook of clinical neurology · 2024Review
- Significance of Preexisting Vector Immunity and Activation of Innate Responses for Adenoviral Vector-Based Therapy.Viruses · 2022Review
- High-Capacity Adenoviral Vectors: Expanding the Scope of Gene Therapy.International journal of molecular sciences · 2020Review
- Bicistronic transfer of CDKN2A and p53 culminates in collaborative killing of human lung cancer cells in vitro and in vivo.Gene therapy · 2020Article
- Externally-Controlled Systems for Immunotherapy: From Bench to Bedside.Frontiers in immunology · 2020Review
- Modulated expression of the HIV-1 2LTR zinc finger efficiently interferes with the HIV integration process.Bioscience reports · 2018Article
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
Glioblastoma multiforme (GBM) is the most commonly occurring primary brain cancer in adults, in whom its highly infiltrative cells prevent total surgical resection, often leading to tumor recurrence and patient death. Our group has discovered a gene therapy approach for GBM that utilizes high-capacity "gutless" adenoviral vectors encoding regulatable therapeutic transgenes. The herpes simplex type 1-thymidine kinase (TK) actively kills dividing tumor cells in the brain when in the presence of the prodrug, ganciclovir (GCV), whereas the FMS-like tyrosine kinase 3 ligand (Flt3L) is an immune-stimulatory molecule under tight regulation by a tetracycline-inducible "Tet-On" activation system that induces anti-GBM immunity. As a prelude to a phase I clinical trial, we evaluated the safety and efficacy of Food and Drug Administration (FDA)-approved doses of the tetracycline doxycycline (DOX) allometrically scaled for rats. DOX initiates the expression of Flt3L, which has been shown to recruit dendritic cells to the brain tumor microenvironment-an integral first step in the development of antitumor immunity. The data revealed a highly safe profile surrounding these human-equivalent doses of DOX under an identical therapeutic window as proposed in the clinical trial. This was confirmed through a neuropathological analysis, liver and kidney histopathology, detection of neutralizing antibodies, and systemic toxicities in the blood. Interestingly, we observed a significant survival advantage in rats with GBM receiving the 300 mg/day equivalent dosage of DOX versus the 200 mg/day equivalent. Additionally, rats rejected "recurrent" brain tumor threats implanted 90 days after their primary brain tumors. We also show that DOX detection within the plasma can be an indicator of optimal dosing of DOX to attain therapeutic levels. This work has significant clinical relevance for an ongoing phase I clinical trial in humans with primary GBM and for other therapeutic approaches using Tet-On transactivation system in humans.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.