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Study of the Efficacy, Biodistribution, and Safety Profile of Therapeutic Gutless Adenovirus Vectors as a Prelude to a Phase I Clinical Trial for Glioblastoma

Creator:

Muhammad, AKM Ghulam; Puntel, Mariana; Candolfi, Marianela; Salem, A; Yagiz, Kader; Farrokhi, C; Kroeger, Kurt M; Xiong, Weidong; Curtin, James F.; Liu, Chunyan; Lawrence, K; Bondale, Niyati; Lerner, Jonathan; Baker, G; Foulad, David; Pechnick, Robert; Palmer, Donna; Ng, Philip; Lowenstein, Pedro; Castro, Maria;

Institution: Dublin Institute of Technology
Subject Keywords: Gene Therapy; Brain Tumors; Glioma; Adenovirus; Immunotherapy; Flt3 ligand; 1.6 BIOLOGICAL SCIENCES, Cell biology,, Biochemistry and molecular biology, 3. MEDICAL AND HEALTH SCIENCES, Gene-based diagnostics and therapeutic interventions, Gene based therapeutics; Biochemistry; Biochemistry, Biophysics, and Structural Biology;
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Description:

Glioblastoma multiforme (GBM) is the most common and most aggressive primary brain tumor in humans. Systemic immunity against gene therapy vectors has been shown to hamper therapeutic efficacy; however, helper-dependent high-capacity adenovirus (HC-Ad) vectors elicit sustained transgene expression, even in the presence of systemic anti-adenoviral immunity. We engineered HC-Ads encoding the conditional cytotoxic herpes simplex type 1 thymidine kinase (TK) and the immunostimulatory cytokine fms-like tyrosine kinase ligand 3 (Flt3L). Flt3L expression is under the control of the regulatable Tet-ON system. In anticipation of a phase I clinical trial for GBM, we assessed the therapeutic efficacy, biodistribution, and clinical and neurotoxicity with escalating doses of HC-Ad-TetOn-Flt3L + HC-Ad-TK in rats. Intratumoral administration of these therapeutic HC-Ads in rats bearing large intracranial GBMs led to long-term survival in ~70% of the animals and development of antiglioma immunological memory without signs of neuropathology or systemic toxicity. Systemic anti-adenoviral immunity did not affect therapeutic efficacy. These data support the idea that it would be useful to develop HC-Ad vectors further as a therapeutic gene-delivery platform to implement GBM phase I clinical trials.

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Muhammad, AKM Ghulam; Puntel, Mariana; Candolfi, Marianela; Salem, A; Yagiz, Kader; Farrokhi, C; Kroeger, Kurt M; Xiong, Weidong; Curtin, James F.; Liu, Chunyan; Lawrence, K; Bondale, Niyati; Lerner, Jonathan; Baker, G; Foulad, David; Pechnick, Robert; Palmer, Donna; Ng, Philip; Lowenstein, Pedro; Castro, Maria; . () Study of the Efficacy, Biodistribution, and Safety Profile of Therapeutic Gutless Adenovirus Vectors as a Prelude to a Phase I Clinical Trial for Glioblastoma [Online]. Available from: http://www.thehealthwell.info/node/638293 [Accessed: 16th January 2018].

  

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