title: Study of the efficacy, biodistribution, and safety profile of therapeutic gutless adenovirus vectors as a prelude to a phase I clinical trial for glioblastoma.
abstract: 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 approximately 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.
authors.affiliation: Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: A K M G
authors.initials: AK
authors.lastname: Muhammad
authors.forename: M
authors.initials: M
authors.lastname: Puntel
authors.forename: M
authors.initials: M
authors.lastname: Candolfi
authors.forename: A
authors.initials: A
authors.lastname: Salem
authors.forename: K
authors.initials: K
authors.lastname: Yagiz
authors.forename: C
authors.initials: C
authors.lastname: Farrokhi
authors.forename: K M
authors.initials: KM
authors.lastname: Kroeger
authors.forename: W
authors.initials: W
authors.lastname: Xiong
authors.forename: J F
authors.initials: JF
authors.lastname: Curtin
authors.forename: C
authors.initials: C
authors.lastname: Liu
authors.forename: K
authors.initials: K
authors.lastname: Lawrence
authors.forename: N S
authors.initials: NS
authors.lastname: Bondale
authors.forename: J
authors.initials: J
authors.lastname: Lerner
authors.forename: G J
authors.initials: GJ
authors.lastname: Baker
authors.forename: D
authors.initials: D
authors.lastname: Foulad
authors.forename: R N
authors.initials: RN
authors.lastname: Pechnick
authors.forename: D
authors.initials: D
authors.lastname: Palmer
authors.forename: P
authors.initials: P
authors.lastname: Ng
authors.forename: P R
authors.initials: PR
authors.lastname: Lowenstein
authors.forename: M G
authors.initials: MG
authors.lastname: Castro
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000818:Animals; D001522:Behavior, Animal; D001932:Brain Neoplasms / Q000523:psychology / Q000628:therapy*; D017321:Clinical Trials, Phase I as Topic; D004306:Dose-Response Relationship, Immunologic; D018628:Gene Dosage; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005909:Glioblastoma / Q000523:psychology / Q000628:therapy*; D006801:Humans; D007150:Immunohistochemistry; D007267:Injections; D009368:Neoplasm Transplantation; D051381:Rats; D016019:Survival Analysis; D014018:Tissue Distribution; D019076:Transgenes / Q000235:genetics
chemical_list: D000276:Adjuvants, Immunologic