title: Phase I trial of adenovirus-mediated p53 gene therapy for recurrent glioma: biological and clinical results.
abstract: OBJECTIVE
  Advances in brain tumor biology indicate that transfer of p53 is an alternative therapy for human gliomas. Consequently, we undertook a phase I clinical trial of p53 gene therapy using an adenovirus vector (Ad-p53, INGN 201).
  
  
  METHODS
  To obtain molecular information regarding the transfer and distribution of exogenous p53 into gliomas after intratumoral injection and to determine the toxicity of intracerebrally injected Ad-p53, patients underwent a two-stage approach. In stage 1, Ad-p53 was stereotactically injected intratumorally via an implanted catheter. In stage 2, the tumor-catheter was resected en bloc, and the postresection cavity was treated with Ad-p53. This protocol provided intact Ad-p53-treated biologic specimens that could be analyzed for molecular end points, and because the resection cavity itself was injected with Ad-p53, patients could be observed for clinical toxicity.
  
  
  RESULTS
  Of fifteen patients enrolled, twelve underwent both treatment stages. In all patients, exogenous p53 protein was detected within the nuclei of astrocytic tumor cells. Exogenous p53 transactivated p21CIP/WAF and induced apoptosis. However, transfected cells resided on average within 5 mm of the injection site. Clinical toxicity was minimal and a maximum-tolerated dose was not reached. Although anti-adenovirus type 5 (Ad5) titers increased in most patients, there was no evidence of systemic viral dissemination.
  
  
  CONCLUSIONS
  Intratumoral injection of Ad-p53 allowed for exogenous transfer of the p53 gene and expression of functional p53 protein. However, at the dose and schedule evaluated, transduced cells were only found within a short distance of the injection site. Although toxicity was minimal, widespread distribution of this agent remains a significant goal.
authors.affiliation: Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA. flang@mdanderson.org
authors.forename: Frederick F
authors.initials: FF
authors.lastname: Lang
authors.forename: Janet M
authors.initials: JM
authors.lastname: Bruner
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Fuller
authors.forename: Kenneth
authors.initials: K
authors.lastname: Aldape
authors.forename: Michael D
authors.initials: MD
authors.lastname: Prados
authors.forename: Susan
authors.initials: S
authors.lastname: Chang
authors.forename: Mitchel S
authors.initials: MS
authors.lastname: Berger
authors.forename: Michael W
authors.initials: MW
authors.lastname: McDermott
authors.forename: Sandeep M
authors.initials: SM
authors.lastname: Kunwar
authors.forename: Larry R
authors.initials: LR
authors.lastname: Junck
authors.forename: William
authors.initials: W
authors.lastname: Chandler
authors.forename: James A
authors.initials: JA
authors.lastname: Zwiebel
authors.forename: Richard S
authors.initials: RS
authors.lastname: Kaplan
authors.forename: W K Alfred
authors.initials: WK
authors.lastname: Yung
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000235:genetics* / Q000628:therapy*; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D015316:Genetic Therapy; D005822:Genetic Vectors; D005910:Glioma / Q000235:genetics* / Q000628:therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D014161:Transduction, Genetic; D016896:Treatment Outcome