title: Combined alloreactive CTL cellular therapy with prodrug activator gene therapy in a model of breast cancer metastatic to the brain.
abstract: OBJECTIVE
  Individual or combined strategies of cellular therapy with alloreactive CTLs (alloCTL) and gene therapy using retroviral replicating vectors (RRV) encoding a suicide prodrug activating gene were explored for the treatment of breast tumors metastatic to the brain.
  
  
  METHODS
  AlloCTL, sensitized to the HLA of MDA-MB-231 breast cancer cells, were examined in vitro for antitumor functionality toward breast cancer targets. RRV encoding the yeast cytosine deaminase (CD) gene was tested in vivo for virus spread, ability to infect, and kill breast cancer targets when exposed to 5-fluorocytosine (5-FC). Individual and combination treatments were tested in subcutaneous and intracranial xenograft models with 231BR, a brain tropic variant.
  
  
  RESULTS
  AlloCTL preparations were cytotoxic, proliferated, and produced IFN-γ when coincubated with target cells displaying relevant HLA. In vivo, intratumorally placed alloCTL trafficked through one established intracranial 231BR focus to another in contralateral brain and induced tumor cell apoptosis. RRV-CD efficiently spread in vivo, infected 231BR and induced their apoptosis upon 5-FC exposure. Subcutaneous tumor volumes were significantly reduced in alloCTL and/or gene therapy-treated groups compared to control groups. Mice with established intracranial 231BR tumors treated with combined alloCTL and RRV-CD had a median survival of 97.5 days compared with single modalities (50-83 days); all experimental treatment groups survived significantly longer than sham-treated groups (median survivals 31.5 or 40 days) and exhibited good safety/toxicity profiles.
  
  
  CONCLUSIONS
  The results indicate combining cellular and suicide gene therapies is a viable strategy for the treatment of established breast tumors in the brain.
authors.affiliation: Department of Neurosurgery, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Hickey
authors.forename: Colin C
authors.initials: CC
authors.lastname: Malone
authors.forename: Kate L
authors.initials: KL
authors.lastname: Erickson
authors.forename: Amy
authors.initials: A
authors.lastname: Lin
authors.forename: Horacio
authors.initials: H
authors.lastname: Soto
authors.forename: Edward T
authors.initials: ET
authors.lastname: Ha
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kamijima
authors.forename: Akihito
authors.initials: A
authors.lastname: Inagaki
authors.forename: Masamichi
authors.initials: M
authors.lastname: Takahashi
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kato
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kasahara
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Mueller
authors.forename: Carol A
authors.initials: CA
authors.lastname: Kruse
mesh_terms: D000256:Adenoviridae; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D003131:Combined Modality Therapy; D043525:Cytosine Deaminase / Q000235:genetics / Q000627:therapeutic use; D005260:Female; D005437:Flucytosine / Q000008:administration & dosage; D041722:Genes, Transgenic, Suicide / Q000235:genetics; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D011355:Prodrugs / Q000008:administration & dosage; D013602:T-Lymphocytes, Cytotoxic
chemical_list: D011355:Prodrugs; D005437:Flucytosine; D043525:Cytosine Deaminase