title: Retroviral replicating vector-mediated gene therapy achieves long-term control of tumor recurrence and leads to durable anticancer immunity.
abstract: BACKGROUND
  Prodrug-activator gene therapy with Toca 511, a tumor-selective retroviral replicating vector (RRV) encoding yeast cytosine deaminase, is being evaluated in recurrent high-grade glioma patients. Nonlytic retroviral infection leads to permanent integration of RRV into the cancer cell genome, converting infected cancer cell and progeny into stable vector producer cells, enabling ongoing transduction and viral persistence within tumors. Cytosine deaminase in infected tumor cells converts the antifungal prodrug 5-fluorocytosine into the anticancer drug 5-fluorouracil, mediating local tumor destruction without significant systemic adverse effects.
  
  
  METHODS
  Here we investigated mechanisms underlying the therapeutic efficacy of this approach in orthotopic brain tumor models, employing both human glioma xenografts in immunodeficient hosts and syngeneic murine gliomas in immunocompetent hosts.
  
  
  RESULTS
  In both models, a single injection of replicating vector followed by prodrug administration achieved long-term survival benefit. In the immunodeficient model, tumors recurred repeatedly, but bioluminescence imaging of tumors enabled tailored scheduling of multicycle prodrug administration, continued control of disease burden, and long-term survival. In the immunocompetent model, complete loss of tumor signal was observed after only 1-2 cycles of prodrug, followed by long-term survival without recurrence for >300 days despite discontinuation of prodrug. Long-term survivors rejected challenge with uninfected glioma cells, indicating immunological responses against native tumor antigens, and immune cell depletion showed a critical role for CD4+ T cells.
  
  
  CONCLUSIONS
  These results support dual mechanisms of action contributing to the efficacy of RRV-mediated prodrug-activator gene therapy: long-term tumor control by prodrug conversion-mediated cytoreduction, and induction of antitumor immunity.
authors.affiliation: Department of Medicine, University of California Los Angeles (UCLA), Los Angeles, California; Department of Cell Biology and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California; Tocagen Inc., San Diego, California; Department of Neurosurgery, University of California Los Angeles, Los Angeles, California.
authors.forename: Kei
authors.initials: K
authors.lastname: Hiraoka
authors.affiliation: Department of Medicine, University of California Los Angeles (UCLA), Los Angeles, California; Department of Cell Biology and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California; Tocagen Inc., San Diego, California; Department of Neurosurgery, University of California Los Angeles, Los Angeles, California.
authors.forename: Akihito
authors.initials: A
authors.lastname: Inagaki
authors.affiliation: Department of Medicine, University of California Los Angeles (UCLA), Los Angeles, California; Department of Cell Biology and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California; Tocagen Inc., San Diego, California; Department of Neurosurgery, University of California Los Angeles, Los Angeles, California.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kato
authors.affiliation: Department of Medicine, University of California Los Angeles (UCLA), Los Angeles, California; Department of Cell Biology and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California; Tocagen Inc., San Diego, California; Department of Neurosurgery, University of California Los Angeles, Los Angeles, California.
authors.forename: Tiffany T
authors.initials: TT
authors.lastname: Huang
authors.affiliation: Department of Medicine, University of California Los Angeles (UCLA), Los Angeles, California; Department of Cell Biology and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California; Tocagen Inc., San Diego, California; Department of Neurosurgery, University of California Los Angeles, Los Angeles, California.
authors.forename: Leah A
authors.initials: LA
authors.lastname: Mitchell
authors.affiliation: Department of Medicine, University of California Los Angeles (UCLA), Los Angeles, California; Department of Cell Biology and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California; Tocagen Inc., San Diego, California; Department of Neurosurgery, University of California Los Angeles, Los Angeles, California.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kamijima
authors.affiliation: Department of Medicine, University of California Los Angeles (UCLA), Los Angeles, California; Department of Cell Biology and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California; Tocagen Inc., San Diego, California; Department of Neurosurgery, University of California Los Angeles, Los Angeles, California.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department of Medicine, University of California Los Angeles (UCLA), Los Angeles, California; Department of Cell Biology and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California; Tocagen Inc., San Diego, California; Department of Neurosurgery, University of California Los Angeles, Los Angeles, California.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsumoto
authors.affiliation: Department of Medicine, University of California Los Angeles (UCLA), Los Angeles, California; Department of Cell Biology and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California; Tocagen Inc., San Diego, California; Department of Neurosurgery, University of California Los Angeles, Los Angeles, California.
authors.forename: Katrin
authors.initials: K
authors.lastname: Hacke
authors.affiliation: Department of Medicine, University of California Los Angeles (UCLA), Los Angeles, California; Department of Cell Biology and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California; Tocagen Inc., San Diego, California; Department of Neurosurgery, University of California Los Angeles, Los Angeles, California.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Kruse
authors.affiliation: Department of Medicine, University of California Los Angeles (UCLA), Los Angeles, California; Department of Cell Biology and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California; Tocagen Inc., San Diego, California; Department of Neurosurgery, University of California Los Angeles, Los Angeles, California.
authors.forename: Derek
authors.initials: D
authors.lastname: Ostertag
authors.affiliation: Department of Medicine, University of California Los Angeles (UCLA), Los Angeles, California; Department of Cell Biology and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California; Tocagen Inc., San Diego, California; Department of Neurosurgery, University of California Los Angeles, Los Angeles, California.
authors.forename: Joan M
authors.initials: JM
authors.lastname: Robbins
authors.affiliation: Department of Medicine, University of California Los Angeles (UCLA), Los Angeles, California; Department of Cell Biology and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California; Tocagen Inc., San Diego, California; Department of Neurosurgery, University of California Los Angeles, Los Angeles, California.
authors.forename: Harry E
authors.initials: HE
authors.lastname: Gruber
authors.affiliation: Department of Medicine, University of California Los Angeles (UCLA), Los Angeles, California; Department of Cell Biology and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California; Tocagen Inc., San Diego, California; Department of Neurosurgery, University of California Los Angeles, Los Angeles, California.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Jolly
authors.affiliation: Department of Medicine, University of California Los Angeles (UCLA), Los Angeles, California; Department of Cell Biology and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California; Tocagen Inc., San Diego, California; Department of Neurosurgery, University of California Los Angeles, Los Angeles, California.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kasahara
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival; D043525:Cytosine Deaminase / Q000235:genetics; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000502:physiology; D005910:Glioma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D006801:Humans; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000628:therapy*; D012190:Retroviridae / Q000502:physiology; D016019:Survival Analysis
chemical_list: D043525:Cytosine Deaminase
keywords: Toca 511; antitumor immunity; prodrug activator gene therapy; retroviral replicating vector