title: Design and selection of Toca 511 for clinical use: modified retroviral replicating vector with improved stability and gene expression.
abstract: Retroviral replicating vectors (RRVs) are a nonlytic alternative to oncolytic replicating viruses as anticancer agents, being selective both for dividing cells and for cells that have defects in innate immunity and interferon responsiveness. Tumor cells fit both these descriptions. Previous publications have described a prototype based on an amphotropic murine leukemia virus (MLV), encoding yeast cytosine deaminase (CD) that converts the prodrug 5-fluorocytosine (5-FC) to the potent anticancer drug, 5-fluorouracil (5-FU) in an infected tumor. We report here the selection of one lead clinical candidate based on a general design goal to optimize the genetic stability of the virus and the CD activity produced by the delivered transgene. Vectors were tested for titer, genetic stability, CD protein and enzyme activity, ability to confer susceptibility to 5-FC, and preliminary in vivo antitumor activity and stability. One vector, Toca 511, (aka T5.0002) encoding an optimized CD, shows a threefold increased specific activity in infected cells over infection with the prototype RRV and shows markedly higher genetic stability. Animal testing demonstrated that Toca 511 replicates stably in human tumor xenografts and, after 5-FC administration, causes complete regression of such xenografts. Toca 511 (vocimagene amiretrorepvec) has been taken forward to preclinical and clinical trials.
authors.affiliation: Tocagen Inc, San Diego, California, USA.
authors.forename: Omar D
authors.initials: OD
authors.lastname: Perez
authors.affiliation: Department of Medicine, University of California Los Angeles (UCLA), Los Angeles, California, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Logg
authors.affiliation: Department of Medicine, University of California Los Angeles (UCLA), Los Angeles, California, USA.
authors.forename: Kei
authors.initials: K
authors.lastname: Hiraoka
authors.affiliation: Tocagen Inc, San Diego, California, USA.
authors.forename: Oscar
authors.initials: O
authors.lastname: Diago
authors.affiliation: Tocagen Inc, San Diego, California, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Burnett
authors.affiliation: Department of Medicine, University of California Los Angeles (UCLA), Los Angeles, California, USA.
authors.forename: Akihito
authors.initials: A
authors.lastname: Inagaki
authors.affiliation: Tocagen Inc, San Diego, California, USA.
authors.forename: Dawn
authors.initials: D
authors.lastname: Jolson
authors.affiliation: Tocagen Inc, San Diego, California, USA.
authors.forename: Karin
authors.initials: K
authors.lastname: Amundson
authors.affiliation: Tocagen Inc, San Diego, California, USA.
authors.forename: Taylor
authors.initials: T
authors.lastname: Buckley
authors.affiliation: Tocagen Inc, San Diego, California, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Lohse
authors.affiliation: Tocagen Inc, San Diego, California, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Lin
authors.affiliation: Tocagen Inc, San Diego, California, USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Burrascano
authors.affiliation: Tocagen Inc, San Diego, California, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Ibanez
authors.affiliation: Department of Medicine, University of California Los Angeles (UCLA), Los Angeles, California, USA.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kasahara
authors.affiliation: Tocagen Inc, San Diego, California, USA.
authors.forename: Harry E
authors.initials: HE
authors.lastname: Gruber
authors.affiliation: Tocagen Inc, San Diego, California, USA. Electronic address: djolly@tocagen.com.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Jolly
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D043525:Cytosine Deaminase / Q000235:genetics / Q000378:metabolism; D005437:Flucytosine / Q000378:metabolism / Q000494:pharmacology; D005472:Fluorouracil / Q000378:metabolism / Q000494:pharmacology; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D009052:Leukemia Virus, Murine / Q000235:genetics*; D051379:Mice; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology; D020871:RNA Stability; D051381:Rats; D019076:Transgenes
chemical_list: D000970:Antineoplastic Agents; D005656:Fungal Proteins; D011355:Prodrugs; D005437:Flucytosine; D043525:Cytosine Deaminase; D005472:Fluorouracil