title: Intravenous administration of retroviral replicating vector, Toca 511, demonstrates therapeutic efficacy in orthotopic immune-competent mouse glioma model.
abstract: Toca 511 (vocimagene amiretrorepvec), a nonlytic, amphotropic retroviral replicating vector (RRV), encodes and delivers a functionally optimized yeast cytosine deaminase (CD) gene to tumors. In orthotopic glioma models treated with Toca 511 and 5-fluorocytosine (5-FC) the CD enzyme within infected cells converts 5-FC to 5-fluorouracil (5-FU), resulting in tumor killing. Toca 511, delivered locally either by intratumoral injection or by injection into the resection bed, in combination with subsequent oral extended-release 5-FC (Toca FC), is under clinical investigation in patients with recurrent high-grade glioma (HGG). If feasible, intravenous administration of vectors is less invasive, can easily be repeated if desired, and may be applicable to other tumor types. Here, we present preclinical data that support the development of an intravenous administration protocol. First we show that intravenous administration of Toca 511 in a preclinical model did not lead to widespread or uncontrolled replication of the RVV. No, or low, viral DNA was found in the blood and most of the tissues examined 180 days after Toca 511 administration. We also show that RRV administered intravenously leads to efficient infection and spread of the vector carrying the green fluorescent protein (GFP)-encoding gene (Toca GFP) through tumors in both immune-competent and immune-compromised animal models. However, initial vector localization within the tumor appeared to depend on the mode of administration. Long-term survival was observed in immune-competent mice when Toca 511 was administered intravenously or intracranially in combination with 5-FC treatment, and this combination was well tolerated in the preclinical models. Enhanced survival could also be achieved in animals with preexisting immune response to vector, supporting the potential for repeated administration. On the basis of these and other supporting data, a clinical trial investigating intravenous administration of Toca 511 in patients with recurrent HGG is currently open and enrolling.
authors.affiliation: 1 Tocagen , San Diego, CA 92109.
authors.forename: Tiffany T
authors.initials: TT
authors.lastname: Huang
authors.forename: Shraddha
authors.initials: S
authors.lastname: Parab
authors.forename: Ryan
authors.initials: R
authors.lastname: Burnett
authors.forename: Oscar
authors.initials: O
authors.lastname: Diago
authors.forename: Derek
authors.initials: D
authors.lastname: Ostertag
authors.forename: Florence M
authors.initials: FM
authors.lastname: Hofman
authors.forename: Fernando Lopez
authors.initials: FL
authors.lastname: Espinoza
authors.forename: Bryan
authors.initials: B
authors.lastname: Martin
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Ibañez
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kasahara
authors.forename: Harry E
authors.initials: HE
authors.lastname: Gruber
authors.forename: Daniel
authors.initials: D
authors.lastname: Pertschuk
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Jolly
authors.forename: Joan M
authors.initials: JM
authors.lastname: Robbins
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000032:analysis; D000963:Antimetabolites / Q000494:pharmacology; D001932:Brain Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D002986:Clinical Trials as Topic; D043525:Cytosine Deaminase / Q000235:genetics* / Q000378:metabolism / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005437:Flucytosine / Q000494:pharmacology; D005656:Fungal Proteins / Q000235:genetics* / Q000378:metabolism / Q000493:pharmacokinetics; D015870:Gene Expression; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D005910:Glioma / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D051379:Mice; D008819:Mice, Nude; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000493:pharmacokinetics; D012190:Retroviridae / Q000235:genetics* / Q000276:immunology; D016019:Survival Analysis; D014018:Tissue Distribution
chemical_list: D057134:Antibodies, Neutralizing; D000963:Antimetabolites; D005656:Fungal Proteins; D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins; D005437:Flucytosine; D043525:Cytosine Deaminase