title: Toca 511 plus 5-fluorocytosine in combination with lomustine shows chemotoxic and immunotherapeutic activity with no additive toxicity in rodent glioblastoma models.
abstract: Toca 511, a gamma retroviral replicating vector encoding cytosine deaminase, used in combination with 5-fluorocytosine (5-FC) kills tumor by local production of 5-fluorouracil (5-FU), inducing local and systemic immunotherapeutic response resulting in long-term survival after cessation of 5-FC. Toca 511 and Toca FC (oral extended-release 5-FC) are under investigation in patients with recurrent high-grade glioma. Lomustine is a treatment option for patients with high-grade glioma.
  
  
  
  We investigated the effects of lomustine combined with Toca 511 + 5-FC in syngeneic orthotopic glioma models. Safety and survival were evaluated in immune-competent rat F98 and mouse Tu-2449 models comparing Toca 511 + 5-FC to lomustine + 5-FC or the combination of Toca 511 + 5-FC + lomustine. After intracranial implantation of tumor, Toca 511 was delivered transcranially followed by cycles of intraperitoneal 5-FC with or without lomustine at the first or fourth cycle.
  
  
  
  Coadministration of 5-FC with lomustine was well tolerated. In F98, combination Toca 511 + 5-FC and lomustine increased median survival, but "cures" were not achieved. In Tu-2449, combination Toca 511 + 5-FC and lomustine increased median survival and resulted in high numbers of cure. Rejection of tumor rechallenge occurred after treatment with Toca 511 + 5-FC or combined with lomustine, but not with lomustine + 5-FC. Mixed lymphocyte-tumor cell reactions using splenocytes from cured animals showed robust killing of target cells in an effector:target ratio-dependent manner with Toca 511 + 5-FC and Toca 511 + 5-FC + lomustine day 10.
  
  
  
  The combination of Toca 511 + 5-FC and lomustine shows promising efficacy with no additive toxicity in murine glioma models. Immunotherapeutic responses resulting in long-term survival were preserved despite lomustine-related myelosuppression.
authors.affiliation: Tocagen Inc., San Diego, California (K.Y., T.T.H., F.L.E., D.M., C.E.I., H.E.G., D.J.J., J.M.R.) kyagiz@tocagen.com.
authors.forename: Kader
authors.initials: K
authors.lastname: Yagiz
authors.affiliation: Tocagen Inc., San Diego, California (K.Y., T.T.H., F.L.E., D.M., C.E.I., H.E.G., D.J.J., J.M.R.).
authors.forename: Tiffany T
authors.initials: TT
authors.lastname: Huang
authors.affiliation: Tocagen Inc., San Diego, California (K.Y., T.T.H., F.L.E., D.M., C.E.I., H.E.G., D.J.J., J.M.R.).
authors.forename: Fernando
authors.initials: F
authors.lastname: Lopez Espinoza
authors.affiliation: Tocagen Inc., San Diego, California (K.Y., T.T.H., F.L.E., D.M., C.E.I., H.E.G., D.J.J., J.M.R.).
authors.forename: Daniel
authors.initials: D
authors.lastname: Mendoza
authors.affiliation: Tocagen Inc., San Diego, California (K.Y., T.T.H., F.L.E., D.M., C.E.I., H.E.G., D.J.J., J.M.R.).
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Ibañez
authors.affiliation: Tocagen Inc., San Diego, California (K.Y., T.T.H., F.L.E., D.M., C.E.I., H.E.G., D.J.J., J.M.R.).
authors.forename: Harry E
authors.initials: HE
authors.lastname: Gruber
authors.affiliation: Tocagen Inc., San Diego, California (K.Y., T.T.H., F.L.E., D.M., C.E.I., H.E.G., D.J.J., J.M.R.).
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Jolly
authors.affiliation: Tocagen Inc., San Diego, California (K.Y., T.T.H., F.L.E., D.M., C.E.I., H.E.G., D.J.J., J.M.R.).
authors.forename: Joan M
authors.initials: JM
authors.lastname: Robbins
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000473:pathology*; D043525:Cytosine Deaminase / Q000008:administration & dosage* / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005437:Flucytosine / Q000008:administration & dosage; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D005909:Glioblastoma / Q000473:pathology*; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods; D008130:Lomustine / Q000008:administration & dosage; D008297:Male; D051379:Mice; D051381:Rats; D011916:Rats, Inbred F344; D012190:Retroviridae
chemical_list: D008130:Lomustine; D005437:Flucytosine; D043525:Cytosine Deaminase
keywords: 5-FC; Toca 511; high-grade gliomas; immunotherapy; lomustine (CCNU)