BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
BACKGROUND: 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. METHODS: 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 mouseTu-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. RESULTS: 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. CONCLUSION: The combination of Toca 511 + 5-FC and lomustine shows promising efficacy with no additive toxicity in murineglioma models. Immunotherapeutic responses resulting in long-term survival were preserved despite lomustine-related myelosuppression.
Authors: Marianela Candolfi; Kader Yagiz; Mia Wibowo; Gabrielle E Ahlzadeh; Mariana Puntel; Homayon Ghiasi; Neha Kamran; Christopher Paran; Pedro R Lowenstein; Maria G Castro Journal: Clin Cancer Res Date: 2014-02-05 Impact factor: 12.531
Authors: Wolfgang Wick; Vinay K Puduvalli; Marc C Chamberlain; Martin J van den Bent; Antoine F Carpentier; Lawrence M Cher; Warren Mason; Michael Weller; Shengyan Hong; Luna Musib; Astra M Liepa; Donald E Thornton; Howard A Fine Journal: J Clin Oncol Date: 2010-02-01 Impact factor: 44.544
Authors: T T Huang; J Hlavaty; D Ostertag; F L Espinoza; B Martin; H Petznek; M Rodriguez-Aguirre; C E Ibañez; N Kasahara; W Gunzburg; H E Gruber; D Pertschuk; D J Jolly; J M Robbins Journal: Cancer Gene Ther Date: 2013-08-23 Impact factor: 5.987
Authors: Roger Yazbeck; Ruth Lindsay; Catherine A Abbott; Kirsten Benkendorff; Gordon S Howarth Journal: Evid Based Complement Alternat Med Date: 2015-05-13 Impact factor: 2.629
Authors: Victor A Levin; Lauren E Abrey; Timothy P Heffron; Peter J Tonge; Arvin C Dar; William A Weiss; James M Gallo Journal: CNS Oncol Date: 2017-07-18
Authors: Timothy F Cloughesy; Joseph Landolfi; Michael A Vogelbaum; Derek Ostertag; James B Elder; Stephen Bloomfield; Bob Carter; Clark C Chen; Steven N Kalkanis; Santosh Kesari; Albert Lai; Ian Y Lee; Linda M Liau; Tom Mikkelsen; Phioanh Nghiemphu; David Piccioni; William Accomando; Oscar R Diago; Daniel J Hogan; Dawn Gammon; Noriyuki Kasahara; Thian Kheoh; Douglas J Jolly; Harry E Gruber; Asha Das; Tobias Walbert Journal: Neuro Oncol Date: 2018-09-03 Impact factor: 12.300
Authors: Kader Yagiz; Maria E Rodriguez-Aguirre; Fernando Lopez Espinoza; Tiffany T Montellano; Daniel Mendoza; Leah A Mitchell; Carlos E Ibanez; Noriyuki Kasahara; Harry E Gruber; Douglas J Jolly; Joan M Robbins Journal: Mol Ther Oncolytics Date: 2017-12-05 Impact factor: 7.200