Toca 511 plus 5-fluorocytosine in combination with lomustine shows chemotoxic and immunotherapeutic activity with no additive toxicity in rodent glioblastoma models.

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.

[1]  R. Stupp,et al.  LB-05PHASE III TRIAL EXPLORING THE COMBINATION OF BEVACIZUMAB AND LOMUSTINE IN PATIENTS WITH FIRST RECURRENCE OF A GLIOBLASTOMA: THE EORTC 26101 TRIAL , 2015 .

[2]  K. Benkendorff,et al.  Combined Effects of Muricid Extract and 5-Fluorouracil on Intestinal Toxicity in Rats , 2015, Evidence-based complementary and alternative medicine : eCAM.

[3]  N. Kasahara,et al.  531. Intravenous Delivery of Toca 511 Gene Therapy in Combination with 5-Fluorocytosine for Intratumoral Production of 5-Fluorouracil in a Colon Cancer Metastasis Model , 2015 .

[4]  S. Taillibert,et al.  The future of high-grade glioma: Where we are and where are we going , 2015, Surgical neurology international.

[5]  N. Kasahara,et al.  Intravenous administration of retroviral replicating vector, Toca 511, demonstrates therapeutic efficacy in orthotopic immune-competent mouse glioma model. , 2015, Human gene therapy.

[6]  Eudocia Q Lee,et al.  Retrospective study of carmustine or lomustine with bevacizumab in recurrent glioblastoma patients who have failed prior bevacizumab. , 2014, Neuro-oncology.

[7]  J. Besalduch,et al.  xCELLigence system for real-time label-free monitoring of growth and viability of cell lines from hematological malignancies , 2014, OncoTargets and therapy.

[8]  P. Lowenstein,et al.  Temozolomide Does Not Impair Gene Therapy-Mediated Antitumor Immunity in Syngeneic Brain Tumor Models , 2014, Clinical Cancer Research.

[9]  W. Günzburg,et al.  Toca 511 gene transfer and 5-fluorocytosine in combination with temozolomide demonstrates synergistic therapeutic efficacy in a temozolomide-sensitive glioblastoma model , 2013, Cancer Gene Therapy.

[10]  E. Hsu,et al.  Regression of glioma tumor growth in F98 and U87 rat glioma models by the Nitrone OKN-007. , 2013, Neuro-oncology.

[11]  D. Lohse,et al.  Design and selection of Toca 511 for clinical use: modified retroviral replicating vector with improved stability and gene expression. , 2012, Molecular therapy : the journal of the American Society of Gene Therapy.

[12]  Harry E. Gruber,et al.  Brain tumor eradication and prolonged survival from intratumoral conversion of 5-fluorocytosine to 5-fluorouracil using a nonlytic retroviral replicating vector , 2011, Neuro-oncology.

[13]  Brian Salmons,et al.  Comparative evaluation of preclinical in vivo models for the assessment of replicating retroviral vectors for the treatment of glioblastoma , 2011, Journal of Neuro-Oncology.

[14]  K. Hopkins,et al.  Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high-grade glioma. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  José Weber Vieira de Faria,et al.  Treatment of recurrent glioblastoma with intra-arterial BCNU [1, 3-bis (2-chloroethyl)-1-nitrosourea]. , 2010, Arquivos de neuro-psiquiatria.

[16]  W. Mason,et al.  Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  G. Reifenberger,et al.  NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  Rolf F. Barth,et al.  Rat brain tumor models in experimental neuro-oncology: the C6, 9L, T9, RG2, F98, BT4C, RT-2 and CNS-1 gliomas , 2009, Journal of Neuro-Oncology.

[19]  Martin Glas,et al.  Long-term survival of patients with glioblastoma treated with radiotherapy and lomustine plus temozolomide. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  M. J. Bryant,et al.  A novel rat model for glioblastoma multiforme using a bioluminescent F98 cell line , 2008, Journal of Clinical Neuroscience.

[21]  R. O’Neill,et al.  Orthotopic transplantation of v-src-expressing glioma cell lines into immunocompetent mice: establishment of a new transplantable in vivo model for malignant glioma. , 2007, Journal of neurosurgery.

[22]  A. Clavreul,et al.  Effects of syngeneic cellular vaccinations alone or in combination with GM-CSF on the weakly immunogenic F98 glioma model , 2006, Journal of Neuro-Oncology.

[23]  B. Yalcin,et al.  Overdose of Lomustine: Report of Two Cases , 2004, Tumori.

[24]  R. Weiss,et al.  Nephrotoxicity of lomustine , 1985, Cancer Chemotherapy and Pharmacology.

[25]  Donald J Buchsbaum,et al.  Intratumoral 5-fluorouracil produced by cytosine deaminase/5-fluorocytosine gene therapy is effective for experimental human glioblastomas. , 2002, Cancer research.

[26]  H. Guchelaar,et al.  Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. , 2000, The Journal of antimicrobial chemotherapy.

[27]  J. Kim,et al.  B7.1 expression by the weakly immunogenic F98 rat glioma does not enhance immunogenicity , 2000, Gene Therapy.

[28]  J. Dichgans,et al.  Characterization of Tu-2449, a glioma cell line derived from a spontaneous tumor in GFAP-v-src-transgenic mice: comparison with established murine glioma cell lines. , 1999, International journal of oncology.

[29]  C. Schwartz.  Long-term survivors of childhood cancer: the late effects of therapy. , 1999, The oncologist.

[30]  J. Moreb,et al.  Multiorgan Failure Associated with Lomusttne Overdose , 1995, The Annals of pharmacotherapy.

[31]  C. Orosz,et al.  Phenotype and functional activity of tumor-infiltrating lymphocytes isolated from immunogenic and nonimmunogenic rat brain tumors. , 1991, Cancer research.

[32]  B. Issell,et al.  The nitrosoureas: carmustine (BCNU) and lomustine (CCNU). , 1982, Cancer treatment reviews.

[33]  Charles Tator,et al.  The effect of phenobarbital on the toxicity and tumoricidal activity of CCNU in a murine brain tumor model. , 1980, Journal of neurosurgery.

[34]  P. Gutin,et al.  DNA damage in the intracerebral rat gliosarcoma 9L treated with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea. , 1977, Cancer research.

[35]  H. Crissman,et al.  Comparative effects of three nitrosourea derivatives on mammalian cell cycle progression. , 1975, Cancer research.

[36]  R. Hahn,et al.  Brief Communication: Therapy of Advanced Colorectal Cancer With a Combination of 5-Flourouracil, Methyl-l,3-cis(2-chlorethyl)-1-nitrosourea, and Vincristine , 1975 .

[37]  R. Hahn,et al.  Therapy of advanced colorectal cancer with a combination of 5-fluorouracil, methyl-1,3-cis(2-chlorethyl)-1-nitrosourea, and vincristine. , 1975, Journal of the National Cancer Institute.