Phase 1 trial of vocimagene amiretrorepvec and 5-fluorocytosine for recurrent high-grade glioma

Toca 511 and Toca FC show promising results in treating recurrent high-grade glioma, and a specific molecular signature correlates with treatment-related survival. Tag-team attack on glioma Toca FC (extended-release 5-fluorocytosine) and Toca 511 (vocimagene amiretrorepvec) are an investigational therapeutic combination for glioma, consisting of two parts: a prodrug that is inactive on its own and a modified virus that infects the tumor and delivers an enzyme, which then activates the drug and allows it to kill the glioma cells. Cloughesy et al. tested this therapy in 45 human patients with recurrent or progressive high-grade glioma and discovered that the treatment was well tolerated and improved survival compared to an external control group. In addition, the authors identified a gene signature that correlated with response to the treatment, which may help identify the patients most likely to benefit from this approach. Toca 511 (vocimagene amiretrorepvec) is an investigational nonlytic, retroviral replicating vector (RRV) that delivers a yeast cytosine deaminase, which converts subsequently administered courses of the investigational prodrug Toca FC (extended-release 5-fluorocytosine) into the antimetabolite 5-fluorouracil. Forty-five subjects with recurrent or progressive high-grade glioma were treated. The end points of this phase 1, open-label, ascending dose, multicenter trial included safety, efficacy, and molecular profiling; survival was compared to a matching subgroup from an external control. Overall survival for recurrent high-grade glioma was 13.6 months (95% confidence interval, 10.8 to 20.0) and was statistically improved relative to an external control (hazard ratio, 0.45; P = 0.003). Tumor samples from subjects surviving more than 52 weeks after Toca 511 delivery disproportionately displayed a survival-related mRNA expression signature, identifying a potential molecular signature that may correlate with treatment-related survival rather than being prognostic. Toca 511 and Toca FC show excellent tolerability, with RRV persisting in the tumor and RRV control systemically. The favorable assessment of Toca 511 and Toca FC supports confirmation in a randomized phase 2/3 trial (NCT02414165).

[1]  G. TwittyChris,et al.  Retroviral Replicating Vectors Deliver Cytosine Deaminase Leading to Targeted 5-Fluorouracil-Mediated Cytotoxicity in Multiple Human Cancer Types. , 2016 .

[2]  D. Jolly,et al.  Retroviral Replicating Vectors Deliver Cytosine Deaminase Leading to Targeted 5-Fluorouracil-Mediated Cytotoxicity in Multiple Human Cancer Types. , 2016, Human gene therapy methods.

[3]  Naoya Hashimoto,et al.  Immunotherapy response assessment in neuro-oncology: a report of the RANO working group. , 2015, The Lancet. Oncology.

[4]  Chibo Hong,et al.  DNA Methylation and Somatic Mutations Converge on the Cell Cycle and Define Similar Evolutionary Histories in Brain Tumors. , 2015, Cancer cell.

[5]  Geoffrey Lee,et al.  A novel literature-based approach to identify genetic and molecular predictors of survival in glioblastoma multiforme: Analysis of 14,678 patients using systematic review and meta-analytical tools , 2015, Journal of Clinical Neuroscience.

[6]  H. Wheeler,et al.  Molecular Heterogeneity in Glioblastoma: Potential Clinical Implications , 2015, Front. Oncol..

[7]  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.

[8]  Peter Canoll,et al.  MRI-localized biopsies reveal subtype-specific differences in molecular and cellular composition at the margins of glioblastoma , 2014, Proceedings of the National Academy of Sciences.

[9]  R. Vernhout,et al.  Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. , 2014, The Lancet. Oncology.

[10]  P. Álvarez,et al.  Prognostic impact of MGMT promoter methylation and MGMT and CD133 expression in colorectal adenocarcinoma , 2014, BMC Cancer.

[11]  Andrew E. Sloan,et al.  Molecular Subtypes of Glioblastoma Are Relevant to Lower Grade Glioma , 2014, PloS one.

[12]  K. Hoang-Xuan,et al.  Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. , 2014, The New England journal of medicine.

[13]  H. Will,et al.  SPOC1-Mediated Antiviral Host Cell Response Is Antagonized Early in Human Adenovirus Type 5 Infection , 2013, PLoS pathogens.

[14]  D. Haussler,et al.  The Somatic Genomic Landscape of Glioblastoma , 2013, Cell.

[15]  T. Mikkelsen,et al.  Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  Cole Trapnell,et al.  TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions , 2013, Genome Biology.

[17]  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.

[18]  R. Stupp,et al.  New prognostic factors and calculators for outcome prediction in patients with recurrent glioblastoma: a pooled analysis of EORTC Brain Tumour Group phase I and II clinical trials. , 2012, European journal of cancer.

[19]  M. Hanna,et al.  MethylMeter(r): A Quantitative, Sensitive, and Bisulfite-Free Method for Analysis of DNA Methylation , 2012 .

[20]  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.

[21]  Susan M. Chang,et al.  Is surgery at progression a prognostic marker for improved 6-month progression-free survival or overall survival for patients with recurrent glioblastoma? , 2011, Neuro-oncology.

[22]  Joel H. Saltz,et al.  The Proneural Molecular Signature Is Enriched in Oligodendrogliomas and Predicts Improved Survival among Diffuse Gliomas , 2010, PloS one.

[23]  Susan Chang,et al.  Phase III randomized trial of CED of IL13-PE38QQR vs Gliadel wafers for recurrent glioblastoma. , 2010, Neuro-oncology.

[24]  A. Abernethy,et al.  Development of the patient-reported version of the common terminology criteria for adverse events (PRO-CTCAE). , 2010 .

[25]  J. Vincent,et al.  5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. , 2010, Cancer research.

[26]  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.

[27]  S. Gabriel,et al.  Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. , 2010, Cancer cell.

[28]  T. Mikkelsen,et al.  Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  E. Kremmer,et al.  SPOC1: a novel PHD-containing protein modulating chromatin structure and mitotic chromosome condensation , 2009, Journal of Cell Science.

[30]  P. Sharp,et al.  Proliferating Cells Express mRNAs with Shortened 3' Untranslated Regions and Fewer MicroRNA Target Sites , 2008, Science.

[31]  N. Matsubara,et al.  Depletion of O6-methylguanine-DNA methyltransferase by O6-benzylguanine enhances 5-FU cytotoxicity in colon and oral cancer cell lines. , 2007, Oncology reports.

[32]  Takahiro Kimura,et al.  Tumor-Selective Gene Expression in a Hepatic Metastasis Model after Locoregional Delivery of a Replication-Competent Retrovirus Vector , 2006, Clinical Cancer Research.

[33]  A. Sonabend,et al.  Oncolytic adenoviral therapy for glioblastoma multiforme. , 2006, Neurosurgical focus.

[34]  M. Chamberlain.  Treatment options for glioblastoma. , 2006, Neurosurgical focus.

[35]  Thomas C. Chen,et al.  Use of replication-competent retroviral vectors in an immunocompetent intracranial glioma model. , 2006, Neurosurgical focus.

[36]  D. Cunningham,et al.  5-Fluorouracil can cross brain–blood barrier and cause encephalopathy: should we expect the same from capecitabine? A case report on capecitabine-induced central neurotoxicity progressing to coma , 2006, Cancer Chemotherapy and Pharmacology.

[37]  D. Klatzmann,et al.  Beyond oncolytic virotherapy: replication-competent retrovirus vectors for selective and stable transduction of tumors. , 2005, Current gene therapy.

[38]  Martin J. van den Bent,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[39]  R. Mirimanoff,et al.  MGMT gene silencing and benefit from temozolomide in glioblastoma. , 2005, The New England journal of medicine.

[40]  N. Rainov.  A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. , 2000, Human gene therapy.

[41]  Scar,et al.  Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. , 2000, The New England journal of medicine.

[42]  H. Yoshiji,et al.  Bystander effect caused by cytosine deaminase gene and 5-fluorocytosine in vitro is substantially mediated by generated 5-fluorouracil. , 1998, Anticancer research.

[43]  C. Richards,et al.  Metabolism of 5-fluorocytosine to 5-fluorouracil in human colorectal tumor cells transduced with the cytosine deaminase gene: significant antitumor effects when only a small percentage of tumor cells express cytosine deaminase. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[44]  John H. Block,et al.  Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry , 1991 .

[45]  A. Pegg,et al.  Mammalian O6-alkylguanine-DNA alkyltransferase: regulation and importance in response to alkylating carcinogenic and therapeutic agents. , 1990, Cancer research.

[46]  T. Cascino,et al.  Response criteria for phase II studies of supratentorial malignant glioma. , 1990, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.