Glioblastoma multiforme (GBM), the most common primary brain tumor in adults, is associated with a dismal prognosis of only 12-15 months despite aggressive surgery, radiation, and chemotherapy. The lack of effective treatment options has made this disease a target for new strategies such as gene therapy. However, the only major Phase III clinical trial of gene therapy, involving the use of conventional replication-defective retrovirus vectors in GBM patients, resulted in disappointingly low and therapeutically inadequate transduction levels on the order of only 0.02%. The inability of standard replication-defective retroviral vectors to achieve effective transduction of tumors in vivo is therefore a major obstacle to gene therapy for gliomas. The use of replication-competent vectors for gene transfer would be more efficient, as each tumor cell that is successfully transduced would itself become a virus-producing cell, sustaining further transduction events even after initial administration. We have previously demonstrated that direct intratumoral injection of murine leukemia virus (MLV)-based replication-competent retrovirus (RCR) vector preparations can achieve tremendously efficient suicide gene transfer in gliomas, with transduction stringently restricted to the actively dividing tumor cells without evidence of significant spread to extratumoral sites, and resulting in significantly prolonged survival upon prodrug administration, without detectable systemic side effects. In collaboration with neurosurgery groups at UCLA, USC, and UCSF, and the National Gene Vector Laboratory (NGVL), here we propose to develop and implement clinical grade RCR vector production (Aim 1), to validate these clinical grade vectors by confirmatory testing of therapeutic efficacy in rodent intracranial glioma models, and in larger canine models (Aim'2), to optimize monitoring methodologies as mandated by FDA guidelines, and to develop clinical trial protocols (Aim 3). Hence, we propose to perform these necessary preclinical translational studies through this U01 mechanism, with the final goal of filing an IND and obtaining approval from the FDA to initiate clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01NS059821-01A2
Application #
7826184
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Mcgavern, Linda
Project Start
2010-06-01
Project End
2014-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
1
Fiscal Year
2010
Total Cost
$1,026,229
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Lin, Amy H; Twitty, Christopher G; Burnett, Ryan et al. (2017) Retroviral Replicating Vector Delivery of miR-PDL1 Inhibits Immune Checkpoint PDL1 and Enhances Immune Responses In Vitro. Mol Ther Nucleic Acids 6:221-232
Cloughesy, Timothy F; Landolfi, Joseph; Hogan, Daniel J et al. (2016) Phase 1 trial of vocimagene amiretrorepvec and 5-fluorocytosine for recurrent high-grade glioma. Sci Transl Med 8:341ra75
Lin, Amy H; Liu, Yanzheng; Burrascano, Cynthia et al. (2016) Extensive Replication of a Retroviral Replicating Vector Can Expand the A Bulge in the Encephalomyocarditis Virus Internal Ribosome Entry Site and Change Translation Efficiency of the Downstream Transgene. Hum Gene Ther Methods 27:59-70
Huang, Tiffany T; Parab, Shraddha; Burnett, Ryan et al. (2015) Intravenous administration of retroviral replicating vector, Toca 511, demonstrates therapeutic efficacy in orthotopic immune-competent mouse glioma model. Hum Gene Ther 26:82-93
Lin, Amy H; Timberlake, Nina; Logg, Christopher R et al. (2014) MicroRNA 142-3p attenuates spread of replicating retroviral vector in hematopoietic lineage-derived cells while maintaining an antiviral immune response. Hum Gene Ther 25:759-71
Burnett, Ryan; Ibañez, Carlos E; Pettersson, Pär L et al. (2014) Maintaining therapeutic activity in the operating room: compatibility of a gamma-retroviral replicating vector with clinical materials and biofluids. Mol Ther Methods Clin Dev 1:14024
Takahashi, Masamichi; Valdes, Gilmer; Hiraoka, Kei et al. (2014) Radiosensitization of gliomas by intracellular generation of 5-fluorouracil potentiates prodrug activator gene therapy with a retroviral replicating vector. Cancer Gene Ther 21:405-410
Yin, D; Zhai, Y; Gruber, H E et al. (2013) Convection-enhanced delivery improves distribution and efficacy of tumor-selective retroviral replicating vectors in a rodent brain tumor model. Cancer Gene Ther 20:336-41
Ostertag, Derek; Amundson, Karin K; Lopez Espinoza, Fernando et al. (2012) Brain tumor eradication and prolonged survival from intratumoral conversion of 5-fluorocytosine to 5-fluorouracil using a nonlytic retroviral replicating vector. Neuro Oncol 14:145-59
Lemp, Nathan A; Hiraoka, Kei; Kasahara, Noriyuki et al. (2012) Cryptic transcripts from a ubiquitous plasmid origin of replication confound tests for cis-regulatory function. Nucleic Acids Res 40:7280-90

Showing the most recent 10 out of 11 publications