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. Therefore, in collaboration with neurosurgery groups at UCLA, USC, and UCSF, and the National Gene Vector Biorepository (NGVB), here we propose to optimize and implement clinical grade RCR vector production and release testing (Aim 1), to re-validate these clinical grade vectors by confirmatory testing of therapeutic efficacy in at least 2 intracranial glioma models from different species per FDA stipulations, as well as re-validation of preclinical toxicology and follow-up monitoring assays as mandated by FDA guidelines (Aim 2), and to evaluate convection-enhanced delivery and non-invasive NMR imaging methodologies and develop clinical trial protocols (Aim 3). 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.
Glioblastoma multiforme (GBM;WHO Grade IV malignant glioma), is the most common form of malignant brain tumor in adults, accounting for 50-60% of primary brain tumors, and 7-10% of childhood intracranial neoplasms. Despite major improvements in neuroimaging, neurosurgery, radiotherapy, and supportive care, the overall prognosis for GBMs is still only 12-15 months, and current treatments only delay recurrence. Hence, there is an unmet need to develop effective new approaches against this devastating disease.
|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|
|Takahashi, M; Valdes, G; Hiraoka, K 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 21:405-10|
|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|
|Logg, Christopher R; Robbins, Joan M; Jolly, Douglas J et al. (2012) Retroviral replicating vectors in cancer. Methods Enzymol 507:199-228|