Abstract Date: 4/7/2014
Manish K. Aghi, MD (San Francisco, CA)
Michael Vogelbaum, MD (Cleveland)
Alastair Martin, PhD
Geoffrey Bates, PhD
John Bringas (San Francisco)
Harry Gruber (San Diego)
Cathy Brewer (Cleveland)
Krystof Bankiewicz (San Francisco)
Dan Pertschuk (San Diego)
Glioblastoma gene therapy has been limited by suboptimal intratumoral spatial distribution of virus. A Phase 1 trial is being conducted in patients with recurrent glioblastoma with a replicating retrovirus Toca 511, in which a cytosine deaminase (CD) transgene converts prodrug 5-fluorocytosine (5-FC) to anti-cancer drug 5-fluorouracil.
Toca 511 was injected intratumorally using a brain biopsy needle (BBN) or with real-time MRI-guided convection-enhanced delivery (CED). Four weeks later, patients received 5-FC every 4 weeks along with serial MRIs until progression. Some patients who progressed underwent post-treatment resection.
Five Toca 511 doses, escalated by half logs, were injected via BBN in 22 patients. Analysis of post-5-FC resected tumors in some patients showed viral protein, DNA, and RNA including CD, but with viral genes only detected in limited amounts and not in all samples (up to ~2000 DNA copies/μg tissue). MRI immediately after injecting Toca 511 plus gadolinium showed imprecise delivery. Therefore, real-time MRI-guided CED was implemented. In 7 patients at a single center (average tumor volume=10.5 cm3, range=2.6-25.0 cm3) 12-70% of tumor volume (mean=45%) was infused. A 14-gauge cannula allowed flow rates up to 50 microL/min without reflux, and 3.1 mL was delivered to 1-3 targets with improved spatial distribution revealed by Vd (volume distribution)/Vi (volume infusion) ratios averaging 1.6 (range=1-3.5). Resection from one patient two months post-CED and one course of Toca FC (extended-release 5-FC) revealed >90,000 viral DNA copies/μg tissue in the infusion location. Histologic necrosis and radiographic regression was also observed post-Toca FC dosing.
Real-time MRI-guided CED of Toca 511 was well tolerated and led to 45-fold more viral DNA detected at subsequent resection than BBN injection and associated tumor response.
Article ID: AA-28632