Current and future strategies for treatment of gliomas: Is gene therapy the solution
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Transcript of Current and future strategies for treatment of gliomas: Is gene therapy the solution
Current and future strategies for treatment of gliomas: Is gene therapy the solution
John E. Trusheim, MDNov 5th, 2016
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GBM: an overview
• Most prevalent and lethal of all brain tumors
• Standard treatment is surgery, followed by radiation therapy or combined radiation therapy and chemotherapy
• Recurrences treated with bevacizumab
• Median survival in glioblastoma patients is about 14.6 months and two-year survival is 30%
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Glioma Survival
5 years
10 years
Grade I Grade II Grade III Grade IV
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Gene therapy for Gliomas
• Major approaches employed for gene therapy of GBM: (1) delivery of suicide genes to convert prodrugs in the tumor and achieve tumor
cell death; (2) delivery of cytokine genes to activate and attract immune cells against the
tumor; (3) delivery of tumor-suppressor genes to reprogram tumor cells into apoptosis; and (4) delivery of conditionally-replicating viruses to specifically lyse tumor cells while sparing normal tissue.
• Approach was found to be well-tolerated but ineffective as poor spread across tumor cells
• Lack of efficacy attributed to inability to infect a majority of cancer cells
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Ongoing GBM Gene Therapy Studies
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Toca 511 advantages over other viruses• Exclusively targets cancer cells
• Cancer cells are not killed due to ‘infection’Toca 511 is able to carry replicating virus and spread through the tumor
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Phase I data
• 45 patients rGBM treated• Survival compared to an external control group• OS 13.6 months (95% confidence interval, 10.8 to 20.0) statistically improved in
comparison to external control• Toca 511 and Toca FC showed excellent tolerability
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Tocagen gene therapy protocol (Phase II/III)
A Phase 2/3 Randomized, Open Label Study of Toca 511, a ‑Retroviral Replicating Vector, Combined With Toca FC versus Standard of Care in Subjects Undergoing Planned Resection
for Recurrent Glioblastoma or Anaplastic Astrocytoma
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High 5-FU in tumor with very short half-life, killing only infected and neighboring tumor cells
Toca 511 administered
Normal Tissue
Tumor
Toca FC(5-FC)
5-FU
CD
5-FU kills dividing tumor cells
Toca 511 spreads selectively through
cancer cells
Toca FC taken orally Converts to 5-FU
CD proteinnormal brainToca 511
necrosis lymphocytes
Toca 511 & FC mode of action
gag pol envU5U3 U5RU3
Cytosine Deaminase CD
Administration and Activation
Toca 511 is an RRV expressing yeast CD gene to convert 5-FC to 5-FU
R
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Study Schema
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Study design
Investigational Product, Dosage and Mode of Administration:
(Experimental Arm)Toca 511 –up to 4 mL injected into the wall of resected cavity (intracranial injections) after tumor resectionToca FC - Oral tablets, 220 mg/kg/day x 7 days during 1st cycle, repeated every 6 weeks
(Standard of Care Arm) Bevacizumab (IV, 10 mg/m2 every 2 weeks)
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Toca 511 handling precautions
• Toca 511 is a live, replication competent retroviral vector. • Precautions appropriate for a Risk Group 2 (RG 2) virus should be
followed. • Biosafety Level 2 (BSL 2) precautions should be followed when handling
and disposing of Toca 511. • Also, each local site’s Institutional Biosafety Committee should assess
training for appropriate individuals prior to their involvement with this study.
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Thank you