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