|
Prodrug Activator: Toca 511 with 5-FC
Overview
For GBM, we intend to evaluate our CAGT™ Prodrug Activator product candidate, Toca 511 with 5-FC. Using this technology in preclinical experimental models, Toca 511 demonstrated the ability to transfer a therapeutic gene called CD to almost 100% of the cancer cells, without harming normal brain tissue. Once inside the cancer cells, this therapeutic gene behaved like a Trojan horse, and after exposure to 5-FC, the cancer cells with the gene were destroyed, without systemic side effects.
The first human study will be performed in patients whose GBM tumors have recurred following surgery, radiation and chemotherapy. These patients currently have no approved systemic curative treatment options and typically survive less than 6 months from recurrence. Three of the leading neurosurgery centers in the United States will be performing this first study. Following this Phase 1/2 study in patients with recurrent GBM, Tocagen plans to study this same Toca 511 with 5-FC in patients with primary GBM and in patients with inoperable GBM. Published data suggests that 5-fluorouracil, 5-FU (5-FU is the activated form of 5-FC) may act synergistically with radiation therapy when used in certain tumors.
What is a Prodrug Activator?
Toca 511 is a live virus that has the ability to carry a therapeutic gene to cancer cells (see Technology). The therapeutic gene carried by the Toca 511 virus is called cytosine deaminase (CD). Once in the cancer cell, the CD gene directs the production of an enzyme (protein) that converts the prodrug, 5-FC, to the anticancer drug, 5-FU. This is why Toca 511 is referred to as a Prodrug Activator - the gene Toca 511 delivers converts an inactive, prodrug, 5-FC, to an active drug, 5-FU, that can kill cancer cells.
What is 5-FC?
5-FC, also known as flucytosine, is an approved oral antibiotic that has been used for almost 40 years to treat serious fungal infections. 5-FC is taken orally which means that patients do not need to stay in the hospital to receive this drug. 5-FC has the unique ability to cross the blood brain barrier and penetrate brain tissue, which is why it is often used to treat fungal brain infections. This also makes 5-FC particularly well suited to our needs in treating brain cancer.
How Do Toca 511 and 5-FC Work Together to Fight Brain Cancer?
Researchers have shown that if the Toca 511 virus is injected into mouse cancerous tumors, the virus spreads the CD gene throughout the cancer. Researchers have also shown that in the mouse cancer cells containing the CD gene, 5-FC is converted to 5-FU, which then kills the cancer. If the mouse is given only a single course of 5-FC, the animal will survive for twice as long as animals not given 5-FC. Interestingly, when the 5-FC treated animals expired, it was found that the cancer still contained the Toca 511 virus and the CD gene. This highlights an important feature of the Toca 511 virus - it permanently integrates into the DNA of the cancer cells. Because of this unique property, investigators theorized that the mice in these studies might respond even better to repeated cycles of 5-FC, and this is exactly what was shown (see Tai et al. (2005). Molecular Therapy. 12: 842-851). In numerous experiments in mice, almost all animals who received the highest dose of Toca 511 once combined with mutiple cycles of 5-FC lived for as long as they were treated with 5-FC.
Evaluating Toca 511 with 5-FC in Brain Cancer Patients
Based on what was learned from animal studies, physicians plan to administer a single injection of Toca 511 into the brain cancer of patients enrolled in clinical trials. This injection will be made through a small hole in the skull, called a burr hole. This procedure is very similar to what patients experience when they have a brain cancer biopsy. For 3 weeks the virus will be allowed to spread through the cancer, carrying the CD gene with it. Patients will then take 5-FC by mouth for 6 days, and these 6-day courses of 5-FC will be repeated every month for 6 months. The size of the cancerous tumor will be measured using MRI scans at approximately 2-month intervals.
Product Candidates
Prodrug Activator: Toca 511
Programs
Brain Cancer (GBM)
Also see:
Breakthrough Technology
|
