How it works
Toca 511 & Toca FC is an innovative therapy developed by Tocagen Inc, based in San Diego. Gene therapy involves the delivery of genes into cancer cells by viral vectors (carriers). The Toca 511/Toca FC system is something of a hybrid therapy which combines a virally delivered gene therapy with an integrated chemotherapy which is central to the functioning of the Toca system. Toca 511 & Toca FC is essentially a method of delivering a highly selective, tumour-specific dose of chemotherapy to dividing tumour cells without the systemic toxicity which almost always occurs with standard chemotherapy techniques.
This high degree of selectivity is acheived by intra-tumoral injection of a retroviral replicating vector (RRV) based on the murine leukemia virus (MLV). This viral vector, called Toca 511, has been engineered to infect dividing cells, without infection of normal tissues. It is also selective for the immunocompromised microenvironment typically found in brain tumours. Furthermore, it has a built-in sensitivity to oral antiviral drugs, providing controllability in the event of viral escape into normal tissue. This virus does not cause an inflammatory immune response, allowing widespread infection of tumour cells (1).
Toca 511 is non-lytic, which means it does not kill the cell it infects. Instead, it transfects, or transmits a transgene to the cell. This gene is derived from yeast and encodes an enzyme called cytosine deaminase (CD) which is able to convert an anti-fungal drug called 5-fluorocytosine (5-FC), also called flucytosine, into a deadly chemotherapy compound called 5-fluorouracil (5-FU). 5-fluorocytosine is an orally available agent which can easily cross the blood-brain barrier (1). Tocagen has developed an extended release formula of 5-FC, called Toca FC, which is used in conjuction with their Toca 511 retroviral vector. This method allows high levels of 5-fluorouracil to locally accumulate and destroy malignant cells, whereas systemic chemotherapy with 5-fluorouracil can’t achieve these levels in the brain due to dose-limiting toxicities in gastrointestinal and bone marrow cells (2).
In trials, recurrent glioma patients are first injected with Toca 511 via a biopsy needle into the tumour site. Alternatively, the tumour cavity may be injected with Toca 511 during surgical resection of the tumour. After four weeks, enough time to allow the virus to spread throughout the tumour cells, Toca FC is taken orally 3 times per day with meals (2) for six days followed by a rest period. The four week cycle is repeated for up to six cycles.
While previous gene therapies used non-replicating viral vectors due to safety concerns, the method proved to be ineffective. Current replicating vectors are engineered to selectively infect malignant cells without spreading to normal body tissues. The replicating viral vectors act as a reservoir for continuous infection of tumour cells and transmission of the cytosine deaminase gene.
Toca 511 & Toca FC therapy has been tested in two different immunocompetent mouse models of glioma. In the longest study, 9 out of 10 mice receiving the optimal dose of Toca 511 with 5-FC survived until the study was terminated at 180 days. In contrast, most of the mice treated with Toca 511 without 5-FC (the control group) were dead before day 60, with a median survival of 33 days (3).
These results in mice are very encouraging. Most therapeutic studies using rodent glioma models merely show a slowing of tumour growth, but typically don’t show a growth arrest or shrinkage of tumours. In the most effective immunotherapy studies done with immunocompetent mouse models, up to 50% or 75% of animals survive to 100 days while all control animals died by days 40-50 (4). The Toca 511/5-FC study in mice with a 6-month (180 day) survival rate of 90% is therefore one of the most impressive studies yet seen using immunocompetent mouse models of glioma.
On this basis, three phase I clinical trials of Toca 511 & Toca FC are underway for recurrent high-grade (WHO III and IV) brain tumour patients. The first began in June 2010, studying transcranial administration of Toca 511 with a biopsy needle, without surgical resection of the tumour. A similar trial, started in January 2012, is studying Toca 511 injected into the tumour cavity following surgical resection of the tumour. A third trial, started in October 2013, is testing intravenous injection of Toca 511. Toca FC is administered orally in all three trials.
These trials are small dose-escalation studies currently recruiting patients at UCLA, UCSD, UCSF, Henry Ford Hospital (Detroit), Cleveland Clinic Foundation, JFK Medical Center (New Jersey), and Ohio State University. Additionally, the Swedish Neuroscience Institute (Seattle) is active in one of the trials but is not currently recruiting.
At the 2013 annual meeting of the Society for Neuro-Oncology (see abstract 006), the investigators of the Toca 511 trials reported that the therapy is well tolerated, selectively infects cancer cells, causes expression of the CD transgene, creates a reservoir for continuous viral production, and in some cases has caused tumour necrosis, shrinkage of progressive tumours, and symptomatic improvements, though no numerical data has yet been published.
November 23, 2014
The first preliminary clinical results of Toca 511 therapy were reported by Timothy Cloughesy at the 2014 annual meeting of the Society for Neuro-Oncology (SNO) which recently took place in Miami. Dr. Cloughesy presented the data from the trial of Toca 511 along with surgical tumour resection. The data cutoff was September 26, 2014. This trial is a dose escalation study, which has included 36 patients across 6 vector (Toca 511) dose cohorts. For the GBM patients, median survival from the start of therapy was 51 weeks (nearly 12 months). Including only patients at first or second recurrence median survival is 59 weeks (13.6 months). Progression-free survival rate at six months is 27% for the GBM patients. Of the 29 patients evaluable for response, 4 patients had a partial response, 7 had stable disease, and 18 had progressive disease. Dr. Cloughesy stated that expression of virus resistance genes in the tumour were anti-correlated with survival following Toca 511 therapy. As this trial is open to patients with multiple prior recurrences, a median survival from start of therapy of 12 months is a positive outcome.
Further information including videos may be found at virtualtrials.com/tocagen
Design and selection of Toca 511 for clinical use: modified retroviral replicating vector with improved stability and gene expression. Perez et al. 2012.
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Products in Development For Malignant Brain Tumors. Tocagen.com
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Brain tumor eradication and prolonged survival from intratumoral conversion of 5-fluorocytosine to 5-fluorouracil using a nonlytic retroviral replicating vector. Ostertag et al. 2012.
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Effective immunotherapy against murine gliomas using type 1 polarizing dendritic cells–significant roles of CXCL10. Fujita et al. 2009.
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