Gene Therapy Shows Early Efficacy Against Recurrent Brain Cancer

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“It is notable that the survival benefit was seen across a range of patients and not just limited to patients with specific genetic mutations.”
— Clark Chen, MD, PhD

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MORE THAN A QUARTER of patients with recurrent high-grade glioma treated with the retroviral vector Toca 511 and the prodrug of the chemotherapy fluorouracil (5-FU), Toca FC, were alive more than 3 years after treatment, according to data from a subset of patients in a phase I clinical trial, Toca 5, presented at the American Association for Cancer Research–National Cancer Institute–European Organisation for Research and Treatment of Cancer International Conference on Molecular Targets and Cancer Therapeutics by Clark Chen, MD, PhD, of the University of Minnesota Medical School.1 

“Given the deadly nature of this disease, 3-year survival is rarely reported in the recurrent setting. It is notable that the survival benefit was seen across a range of patients and not just limited to patients with specific genetic mutations,” said Dr. Chen. “This finding indicates that many patients could benefit from this treatment.” 

Treatment and Response 

THE TREATMENT for the 56 patients with recurrent high-grade glioma in this clinical trial involved 2 steps. First, patients were injected with Toca 511, which is a replicating virus that only infects actively dividing tumor cells. Once inside the cancer cell, the virus delivers a gene for the enzyme cytosine deaminase. As the virus replicates and spreads to other cancer cells, it programs them to make cytosine deaminase. Next, patients received a pill, Toca FC, which is an inert compound. Once inside the cancer cell, cytosine deaminase converts Toca FC into the anticancer drug 5-FU. In addition to destroying cancer cells, 5-FU kills certain immune suppressive myeloid cells, thus boosting the patient’s immune system to recognize and attack the cancer cells. 

Within a subgroup of 23 patients who match the entry criteria for the ongoing phase II/III trial, Dr. Chen noted that 5 patients are experiencing a durable complete response, with a median of at least 35.7 months. In addition, there were 5 patients who achieved stable disease, bringing the number of patients who derived benefit from Toca 511 to 10 (43.4%). 

“This treatment has a very favorable safety profile,” Dr. Chen added. “The Toca 511 therapy approach spares the body from exposure to systemic chemotherapy, while creating high concentration of chemotherapy in the tumor cells and their microenvironment.” 

Overall Survival 

THE MEDIAN SURVIVAL in this trial is nearly double compared to historical data, according to Dr. Chen. In the subgroup, median survival was 14.4 months, compared to approximately 8 months for historical controls. In contrast to the ongoing, durable responses observed in this study, patients treated with the chemotherapy lomustine had an overall response rate of about 4.3%, which, like bevacizumab (Avastin), was not durable and typically lasted a few months. 

“Brain cancer is one of the deadliest cancers, giving urgency to finding an effective treatment,” Dr. Chen said. “The 160,000-people diagnosed with high-grade gliomas worldwide each year demonstrate the high unmet need of this disease. The data generated in the Toca 511 research provides hope for patients with brain cancer and their families.” 

A limitation of the study is that it was a single arm trial without a control group. “The ongoing randomized phase II/III trial will be important to confirm the promising safety and efficacy results reported in this phase I study.” Dr. Chen noted. ■

DISCLOSURE: Dr. Chen has been and advisor or consultant and received honoraria from Tocagen, MRI Intervention, Varian, and Monteris. 


1. Chen C: 2017 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. Abstract A085. Presented October 27, 2017.