Gene Therapy Shows Early Efficacy Against Recurrent Brain Cancer

October 27, 2021

PHILADELPHIA —More than a quarter of patients with recurrent high-grade glioma, a form of brain cancer, treated with the retroviral vector Toca 511 and the prodrug of the chemotherapy 5-fluorouracil, Toca FC, were alive more than three years after treatment, according to data from a subset of patients in a phase I clinical trial presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held Oct. 26-30.

“Given the deadly nature of this disease, three-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 Clark Chen, MD, PhD, Lyle French Chair in Neurosurgery and Head of the University of Minnesota Medical School Department of Neurosurgery in Minneapolis. “This finding indicates that many patients could benefit from this treatment.”

The treatment for the 56 patients with recurrent high-grade glioma in this clinical trial involved two steps. First, patients were injected with Toca 511, which is a replicating virus that selectively infects actively dividing tumor cells. Once inside the cancer cell, the virus delivers a gene for an enzyme, cytosine deaminase (CD). As the virus replicates and spreads to other cancer cells, it programs them to make CD. Next, patients received a tablet, Toca FC, which is an inert compound. Once inside the cancer cell, CD converts Toca FC into the anticancer drug 5-fluorouracil, which kills the cancer cell.

In addition to destroying cancer cells, 5-fluorouracil kills certain immune suppressive myeloid cells, thus boosting the patient’s immune system to recognize and attack the cancer cells.

“The treatment we tested in this trial delivers local chemotherapy specifically to the brain tumor. Toca 511 and Toca FC work together to turn the brain tumor into a factory that produces an anticancer drug while also activating the immune system through a combination of mechanisms, which together work to attack the cancer,” Chen said.

Within a subgroup of 23 patients that match the entry criteria for an ongoing phase III trial (Toca 5, clinical trial identifier NCT02414165), Chen noted that five patients are experiencing a durable complete response with a median of at least 35.7 months. In addition, there were five patients who achieved stable disease, bringing the number of patients who derived clinical benefit from Toca 511 to 10 (or 43.4 percent of the patients who underwent Toca 511 therapy). Stories of patients who are experiencing durable responses are available.

“This treatment has a very favorable safety profile,” 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.”

The median survival in this trial is nearly double compared to historical data, according to Chen. In the subgroup, median survival was 14.4 months, compared to approximately eight 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 percent, 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,” Chen said. “The 160,000 people diagnosed with high-grade gliomas worldwide each year—and high-profile cases including U.S. Senator John McCain, Senator Edward Kennedy, and Beau Biden—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 III trial will be important to confirm the promising safety and efficacy results reported in this phase I study.” Chen noted.

This study was sponsored by Tocagen. Chen is a consultant for Tocagen and a participating investigator in the Toca 5 trial.