A combination of retroviral gene therapy and chemotherapy administered as a prodrug significantly increased survival times of patients with recurrent high-grade glioma in a phase I trial.

Median overall survival for 45 patients receiving the combination of Tocagen Inc.'s Toca-511 (vocimagene amiretrorepvec) and Toca FC (extended-release 5-fluorocytosine), a prodrug of the standard chemotherapy 5-FU, increased by more than six months. In the grim world of high-grade glioma, those 6.5 months represented a near doubling of median overall survival time in comparison to historical controls and patients treated with the chemotherapy drug lomustine.

But in the opinion of Harry Gruber, the most impressive part of the data – "because it looks like immunotherapy" – is that the survival curve has what's known in statistical parlance as a tail, with a significant fraction of patients surviving for what is considered long periods of time in the world of brain tumors.

At two years, the overall survival rate was 40 percent in the high-dose cohort, with an overall survival rate of all patients at 29 percent. The two-year overall survival rate of historical controls with recurrent glioblastoma is 9 percent.

The longest such response in the trial, which is still ongoing, is nearly four years.

Gruber also noted that the patients are not just surviving, but are doing well after their treatment.

"They go back to work, they have normal lives," he said. One patient on the trial became a father two years after his recurrence.

Gruber is the CEO of Tocagen and a co-author on the paper reporting the findings, which the team published in the June 1, 2016, issue of Science Translational Medicine.

2015's approval of Imlygic (talimogene laherparepvec/T-vec, Amgen Inc.) for the treatment of melanoma marked the first FDA win for oncolytic viruses, which, broadly speaking, infect cancer cells and stimulate an immune response to them, though the details vary by therapy.

Tocagen's Toca-511/Toca FC is a variation on that theme. The retroviral part of the combination.

Toca-511 is "a conditionally oncolytic virus with a prodrug activator gene," Gruber told Medical Device Daily.

The gene, cytosine deaminase, metabolizes FC, an antifungal drug that crosses the blood-brain barrier, into 5-FU.

Toca-511 is somewhat unusual in that it uses a channel, PIT-2, to enter cells. That channel is present on most cells, normal and tumor alike. "The selectivity is not through the channel," Gruber explained.

But normal cells rapidly clear the retrovirus, while tumor cells are vulnerable to its becoming integrated because they have defects in interferon signaling.

As a result, 5-FC can be given systemically, but 5-FU levels are high specifically in the tumor.

In preclinical experiments, the 5-FU produced by the transgene killed off both the cells producing it and neighboring cells. As tumor cells died, they set off an immune response, predictably enough – "we expected that," Gruber said.

What the team did not expect was that "the immunotherapy component was the more dominant of the two – that was a big surprise to us."

The reason appears to be that 5-FU does not just kill cancer cells. A few years ago, researchers at the French INSERM Institute reported that immunosuppressive myeloid cells were also highly sensitive to 5-FU – "more sensitive than many cancers," Gruber said.

As a result, treating with the combination of Toca-511 and Toca FC led to "an immune response without the brake."

But that brake is only off in the tumor, which means that both the chemotherapy's and the immunotherapy's toxicity are largely confined to the tumor.

"It's the selectivity of the 5-FU in the tumor that's so critical," Gruber stressed.

The retroviral vector was equally able to infect all subtypes of brain tumors, though the team identified a molecular signature that predicted a clinical response.

Based on the results of the phase I trial, the team has initiated a "registration-quality" trial that is now enrolling patients.

The team is also testing the approach, for now preclinically, in other tumor types as well as in brain metastases.