A common cold virus engineered to attack the most common and deadly of brain tumours allowed 20 percent of patients with recurrent glioblastoma to live for three years or longer, researchers from The University of Texas MD Anderson Cancer Center report on a phase I clinical trial in the Journal of Clinical Oncology.
The altered adenovirus, called Delta-24-RGD or DNX-2401, was injected one time directly into the tumours of 25 patients whose glioblastoma had recurred after surgery and other treatments, a patient group that typically has a median survival of six months.
“Of those five long-term survivors, three had durable complete responses, which is impressive for a phase I clinical trial in glioblastoma,” said lead author Frederick Lang, M.D., professor of Neurosurgery. “Many phase I trials might have one patient who does well, so our result is unusual, but we’re always cautious in assessing results with this very difficult disease.”
Toxicities were minimal, with two patients experiencing low-grade side effects related to treatment.
Dose escalation proceeded to the highest concentration of the virus that could be manufactured, with no dose-limiting side effects.
Eighteen patients (72 percent) had some tumour reduction.
Median overall survival was 9.5 months.
Imaging of treated patients and analysis of surgically removed tumours from 12 other patients treated with the targeted virus before surgery in a separate part of the trial confirmed both the original tumour-killing mechanism and a resulting immune reaction that the researchers think is behind the long-term responses.
“We designed DNX-2401 to specifically infect cancer cells, replicate inside those cells to kill them, and spread from cell to cell in a destructive wave throughout the tumour,” said senior author and drug co-inventor Juan Fueyo, M.D., professor of Neuro-Oncology. “The clinical trial shows that happens, as predicted by our preclinical research, and it also shows that in some patients, viral infection was followed by an immune reaction to the glioblastoma that led to the strong responses.”
In the three complete responses, imaging showed evidence of inflammation and immune activity a month after treatment, followed by a steady decline in tumour size until at least 95 percent of it vanished.
“In the case of these long-term complete responders, the virus breaks the tumour’s shield against immune response by killing cells, creating multiple antigen targets for the immune system,” said co-inventor Candelaria Gomez-Manzano, M.D., associate professor of Neuro-Oncology. “These tumours are then completely destroyed.”
Glioblastomas normally do not attract the attention of the immune system, with virtually no penetration of tumours by T cells, white blood cells that attack invaders and abnormal cells.
The study showed the immune system wiped out the virus within a month, but tumour reduction in complete responders continued for a year or longer.
Analysis of the surgically removed tumours from the second part of the trial showed widespread cell death in the tumours and infiltration of T cells.
With no detectable tumour, minimal initial side effects and no ongoing treatment with other methods that come with stronger side effects, such as radiation and chemotherapy, patients’ quality of life is good, the researchers note.
However, about three or four years later, all three patients had recurrences which ultimately proved fatal.
In two cases, the tumour that came back was a gliosarcoma, substantially different from the original glioblastoma.
All three lived for at least 4.8 years after treatment, with two having progression-free survival of 42.5 months and 36.4 months.
“We have work to do in the lab to understand how we might permanently defeat these tumours and extend the impact of treatment to more of the 80 percent who did not have a strong response,” Fueyo said.
The team is conducting research to add new factors to the virus that will stimulate immune response.
Source: MD Anderson Cancer Center