Smart bomb virus shows promise as a brain tumor immunotherapy
Husband-and-wife researchers Candelaria Gomez-Manzano and Juan Fueyo found a way to turn the virus that causes the common cold into a cancer-seeking missile. They named it Delta 24. Photo: Wyatt McSpadden
A cold virus engineered to attack the most common and deadly of brain tumors allowed 20% of patients with recurrent glioblastoma to live for three years or longer, researchers from MD Anderson report in the Journal of Clinical Oncology.
In a phase I clinical trial, the altered adenovirus, called Delta-24-RGD or DNX-2401, was injected one time directly into the tumors 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%) had some tumor reduction. Median overall survival was 9.5 months.
Imaging of treated patients and analysis of surgically removed tumors from 12 other patients treated with the targeted virus before surgery in a separate part of the trial confirmed both the original tumor-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 tumor,” 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 tumor size until at least 95% of it vanished.
Glioblastomas normally do not attract the attention of the immune system, with virtually no penetration of tumors 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 tumor reduction in complete responders continued for a year or longer. Analysis of the surgically removed tumors from the second part of the trial showed widespread cell death in the tumors and infiltration of T cells.
With no detectable tumor, 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.