Virus vs. tumor
HOUSTON—As reported by Scott Merville of the University of Texas MD Anderson Cancer Center, data from a Phase 1 clinical trial showed that a cold virus that was engineered to go after glioblastoma—the most common and deadly form of brain cancer—led to 20 percent of patients with recurrent glioblastoma living for three years or longer.
The MD Anderson researchers’ findings were outlined in a paper titled “Phase I Study of DNX-2401 (Delta-24-RGD) Oncolytic Adenovirus: Replication and Immunotherapeutic Effects in Recurrent Malignant Glioma,” which was published online ahead of print in the Journal of Clinical Oncology.
In the clinical trial, the altered adenovirus, called Delta-24-RGD or DNX-2401, was injected directly into the tumors a single time in 25 patients whose glioblastoma had recurred after surgery and other treatments. Such patients usually exhibit a median survival of just six months.
“Of those five long-term survivors, three had durable complete responses, which is impressive for a Phase 1 clinical trial in glioblastoma,” said lead author Dr. Frederick Lang, a professor of neurosurgery. “Many Phase 1 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 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,” explained senior author and drug co-inventor Dr. Juan Fueyo, a 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 percent of it vanished.
“In the case of these long-term complete responders, the virus breaks the tumor’s shield against immune response by killing cells, creating multiple antigen targets for the immune system,” said co-inventor Dr. Candelaria Gomez-Manzano, an associate professor of neuro-oncology. “These tumors are then completely destroyed.”
Glioblastomas normally do not attract the attention of the immune system, with virtually no penetration of tumors by T 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.
As the abstract for the published paper noted, “Treatment with DNX-2401 resulted in dramatic responses with long-term survival in recurrent high-grade gliomas that are probably due to direct oncolytic effects of the virus followed by elicitation of an immune-mediated antiglioma response.”
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.
(Source: MD Anderson Cancer Center; material above has been edited slightly and expanded slightly from the original piece written by Scott Merville for the MD Anderson website)