Intratumoral delivery of an engineered oncolytic virus (DNX-2401) targeting glioblastoma (GBM) cells combined with subsequent immunotherapy was safe and improved survival outcomes in a subset of patients with recurrent GBM, according to results from a multi-institutional Phase I/II clinical trial co-led by researchers at The University of Texas MD Anderson Cancer Center and the University of Toronto.
The study, published today in Nature Medicine, met its primary safety endpoint and demonstrated the combination was well tolerated overall with no dose-limiting toxicities. The study did not meet its primary efficacy endpoint of objective response rate, but the combination achieved a 12-month overall survival (OS) rate of 52.7%, which is greater than the prespecified efficacy threshold of 20%. Three patients remained alive at 45, 48 and 60 months after treatment.
“This viral therapy is a different approach to the current standard of care,” said co-corresponding author Frederick Lang, M.D., chair of Neurosurgery. “Our previous trial demonstrated that not only does the virus act by killing cancer cells directly, it also effectively activates the innate immune system to convert these immunologically cold tumors into hot tumors. This led us to evaluate a combination with checkpoint inhibitors, which we now see can improve survival outcomes in a subset of patients.”
Glioblastoma is an aggressive brain cancer with a median OS of six months; patients typically experience recurrence with standard radiation and chemotherapy approaches. While immune checkpoint blockade has improved outcomes in other cancer types, the unique immunosuppressive tumor microenvironment in recurrent GBM shields it against immune cell infiltration, making it notoriously difficult to treat with immunotherapy.
Smart virus is efficient at eliminating GBM cells and activating immune response
Together with Lang, Juan Fueyo, M.D., and Candelaria Gomez-Manzano, M.D., both professors of Neuro-Oncology, are the co-inventors of DNX-2401, a cold virus engineered to selectively target and invade GBM cells while avoiding normal cells.
In previous Phase I trial results, DNX-2401 monotherapy effectively induced cancer cell death and changed the microenvironment to allow for increased T cell infiltration, resulting in an anti-tumor immune response. Twenty percent of patients with recurrent GBM remained alive for at least three years, and tumor reduction in complete responders continued for more than a year.
These results showed an increase in PD-1 checkpoint expression following treatment, suggesting that the immune system may be primed to respond to anti-PD-1 immunotherapy. Preclinical models supported this hypothesis, as treatment with pembrolizumab one week after DNX-2401 treatment improved survival outcomes compared to either treatment alone.
“Injecting a virus into a patient’s brain tumor is disruptive science, because this therapeutic strategy aims to awaken the patient’s immune system and trigger a healing from within,” Fueyo said. “After injection, patients that respond well develop inflammation inside the tumor, triggering an immune response that first kills the virus. Once the virus is wiped out, the continued immune reaction, stimulated by additional immunotherapy, destroys the cancer cells in a tightly regulated way without the side effects common to chemotherapy or radiation therapy.”
