Combination approach is safe and improves survival outcomes in some patients with glioblastoma

Intratumoral delivery of a genetically engineered oncolytic virus (DNX-2401) targeting glioblastoma (GBM) cells followed by immunotherapy, according to the results of a multicenter phase I/II clinical trial was found to be safe and to improve survival outcomes in some patients with recurrent GBM. The trial was jointly led by researchers at the University of Texas MD Anderson Cancer Center and the University of Toronto.

This research is today natural medicine, met the primary safety endpoints, demonstrating that the combination had no dose-limiting toxicity and was well tolerated overall.This study did not meet key criteria efficacy However, this combination therapy achieved a 12-month overall survival (OS) of 52.7%. This is above the pre-specified effectiveness threshold of 20%. Three patients were alive at 45, 48 and 60 months after treatment.

This virotherapy is a different approach than the current standard of care. Our previous studies showed that the virus not only acts by directly killing cancer cells, but also effectively activates the innate immune system to transform these immunologically cold tumors into hot tumors. I have also demonstrated that This led us to evaluate its combination with checkpoint inhibitors, which are now found to improve survival outcomes in some patients. ”

Frederick Lang, M.D., Chief of Neurosurgery, Co-corresponding author

Glioblastoma is an aggressive brain tumor with a median survival of 6 months. Patients usually experience recurrence with standard radiotherapy and chemotherapy. Immune checkpoint blockade has improved outcomes in other cancer types, but in recurrent GBM, a unique immunosuppressive tumor microenvironment prevents immune cell infiltration and is notoriously difficult to treat with immunotherapy. is.

Smart virus efficiently eliminates GBM cells and activates immune response

With Lang, professors of neuro-oncology, Juan Fueyo, M.D., and Candelaria Gomez-Manzano, M.D., have developed a common cold virus, DNX- Co-inventor of 2401.

Results from a previous Phase I trial showed that DNX-2401 monotherapy effectively induced cancer cell death and altered the microenvironment to enable increased cancer cell death. T cells Infiltration occurs and an anti-tumor immune response is triggered. His 20% of recurrent GBM patients survived for at least 3 years, and complete responder tumor regression lasted him more than 1 year.

These results demonstrate increased PD-1 checkpoint expression after treatment and suggest that the immune system may be primed to respond to anti-PD-1 immunotherapy. Preclinical models supported this hypothesis, as treatment with pembrolizumab 1 week after DNX-2401 treatment improved survival outcomes compared with either treatment alone.

“Injecting a virus into a patient’s brain tumor is a disruptive science because this therapeutic strategy aims to awaken the patient’s immune system and trigger healing from within,” Hueyo said. . “After the injection, well-responded patients develop inflammation within the tumor, triggering an immune response that kills the virus first. It destroys cancer cells in a controlled manner.” It does not have the side effects that are common with chemotherapy and radiation therapy. ”

Combination therapy prolongs survival and improves quality of life for some patients

The current trial was designed to evaluate the combination of intratumoral DNX-2401 followed by intravenous pembrolizumab. The study enrolled 49 patients with recurrent GBM from multiple centers between September 28, 2016, and January 17, 2019. The median age of patients was 53 years, and 41% were female.

Forty-eight of the 49 patients (98%) were treated with one dose of DNX-2401 after biopsy, followed by pembrolizumab 1 week later. The majority of adverse events were grade 1 or 2, the most common being cerebral edema (37%), headache (31%) and fatigue (29%).

The combination provided clinical benefit, defined as stable disease or better, in more than half of patients (56.2%). Five patients had objective responses, and two experienced tumor shrinkage of 80% or greater at 6 months follow-up. By 18 months, these two of her patients had fully responded without showing disease progression.

Exploratory gene expression and immunophenotypic analyzes also revealed that objective responses occurred in patients with moderately inflamed tumor microenvironment and moderate PD-1 expression. For this reason, it deserves further investigation to determine which patient characteristics are likely to benefit from this treatment.

Although this study did not meet its primary efficacy endpoint, it validates the use of DNX-2401 in combination with immune checkpoint inhibitors as a safe approach that opens the door to exploring other combinations Did. For example, researchers found that specimens from 10 patients showed elevated levels of several immune checkpoints, including LAG3, TIGIT, and B7-H3, after treatment, suggesting that these proteins are potentially Emphasized as a therapeutic target.

“While research with this ‘smart virus’ is ongoing, it is encouraging to continue to observe a small number of patients who have achieved very dramatic eradication of their tumors,” said Gomezmanzano. “These results motivate us to continue searching for the best combination strategies that can optimize the use of this virus to improve patient outcomes.”

Clinical trials are now underway using mesenchymal stem cells to deliver more smart viruses to and through tumors more extensively. Future clinical trials will evaluate alternative therapies such as checkpoint inhibitors and CAR T-cell therapy in combination with DNX-2401.

This research was supported by DNATrix, Inc. and Merck & Co.