Intratumoral delivery of the engineered oncolytic virus DNX-2401 in combination with subsequent immunotherapy with pembrolizumab may be safe and effective at improving survival outcomes in patients with recurrent glioblastoma, according to a study published by Nassiri et al in Nature Medicine.
Background
Patients with glioblastoma typically experience disease recurrence after standard radiation and chemotherapy treatment approaches and a median overall survival of 6 months. Although immune checkpoint inhibitors have improved outcomes in other cancer types, the unique immunosuppressive tumor microenvironment in recurrent glioblastoma shields it against immune cell infiltration—making it notoriously difficult to treat with immunotherapy.
DNX-2401 is a cold virus engineered to selectively target and invade glioblastoma cells while avoiding normal cells.
“This viral therapy is a different approach to the current standard of care,” explained co–senior study author Frederick Lang, MD, FACS, FAANS, FAAAS, Professor and Chair of the Department of Neurosurgery in the Division of Surgery at The University of Texas MD Anderson Cancer Center as well as Adjunct Professor of Neurosurgery at the Baylor College of Medicine. “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 [immune] checkpoint inhibitors, which we now see can improve survival outcomes in [this] subset of patients,” he added.
Previous Trial Results: DNX-2401 May Eliminate Glioblastoma and Activate Immune Response
In a previous phase I trial, researchers discovered that DNX-2401 monotherapy effectively induced cancer cell death and altered the tumor microenvironment to allow for increased T-cell infiltration in patients with recurrent glioblastoma—resulting in an antitumor immune response. After completing the treatment, the patients experienced a 3-year survival rate of 20%, and tumor reduction in those who experienced complete responses continued for over 1 year.
Additionally, the patients demonstrated 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. The researchers noted that treatment with pembrolizumab 1 week after administering DNX-2401 improved survival outcomes compared with 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,” said co–study author Juan Fueyo, MD, FAAN, FAAAS, Professor of Neuro-Oncology and Director of Neuro-Oncology Experimental Research in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. “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,” he explained.
New Study Methods and Results: Combination Therapy May Improve Survival, Quality of Life
In the new phase I/II clinical trial, the researchers evaluated the safety and efficacy of the combination of intratumoral DNX-2401 followed by intravenous pembrolizumab in 49 patients with a median age of 53 years who had recurrent glioblastoma from September 28, 2016, to January 17, 2019. Among the patients involved in the trial, 98% of them (n = 48/49) were treated with one dose of DNX-2401 after biopsy, followed by pembrolizumab given 1 week later.
The researchers found that 56.2% of the patients who received the combination therapy achieved a clinical benefit of stable disease or better. In addition, after 6 months of follow-up, five patients had objective responses and two patients experienced a tumor reduction of 80% or more. By 18 months of follow-up, both patients who experienced significant tumor reduction had a complete response without evidence of disease progression.
Exploratory gene expression and immunophenotypic analysis also revealed that objective response occurred in patients with a moderately inflamed tumor microenvironment and modest PD-1 expression—meriting further investigation into which patient characteristics might determine who is more likely to benefit from this treatment.
The researchers reported that the study met its primary safety endpoint and demonstrated that the combination therapy was well tolerated overall with no dose-limiting toxicities. Although the study did not meet its primary efficacy endpoint of objective response rate, patients who received the combination therapy achieved a 12-month overall survival rate of 52.7%—which is greater than the prespecified efficacy threshold of 20%. Further, three patients remained alive at 45, 48, and 60 months after treatment.
The majority of adverse events were grade 1 or 2, with 37%, 31%, and 29% of the patients experiencing brain edemas, headaches, and fatigue, respectively.
Conclusions
Although this study did not meet its primary efficacy endpoint, it did validate the use of DNX-2401 in combination with immune checkpoint inhibitors as a safe approach that potentially opens the door to other combination therapies. For instance, the researchers found that specimens from 10 patients showed elevated levels of several immune checkpoints after treatment—including LAG3, TIGIT, and B7-H3—highlighting that these proteins may be used as potential therapeutic targets.
“Our studies using this ‘smart virus’ are ongoing, but we are encouraged that we continue to see a small number of patients who have a very dramatic eradication of the tumor,” highlighted co–study author Candelaria Gomez-Manzano, MD, Professor of Neuro-Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. “These results motivate us to keep searching for the best combination strategy that can optimize the use of this virus to improve patient outcomes,” she concluded.
The researchers are currently exploring the use of mesenchymal stem cells to deliver a larger amount of DNX-2401 to the tumor and more widely throughout the tumor in further clinical trials. Future clinical trials will evaluate alternative treatments, such as immune checkpoint inhibitors or chimeric antigen receptor T-cell therapy in combination with DNX-2401.
Disclosure: The research in this study was supported by DNATrix, Inc. and Merck & Co. For full disclosures of the study authors, visit nature.com.
