Oncolytic adenovirus shows potential in pediatric diffuse intrinsic pontine glioma
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The oncolytic adenovirus DNX-2401 appeared safe and feasible among a small cohort of pediatric patients with diffuse intrinsic pontine glioma, according to study results published in The New England Journal of Medicine.
Rationale and methods
“Diffuse intrinsic pontine glioma is a terrible pediatric brain tumor that currently has no cure,” Marta Maria Alonso Roldan, PhD, professor in pediatrics and co-director of the Advanced Therapies for Pediatric Tumors Laboratory in the solid tumor program of University Clinic of Navarra in Spain, told Healio. “Oncolytic viruses have shown promise in brain tumors, and we had preclinical data in diffuse intrinsic pontine glioma models that the oncolytic virus [DNX-2401, DNAtrix] was not only safe but also showed promising efficacy in increasing OS in mice bearing these tumor types. The next step was to translate this promising strategy to the clinic in a phase 1 clinical trial.”
The single-center, dose-escalation study included 12 patients (median age, 9 years; 58% female) with newly diagnosed diffuse intrinsic pontine glioma. Patients received a single infusion of DNX-2401, also known as tasadenoturev or Delta-24-RGD (arginine-glycine-aspartic acid), followed by radiotherapy.
Safety and adverse events served as the primary objective. Secondary objectives included OS, quality of life and objective response rate.
Median follow-up was 17.8 months.
Key findings
The first four patients received 1x10¹ and the other eight patients received 5x10¹ viral particles of DNX-2401, and all but one patient received subsequent radiotherapy.
Common adverse events included headache, neurologic deterioration and vomiting (nine patients each), fatigue in eight patients and fever in six patients. One patient developed hemiparesis and one developed tetraparesis.
Grade 3 adverse events included headache (n = 1), one-sided muscle weakness (n = 2) and neurologic deterioration (n = 1). No grade 4 or grade 5 events occurred.
Results showed nine patients experienced a reduction in tumor size, three patients had a partial response and eight patients had stable disease. Median PFS was 10.7 months and median OS was 17.8 months.
Two patients remained alive at last follow-up, with one patient free of tumor progression at 38 months.
Researchers observed alteration of the tumor microenvironment and T-cell repertoire on a tumor sample obtained during autopsy from one patient and from peripheral-blood studies.
“The virus is safe to deliver to the brainstem of children aged 2 to 18 years, and all children were home within 2 to 3 days after the virus infusion,” Alonso Roldan said. “The OS is also very encouraging and better than the OS observed with other prior therapies. Additionally, we were able to learn that an immune response was mounted and we could study the tumor microenvironment before the viral infection.”
Implications
The safety profile and promising efficacy observed in this trial opened the door to continue investigating this treatment, according to Alonso Roldan.
“The next steps are to open a larger clinical trial to get closer to regulatory agency approval and to improve the efficacy of the virus in the laboratory to make it more potent,” she added.
Findings from the current study and other previous early-phase trials have shown evidence of biologic activity from oncolytic viruses, generating a glimmer of hope for patients with brain tumors and their families, according to an accompanying editorial by Evanthia Galanis, MD, researcher in the department of oncology at Mayo Clinic.
“We know, however, that the path from demonstration of biologic activity in early trials to final approval of a new agent, which makes a treatment available to patients, can be long and convoluted,” Galanis wrote.
“Viral entry in tumor cells, which is determined by viral receptor expression on the target tumor, is necessary but in itself not adequate for viral replication in malignant cells, if they are not permissive,” Galanis added. “Permissiveness of gliomas to viral replication and oncolytic cell death can be determined by the expression of interferon-stimulated genes as shown for other oncolytic platforms, such as measles virus. The questions remain as to what degree of viral replication is necessary to produce a sufficient immunostimulatory effect and how preexisting antiviral immune response may influence this effect.”
References:
- Galanis E. N Engl J Med. 2022;doi:10.1056/NEJMe2205032.
- Gállego Pérez-Larraya J, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2202028.
For more information:
Marta Maria Alonso Roldan, PhD, can be reElSueno de Vickyached at mmalonso@unav.es.
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