In a Spanish single-institution study reported in The New England Journal of Medicine, Pérez‑Larraya et al found that intratumoral infusion of the oncolytic adenovirus DNX-2401 followed by radiotherapy showed activity in newly diagnosed pediatric patients with diffuse intrinsic pontine glioma (DIPG), a highly aggressive and difficult-to-treat brain tumor.
Study Details
In the study, 12 patients aged 3 to 12 years were enrolled at the University of Navarra between December 2017 and January 2020. Patients received a single infusion of DNX-2401 through a catheter placed in the cerebellar peduncle at doses of 1 × 1010 (first four patients) or 5 × 1010 (next eight patients) viral particles. Subsequent radiotherapy was received by 11 patients.
Responses
Over a median follow-up of 17.8 months (range = 5.9–33.5 months), a reduction in tumor size assessed on magnetic resonance imaging was observed in nine patients; partial response was observed in three patients, and stable disease was seen in eight patients.
Median progression-free survival was 10.7 months. Median overall survival was 17.8 months, with an 18-month rate of 50%. Three patients remained alive at 19.6, 31.4, and 33.5 months at data cutoff for the current analysis. At the time of reporting, two patients remained alive, with one being free of tumor progression at 38 months.
Examination of a tumor sample obtained during autopsy from one patient and peripheral blood studies showed alterations of the tumor microenvironment and T-cell repertoire. For example, in the autopsy study, tumor-infiltrating macrophages showed an upregulation of pathways associated with viral processes and enhanced immune response. Chemoattractant signaling from the tumor-infiltrating macrophages was associated with an increase in tumor-infiltrating lymphocytes, including cytotoxic, effector memory, and regulatory T cells.
Adverse Events
The most common adverse events of any grade were headache, neurologic deterioration, and vomiting (nine patients each), fatigue (eight patients), and fever (six patients). Serious adverse events occurred in three patients, consisting of transient grade 3 hemiparesis related to biopsy, grade 3 neurologic deterioration of increased bilateral oculomotor paresis and tetraparesis, and grade 1 abdominal pain, respectively. A total of four grade 3 adverse events were observed; no grade 4 or 5 events occurred.
Conclusion
The investigators concluded, “Intratumoral infusion of oncolytic virus DNX-2401 followed by radiotherapy in pediatric patients with DIPG resulted in changes in T-cell activity and a reduction in or stabilization of tumor size in some patients, but was associated with adverse events.... The results of the current study suggest that intratumoral infusion of DNX-2401 before radiation therapy is feasible in children with DIPG, providing a rationale for the conduct of a larger trial.”
Marta M. Alonso, PhD, of the Health Research Institute of Navarra, University of Navarra, Pamplona, is the corresponding author for The New England Journal of Medicine article.
Disclosure: The study was funded by the European Research Council under the European Union’s Horizon 2020 Research and Innovation Program and others. For full disclosures of the study authors, visit nejm.org.
