Abstract
Infusion of an oncolytic virus followed by radiotherapy led to responses and prolonged survival in patients with DIPG.
Major Finding: Infusion of an oncolytic virus followed by radiotherapy led to responses and prolonged survival in patients with DIPG.
Concept: DNX-2401 resulted in changes in T-cell activity and reshaping of the immune microenvironment.
Impact: This study provides evidence of safety, feasibility, and potential activity of DNX-2401 in DIPG, encouraging further trials.
Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain stem tumor, accounting for the majority of brain tumor–related death in pediatric patients. Given risks that preclude surgical resection, radiotherapy is available as standard of care for patients with DIPG, although prognosis remains poor with a median survival of 1 year. To address the need for improved therapies, Gállego Pérez-Larraya, Garcia-Moure, Tejada, Alonso, and colleagues initiated a single-center, phase I clinical trial of the oncolytic adenovirus DNX-2401, designed to replicate within tumor cells for selective cell killing in newly diagnosed patients with DIPG, enrolling seven female and five male patients between the ages of 3 and 18 years old. The primary objective was to assess safety and adverse events, and the secondary objectives were to determine the overall survival and overall response rate, assess the effect on quality of life, and collect tumor biopsies and peripheral blood samples for correlative studies. Among the 12 patients, four received 1 × 1010 viral particles of DNX-2401, while eight received 5 × 1010 viral particles, and postoperative MRI confirmed viral delivery without acute complications from surgery. Eleven of 12 patients received radiotherapy following DNX-2401 treatment. Frequent adverse events included headache, nausea, vomiting, and fatigue, and of the 12 patients, nine had at least one adverse event deemed possibly related to the intratumoral delivery of DNX-2401. No grade 4 or grade 5 adverse events were observed. Three patients (25%) experienced a partial response (3.5, 7.6, and 10.3 months) and eight had stable disease for a disease control rate of 92%. The median overall survival was 17.8 months, the overall survival rate at 18 months was 50%, and the overall survival rate at 24 months was 25%, with one patient remaining free of progression for 38 months. Molecular characterization and immune phenotyping of tumor samples before and after treatment suggested evidence of direct oncolytic activity, in line with preclinical data. In summary, this work demonstrates the feasibility of oncolytic viral therapy in DIPG and provides rationale for a larger trial in pediatric patients.
Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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