Oncolytic DNX-2401 Virus for Pediatric Diffuse Intrinsic Pontine Glioma

Jaime Gállego Pérez-Larraya, Marc Garcia-Moure, Sara Labiano, Ana Patiño-García, Jessica Dobbs, Marisol Gonzalez-Huarriz, Marta Zalacain, Lucia Marrodan, Naiara Martinez-Velez, Montserrat Puigdelloses, Virginia Laspidea, Itziar Astigarraga, Blanca Lopez-Ibor, Ofelia Cruz, Miren Oscoz Lizarbe, Sandra Hervas-Stubbs, Gorka Alkorta-Aranburu, Ibon Tamayo, Beatriz Tavira, Ruben Hernandez-AlcocebaChris Jones, Gitanjali Dharmadhikari, Cristian Ruiz-Moreno, Henk Stunnenberg, Esther Hulleman, Jasper van der Lugt, Miguel Á Idoate, Ricardo Diez-Valle, Inés Esparragosa Vázquez, Maria Villalba, Carlos de Andrea, Jorge M. Núñez-Córdoba, Brett Ewald, Joan Robbins, Juan Fueyo, Candelaria Gomez-Manzano, Frederick F. Lang, Sonia Tejada, Marta M. Alonso

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BACKGROUND Pediatric patients with diffuse intrinsic pontine glioma (DIPG) have a poor prognosis, with a median survival of less than 1 year. Oncolytic viral therapy has been evaluated in patients with pediatric gliomas elsewhere in the brain, but data regarding oncolytic viral therapy in patients with DIPG are lacking. METHODS We conducted a single-center, dose-escalation study of DNX-2401, an oncolytic adenovirus that selectively replicates in tumor cells, in patients with newly diagnosed DIPG. The patients received a single virus infusion through a catheter placed in the cerebellar peduncle, followed by radiotherapy. The primary objective was to assess the safety and adverse-event profile of DNX-2401. The secondary objectives were to evaluate the effect of DNX-2401 on overall survival and quality of life, to determine the percentage of patients who have an objective response, and to collect tumor-biopsy and peripheral-blood samples for correlative studies of the molecular features of DIPG and antitumor immune responses. RESULTS A total of 12 patients, 3 to 18 years of age, with newly diagnosed DIPG received 1×10 10 (the first 4 patients) or 5×10 10 (the subsequent 8 patients) viral particles of DNX-2401, and 11 received subsequent radiotherapy. Adverse events among the patients included headache, nausea, vomiting, and fatigue. Hemiparesis and tetra-paresis developed in 1 patient each. Over a median follow-up of 17.8 months (range, 5.9 to 33.5), a reduction in tumor size, as assessed on magnetic resonance imaging, was reported in 9 patients, a partial response in 3 patients, and stable disease in 8 patients. The median survival was 17.8 months. Two patients were alive at the time of preparation of the current report, 1 of whom was free of tumor progression at 38 months. Examination of a tumor sample obtained during autopsy from 1 patient and peripheral-blood studies revealed alteration of the tumor microenvironment and T-cell repertoire. CONCLUSIONS 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.

Original languageEnglish
Pages (from-to)2471-2481
Number of pages11
JournalThe New England journal of medicine
Issue number26
Publication statusPublished - 30 Jun 2022

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