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Oncolytic DNX-2401 Virus for Pediatric Diffuse Intrinsic Pontine Glioma

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

Abstract

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

Download a PDF of the Research Summary.

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 1×1010 (the first 4 patients) or 5×1010 (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 tetraparesis 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. (Funded by the European Research Council under the European Union’s Horizon 2020 Research and Innovation Program and others; EudraCT number, 2016-001577-33; ClinicalTrials.gov number, NCT03178032.)

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Oncolytic Virus for Pediatric Pontine Glioma
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Funding and Disclosures

Supported by the European Research Council under the European Union’s Horizon 2020 Research and Innovation Program (817884 ViroPedTher, to Dr. Alonso) and grants from the Fundación ACS and the Fundación Adey (to Drs. Patiño-García and Alonso). The authors’ work is supported by a grant from the Departamento de Salud del Gobierno de Navarra (54/2018, to Dr. Patiño-García), a postdoctoral fellowship from the ChadTough Defeat DIPG Foundation (to Dr. Garcia-Moure), a predoctoral fellowship from Gobierno de Navarra (to Ms. Laspidea), grants from the Instituto de Salud Carlos III y Fondos Feder (PI19/01896, to Dr. Alonso, and PI18/00164, to Dr. Patiño-García), a grant from Amigos de la Universidad de Navarra (to Dr. Puigdelloses), grants from the Fundación la Caixa and the Fundación Caja Navarra (to Drs. Patiño-García and Alonso), a grant from the Fundación El Sueño de Vicky (to Drs. Patiño-García and Alonso), a grant from the Asociación Pablo Ugarte-Fuerza Julen (to Drs. Patiño-García and Alonso), the Department of Defense Team Science Award under grant CA 160525 (to Drs. Alonso, Gomez-Manzano, and Fueyo), and a grant from Abbie’s Army (to Dr. Jones).

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Drs. Gállego Pérez-Larraya and Garcia-Moure and Drs. Tejada and Alonso contributed equally to this article.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

We thank the patients and their families for their participation in the study; the clinical trial unit, data managers, nurses, and V. Rodrigo, M. Giráldez, P. Domínguez, R. García-Eulate, A. Vieco, A. Oliver, A. Martínez-Simón, C. Honorato, B. Bejarano, and other physicians involved in the study for their support and care; J.M. Galindo and E. Zaragozá for their assistance in the study; D. Liebowitz for critical review of the study; P. Esquiroz for formatting the earlier versions of the figures; the Calero and Serrano family for their support; and the personnel at the biobank of the University of Navarra for their collaboration.

Author Affiliations

From the Health Research Institute of Navarra (J.G.P.-L., M.G.-M., S.L., A.P.-G., M.G.-H., M.Z., L.M., N.M.-V., M.P., V.L., S.H.-S., I.T., B.T., R.H.-A., M.V., C.A., S.T., M.M.A.), the Program in Solid Tumors (J.G.P.-L., M.G.-M., S.L., A.P.-G., M.G.-H., M.Z., L.M., N.M.-V., M.P., V.L., B.T., S.T., M.M.A.), the Program in Immunology (S.H.-S.), and the Program in Gene Therapy and Regulation of Gene Expression (R.H.-A.), Foundation for the Applied Medical Research, the Departments of Neurology (J.G.P.-L., I.E.V.), Pediatrics (M.G.-M., S.L., A.P.-G., M.G.-H., M.Z., L.M., N.M.-V., M.P., V.L., M.M.A.), Pathology (M.V., C.A.), and Neurosurgery (S.T.) and the Division of Biostatistics, Research Support Service, Central Clinical Trials Unit (J.M.N.-C.), Clínica Universidad de Navarra, the Service of Pediatric Hemato-Oncology, Hospital Universitario de Navarra (M.O.L.), Center for Applied Medical Research (CIMA) LAB Diagnostics, University of Navarra and Healthcare Research Institute of Navarra (G.A.-A.), and the Bioinformatics Platform, CIMA, University of Navarra (I.T.), Pamplona, the Department of Pediatric Oncology, Biocruces Bizkaia Health Research Institute, Barakaldo (I.A.), the Pediatric Department, Faculty of Medicine and Nursing, University of the Basque Country, Leioa (I.A.), the Department of Pediatric Oncology, Montepríncipe Hospital (B.L.-I.), the Department of Neurosurgery, Quirón Hospitals (R.D.-V., S.T.), and Centro de Investigación Biomédica en Red de Cáncer (M.V.), Madrid, the Department of Pediatric Oncology, Neuro-Oncology Unit, Hospital Sant Joan de Deu, Barcelona (O.C.), and the Department of Pathology, University Hospital Virgen Macarena and School of Medicine, University of Seville, Seville (M.Á.I.) — all in Spain; DNAtrix, Carlsbad, CA (J.D., B.E., J.R.); the Division of Molecular Pathology, Institute of Cancer Research, London (C.J.); the Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands (G.D., C.R.-M., H.S., E.H., J.L.); and the Departments of Neuro-Oncology (J.F., C.G.-M.) and Neurosurgery (F.F.L.), University of Texas M.D. Anderson Cancer Center, Houston.

Dr. Alonso can be contacted at or at CIMA Building, Lab 2.03, Pio XII 55, 31008, Pamplona, Spain.

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