Detalle Publicación

Phase I study of DNX-2401 (Delta-24-RGD) oncolytic adenovirus: replication and Immunotherapeutic effects in recurrent malignant glioma

Autores: Lang, F. F. (Autor de correspondencia); Conrad, C.; Gomez-Manzano, C.; Yung, W. K. A.; Sawaya, R.; Weinberg, J. S.; Prabhu, S. S.; Rao, G.; Fuller, G. N.; Aldape, K. D.; Gumin, J. ; Vence, L. M. ; Wistuba, I. ; Rodriguez-Canales, J.; Villalobos, P. A.; Dirven, C. M. F.; Tejada Solís, Sonia; Diez Valle, Ricardo; Alonso Roldán, Marta María; Ewald, B.; Peterkin, J. J.; Tufaro, F.; Fueyo, J.
ISSN: 0732-183X
Volumen: 36
Número: 14
Páginas: 1419 - 27
Fecha de publicación: 2018
PurposeDNX-2401 (Delta-24-RGD; tasadenoturev) is a tumor-selective, replication-competent oncolytic adenovirus. Preclinical studies demonstrated antiglioma efficacy, but the effects and mechanisms of action have not been evaluated in patients.MethodsA phase I, dose-escalation, biologic-end-point clinical trial of DNX-2401 was conducted in 37 patients with recurrent malignant glioma. Patients received a single intratumoral injection of DNX-2401 into biopsy-confirmed recurrent tumor to evaluate safety and response across eight dose levels (group A). To investigate the mechanism of action, a second group of patients (group B) underwent intratumoral injection through a permanently implanted catheter, followed 14 days later by en bloc resection to acquire post-treatment specimens.ResultsIn group A (n = 25), 20% of patients survived > 3 years from treatment, and three patients had a 95% reduction in the enhancing tumor (12%), with all three of these dramatic responses resulting in > 3 years of progression-free survival from the time of treatment. Analyses of post-treatment surgical specimens (group B, n = 12) showed that DNX-2401 replicates and spreads within the tumor, documenting direct virus-induced oncolysis in patients. In addition to radiographic signs of inflammation, histopathologic examination of immune markers in post-treatment specimens showed tumor infiltration by CD8(+) and T-bet(+) cells, and transmembrane immunoglobulin mucin-3 downregulation after treatment. Analyses of patient-derived cell lines for damage-associated molecular patterns revealed induction of immunogenic cell death in tumor cells after DNX-2401 administration.ConclusionTreatment with DNX-2401 resulted in dramatic responses with long-term survival in recurrent high-grade gliomas that are probably due to direct oncolytic effects of the virus followed by elicitation of an immune-mediated antiglioma response.