Publicaciones científicas

Phase I Study of DNX-2401 (Delta-24-RGD) Oncolytic Adenovirus: Replication and Immunotherapeutic Effects in Recurrent Malignant Glioma

12-feb-2018 | Revista: Journal of Clinical Oncology

Lang FF (1), Conrad C (1), Gomez-Manzano C (1), Yung WKA (1), Sawaya R (1), Weinberg JS (1), Prabhu SS (1), Rao G (1), Fuller GN (1), Aldape KD (1), Gumin J (1), Vence LM (1), Wistuba I (1), Rodriguez-Canales J (1), Villalobos PA (1), Dirven CMF (1), Tejada S (1), Valle RD (1), Alonso MM (1), Ewald B (1), Peterkin JJ (1), Tufaro F (1), Fueyo J (1).

(1) Frederick F. Lang, Charles Conrad, Candelaria Gomez-Manzano, W.K. Alfred Yung, Raymond Sawaya, Jeffrey S. Weinberg, Sujit S. Prabhu, Ganesh Rao, Gregory N. Fuller, Kenneth D. Aldape, Joy Gumin, Luis M. Vence, Ignacio Wistuba, Jaime Rodriguez-Canales, Pamela A. Villalobos, and Juan Fueyo, The University of Texas MD Anderson Cancer Center; Brett Ewald, Joanna J. Peterkin, and Frank Tufaro, DNAtrix, Houston, TX; Clemens M.F. Dirven, Erasmus University Medical Center, Rotterdam, the Netherlands; and Sonia Tejada, Ricardo D. Valle, and Marta M. Alonso, Clínica Universidad de Navarra, Pamplona, Spain.


RESUMEN

Purpose
DNX-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.

Methods
A 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.

Results
In 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.

Conclusion
Treatment 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.

CITA DEL ARTÍCULO  J Clin Oncol. 2018 Feb 12:JCO2017758219. doi: 10.1200/JCO.2017.75.8219

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