Becher, O.J. (Oren J.)

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20192

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    The oncolytic virus Delta-24-RGD elicits an antitumor effect in pediatric glioma and DIPG mouse models
    (Springer Science and Business Media LLC, 2019) Mackay, A. (Alan); Patiño-García, A. (Ana); Aldave, G. (Guillermo); Alonso-Roldán, M.M. (Marta María); El-Habr, E. (Elías); Gomez-Manzano, C. (Candelaria); Chneiweiss, H. (Hervé); Zalacain, M. (Marta); Martinez-Velez, N. (Naiara); Marigil, M. (Miguel); Raabe, E. (Eric); Aristu-Mendioroz, J.J. (José Javier); García-Barchino, M.J. (María José); Martinez-Climent, J.A. (José Ángel); Gonzalez-Huarriz, M. (Marisol); Tejada-Solis, S. (Sonia); Monje, M. (Michelle); Marrodán, L. (Lucía); Ramos, L.I. (Luis Isaac); Diez-Valle, R. (Ricardo); Garcia-Moure, M. (Marc); Junier, M.P. (Marie Pierre); Varela-Guruceaga, M. (Maider); Puigdelloses-Vallcorba, M. (Montserrat); Laspidea, V. (Virginia); Fueyo, J. (Juan); Gallego-Perez-Larraya, J. (Jaime); Becher, O.J. (Oren J.); Jiang, H. (Hong); Jones, C. (Chris)
    Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors in desperate need of a curative treatment. Oncolytic virotherapy is emerging as a solid therapeutic approach. Delta-24-RGD is a replication competent adenovirus engineered to replicate in tumor cells with an aberrant RB pathway. This virus has proven to be safe and effective in adult gliomas. Here we report that the administration of Delta-24-RGD is safe in mice and results in a significant increase in survival in immunodeficient and immunocompetent models of pHGG and DIPGs. Our results show that the Delta-24-RGD antiglioma effect is mediated by the oncolytic effect and the immune response elicited against the tumor. Altogether, our data highlight the potential of this virus as treatment for patients with these tumors. Of clinical significance, these data have led to the start of a phase I/II clinical trial at our institution for newly diagnosed DIPG (NCT03178032).
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    Delta-24-RGD combined with radiotherapy exerts a potent antitumor effect in diffuse intrinsic pontine glioma and pediatric high grade glioma models
    (Springer Science and Business Media LLC, 2019) Patiño-García, A. (Ana); Alonso-Roldán, M.M. (Marta María); Gomez-Manzano, C. (Candelaria); Martinez-Velez, N. (Naiara); Marigil, M. (Miguel); Aristu-Mendioroz, J.J. (José Javier); Gonzalez-Huarriz, M. (Marisol); Tejada-Solis, S. (Sonia); Ramos, L.I. (Luis Isaac); Diez-Valle, R. (Ricardo); Garcia-Moure, M. (Marc); Fueyo, J. (Juan); Becher, O.J. (Oren J.)
    Pediatric high grade gliomas (pHGG), including diffuse intrinsic pontine gliomas (DIPGs), are aggressive tumors with a dismal outcome. Radiotherapy (RT) is part of the standard of care of these tumors; however, radiotherapy only leads to a transient clinical improvement. Delta-24-RGD is a genetically engineered tumor-selective adenovirus that has shown safety and clinical efficacy in adults with recurrent gliomas. In this work, we evaluated the feasibility, safety and therapeutic efficacy of Delta-24-RGD in combination with radiotherapy in pHGGs and DIPGs models. Our results showed that the combination of Delta-24-RGD with radiotherapy was feasible and resulted in a synergistic anti-glioma effect in vitro and in vivo in pHGG and DIPG models. Interestingly, Delta-24-RGD treatment led to the downregulation of relevant DNA damage repair proteins, further sensitizing tumors cells to the effect of radiotherapy. Additionally, Delta-24-RGD/radiotherapy treatment significantly increased the trafficking of immune cells (CD3, CD4+ and CD8+) to the tumor niche compared with single treatments. In summary, administration of the Delta-24-RGD/radiotherapy combination to pHGG and DIPG models is safe and significantly increases the overall survival of mice bearing these tumors. Our data offer a rationale for the combination Delta-24-RGD/radiotherapy as a therapeutic option for children with these tumors. SIGNIFICANCE: Delta-24-RGD/radiotherapy administration is safe and significantly increases the survival of treated mice. These positive data underscore the urge to translate this approach to the clinical treatment of children with pHGG and DIPGs.