Abstract 3117: Delta-24-RGD/DNX-2401: Oncolytic virotherapy for pediatric high grade glioma and DIPG
Authors: Martinez-Velez Naiara , Garcia-Moure Marc , Laspidea Virginia , Varela Maider , Becher Oren , Gomez-Manzano Candelaria , Fueyo Juan , Patiño Ana , Diez-Valle Ricardo , Tejada-Solis Sonia , Alonso Marta M. 
Published: August 2019

Abstract
Pediatric High Grade Glioma (pHGG), including Diffuse Intrinsic Pontine Glioma (DIPG) are the most common and aggressive pediatric brain tumor. Despite great strides in the knowledge of their genetic make-up and new therapies, the outcome for children affected with these malignancies remains dismal. Therefore, it is critical to implement new therapeutic approaches that improve the survival and quality of life of these kids. Delta-24-RGD (DNX-2401 in the clinic), is a tumor specific oncolytic adenovirus that has been tested in preclinical and clinical studies in adult high grade glioma, demonstrating its safe profile and certain degree of efficacy. The objective of this work was to evaluate the safety and the antitumor effect of DNX-2401 in pHGG and DIPGs. Delta-24-RGD showed a potent antitumor effect in a battery of pHGG (N=5) and DIPGs (N=6) cell lines (IC50 ranging from 1 to 50 MOIs) that was mediated by an effective replication. Moreover, Delta-24-RGD administration to mice bearing pHGG and DIPG tumors resulted in a significantly increase in the overall survival, and in some cases leading to 50% of long-term survivors. Clinical trials with DNX-2401 have shown that the immune response triggered in a subset of glioma patients is the responsible for the durable responses observed. Therefore, we assessed viral efficacy in two immunocompetent models bearing mice DIPG tumors. Delta-24-RGD, administered in mice brainstem, was well tolerated and no signs of toxicity were observed. Importantly, Delta-24-RGD treatment resulted in a significant survival benefit in immunocompent DIPG orthotopic models. Tumor examination showed that Delta-24-RGD also promoted an increase in T-cell infiltration (CD3+, CD4+ and CD8+; p&lt;0.001) within the tumor. mRNA expression levels of IFNg, CD8a and CD4 were also increased in treated tumors (p&lt;0.001). In addition, esplenocytes from Delta-24-RGD treated mice significantly increase the IFNg production (p&lt;0.0001) when were co-cultured with DIPG tumor cells. In summary, Delta-24-RGD administration triggers an immune response against DIPG tumors These encouraging preclinical results allowed us to propose a phase 1 clinical trial for naïve DIPGs to evaluate the safety and feasibility of injecting this virus into the pons (NCT03178032). DIPG patients undergo a tumor biopsy and immediately after DNX-2401 is infused intratumorally, using the same biopsy route. Up to date 6 patients have been treated with the virus (with up to 3x1010 viral particles in 1mL). The biopsy and the virus injection were well tolerated by the patients and they were home 3 to 4 days after the surgery. In the next months will have more information regarding the possible effect of the virus. We believe that the information acquired through this study could serve to develop or improve new therapies in the battle against DIPG and constitute a paradigm change in the treatment of this devastating tumor.
Citation Format: Naiara Martinez-Velez, Marc Garcia-Moure, Virginia Laspidea, Maider Varela, Oren Becher, Candelaria Gomez-Manzano, Juan Fueyo, Ana Patiño, Ricardo Diez-Valle, Sonia Tejada-Solis, Marta M. Alonso. Delta-24-RGD/DNX-2401: Oncolytic virotherapy for pediatric high grade glioma and DIPG [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3117.