Abstract 704: Therapeutic potential of Delta24-ACT, a novel immunostimulatory oncolytic adenovirus, for the treatment of pediatric solid tumors: Initial study in pHGG, DIPG and osteosarcoma

Abstract

Abstract Pediatric High Grade Glioma (pHGG), including Diffuse Intrinsic Pontine Glioma (DIPG), and osteosarcoma are amongst the most common and lethal pediatric solid tumors. Despite improvements in surgery, radiotherapy and chemotherapy, the outcome for children affected with these malignancies remains dismal since the current treatments are ineffective and inflict severe side effects. Thus, it is critical to implement novel and radically different therapeutic approaches to improve the survival and quality of life of these children. Delta24 is a modified adenovirus with a tumor dependent replication, and its antitumor effect has been tested in preclinical and clinical models of both high grade glioma and osteosarcoma. The adenovirus destroys the tumor mass as it replicates within the tumor. Additionally, the adenovirus infection triggers the recruitment of lymphocytes to the tumor. However, tumors are often characterized by an immunosuppressive environment that hampers the synergistic effect mediated by the virus and the immune system. Here we describe the generation of a new oncolytic adenovirus Delta24-ACT, based on the Delta24 platform, encoding an immunostimulatory protein. For this project we used relevant immunocompetent pediatric solid models. The toxicity of the virus was assessed by dose-escalation experiments. Delta24-ACT was well tolerated and did not lead to important adverse effects. The antitumor effect of Delta24-ACT was evaluated in immunocompetent mice bearing orthotopic supratentorial glioma, DIPG or local osteosarcoma that spontaneously metastasize to lungs, obtaining significant tumor shrinkage or complete elimination in some of them. Delta24-ACT also promoted an increased T-cell infiltration within the tumor and an enhanced antitumor immune response. Of importance, treatment with Delta24-ACT led to a significant increase in median survival in all the tumor models tested and resulted in long-term survivors free of disease. Furthermore, in our osteosarcoma model local treatment of primary tumors led to the regression of spontaneous lung metastases, which are usually the leading cause of death in most of the patients affected by osteosarcoma. Currently, we are performing re-challenge experiments to evaluate a possible memory effect mediated by the virus and mechanistic studies to elucidate the mechanism of action. Altogether, these results demonstrate the potential therapeutic benefit of Delta24-ACT adenovirus in the treatment of pediatric solid tumors such as pHGG, DIPG and osteosarcoma, representing an important milestone in the fight against cancer. Citation Format: Marc Garcia Moure, Naiara Martínez-Vélez, Enric Xipell, Marisol González-Huarriz, Ana Patiño, Oren J. Becher, Cande Gómez-Manzano, Juan Fueyo, Marta M. Alonso. Therapeutic potential of Delta24-ACT, a novel immunostimulatory oncolytic adenovirus, for the treatment of pediatric solid tumors: Initial study in pHGG, DIPG and osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 704. doi:10.1158/1538-7445.AM2017-704