ATRT-03. EFFICACY OF THE ONCOLYTIC ADENOVIRUS DELTA-24-RGD AS A THERAPEUTIC AGENT FOR THE TREATMENT OF PEDIATRIC EMBRYONAL BRAIN TUMORS

ABSTRACT: Abstract Atypical teratoid/rhabdoid tumors (ATRTs) and primitive neuroectodermal tumors (PNETs) are two rare primary embryonal brain tumors, which are among the most frequent solid brain tumors in infants under one year old. The outcome for these children remains dismal, especially in ATRTs which have a 2-year overall survival below 20%. Therefore, we need to find out new efficient and safe therapeutic options for these children. Delta-24-RGD (DNX-2401 in the clinic) is an oncolytic adenovirus that has already been tested in Phase I/II clinical trials in patients affected by recurrent glioblastoma (NCT00805376; NCT01956734), demonstrating anti-tumor effect without any evidence of severe side effect associated with viral administration. Of interest for pediatric brain tumors, an ongoing Phase I trial using Delta-24-RGD for the treatment of diffuse intrinsic pontine gliomas (NCT03178032) has also demonstrated a safe profile in these children. For these reasons, we propose to evaluate the anti-tumor effect of Delta-24-RGD in preclinical models of ATRT and PNET. The virus was able to infect and replicate in tumor cell cultures (three models of ATRT and four of PNET), inducing a potent cytotoxic effect. In addition, this cytotoxicity resulted in the released the immunogenic cell death markers Hsp70, Hsp90, HMGB1 and ATP, as well as an increased calreticulin exposure in the outer cell surface. Although not conclusive, the presence of these markers suggest the triggering of an anti-tumor immune response. Intratumoral administration of the virus extended significantly the overall survival of mice bearing ATRT or PNET xenografts, leading to up to 40% of long-term survivors. We are currently setting up an intraventricular model of disseminated disease, since most of patients with ATRT actually die due to the presence of metastases. In conclusion, these results demonstrate that Delta-24-RGD could be a feasible therapeutic option for children with PNETs and AT/RTs.

SUBMITTER: Garcia-Moure M 

PROVIDER: S-EPMC6477196 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature