Dottorato in INNOVATION IN IMMUNO-MEDIATED AND HEMATOLOGICAL DISORDERS

Titolo della tesi: Novel approach for treatment of Pediatric High-Grade gliomas through the combination of oncolytic adenoviruses and gene therapy encoding a BiTE directed to the EphA2 tumor

Pediatric high-grade gliomas (pHGGs) are amongst the most common and incurable malignant neoplasms of childhood. To develop an effective treatment, we aimed at improving the suboptimal antitumor efficacy of Oncolytic Adenoviruses (OA) by testing the combination with a gene-therapy approach using a Bispecific-T-cell-Engager (BiTE) directed towards the erythropoietin-producing, human-hepatocellular-carcinoma-A2-receptor (EphA2), conveyed by a replication-incompetent adenoviral vector (EAd). After confirming the relevance of EphA2 as target, documenting a significant correlation with worse clinical outcome, we showed that the proposed strategy provides significant EphA2-BiTE amplification and enhanced tumor cell apoptosis, upon co-culture with T-cells. Moreover, T-cell activation through an agonistic anti-CD28 antibody further increased the activation/proliferation profile and functional response against infected tumor cells, inducing eradication of highly resistant, primary pHGG cells. These in vitro observations translated into significant tumor control in vivo, in both subcutaneous and a more challenging orthotopic model, thus supporting the clinical translation of the approach.