Oncolytic adenovirus and gene therapy with EphA2-BiTE for the treatment of pediatric high-grade gliomas. Issue 5 (7th May 2021)

• Record Type: Journal Article
• Authors: Arnone, Claudia Manuela; Polito, Vinicia Assunta; Mastronuzzi, Angela; Carai, Andrea; Diomedi, Francesca Camassei; Antonucci, Laura; Petrilli, Lucia Lisa; Vinci, Maria; Ferrari, Francesco; Salviato, Elisa; Scarsella, Marco; De Stefanis, Cristiano; Weber, Gerrit; Quintarelli, Concetta; De Angelis, Biagio; Brenner, Malcolm K; Gottschalk, Stephen; Hoyos, Valentina; Locatelli, Franco; Caruana, Ignazio; Del Bufalo, Francesca
• Is Part Of: Journal for immunotherapy of cancer. Volume 9:Issue 5(2021)
• Publication Date: 2021-05-07
• Subjects: pediatrics -- brain neoplasms -- oncolytic virotherapy -- antibodies -- neoplasm -- translational medical research; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2020-001930
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : Background: Pediatric high-grade gliomas (pHGGs) are among the most common and incurable malignant neoplasms of childhood. Despite aggressive, multimodal treatment, the outcome of children with high-grade gliomas has not significantly improved over the past decades, prompting the development of innovative approaches. Methods: To develop an effective treatment, we aimed at improving the suboptimal antitumor efficacy of oncolytic adenoviruses (OAs) 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 (EphA2 adenovirus (EAd)). The combinatorial approach was tested in vitro, in vivo and thoroughly characterized at a molecular level. Results: After confirming the relevance of EphA2 as target in pHGGs, documenting a significant correlation with worse clinical outcome of the patients, we showed that the proposed strategy provides significant EphA2-BiTE amplification and enhanced tumor cell apoptosis, on coculture with T cells. Moreover, T-cell activation through an agonistic anti-CD28 antibody further increased the activation/proliferation profiles and functional response against infected tumor cells, inducing eradication of highly resistant, primary pHGG cells. The gene-expression analysis of tumor cells and T cells, after coculture, revealed the importance of both EphA2-BiTE and costimulation in the proposed system. These in vitro observations translated into significant tumor control in vivo, in both subcutaneous and a more challenging orthotopic model. Conclusions: The combination of OA and EphA2-BiTE gene therapy strongly enhances the antitumor activity of OA, inducing the eradication of highly resistant tumor cells, thus supporting the clinical translation of the approach.