RT Journal Article
SR Electronic
T1 Oncolytic adenovirus and gene therapy with EphA2-BiTE for the treatment of pediatric high-grade gliomas
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e001930
DO 10.1136/jitc-2020-001930
VO 9
IS 5
A1 Arnone, Claudia Manuela
A1 Polito, Vinicia Assunta
A1 Mastronuzzi, Angela
A1 Carai, Andrea
A1 Diomedi, Francesca Camassei
A1 Antonucci, Laura
A1 Petrilli, Lucia Lisa
A1 Vinci, Maria
A1 Ferrari, Francesco
A1 Salviato, Elisa
A1 Scarsella, Marco
A1 De Stefanis, Cristiano
A1 Weber, Gerrit
A1 Quintarelli, Concetta
A1 De Angelis, Biagio
A1 Brenner, Malcolm K
A1 Gottschalk, Stephen
A1 Hoyos, Valentina
A1 Locatelli, Franco
A1 Caruana, Ignazio
A1 Del Bufalo, Francesca
YR 2021
UL http://jitc.bmj.com/content/9/5/e001930.abstract
AB 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.Data are available upon reasonable request.