Oncolytic adenovirus and gene therapy with EphA2-BiTE for the treatment of pediatric high-grade gliomas

Claudia Manuela Arnone, Vinicia Assunta Polito, Angela Mastronuzzi, Andrea Carai, Francesca Camassei Diomedi, Laura Antonucci, Lucia Lisa Petrilli, Maria Vinci, Francesco Ferrari, Elisa Salviato, Marco Scarsella, Cristiano De Stefanis, Gerrit Weber, Concetta Quintarelli, Biagio De Angelis, Malcolm K. Brenner, Stephen Gottschalk, Valentina Hoyos, Franco Locatelli, Ignazio CaruanaFrancesca Del Bufalo

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Article numbere001930
JournalJournal for immunotherapy of cancer
Volume9
Issue number5
DOIs
StatePublished - May 7 2021

Keywords

  • antibodies
  • brain neoplasms
  • neoplasm
  • oncolytic virotherapy
  • pediatrics
  • translational medical research

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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