Delta-24-RGD, an Oncolytic Adenovirus, Increases Survival and Promotes Proinflammatory Immune Landscape Remodeling in Models of AT/RT and CNS-PNET

• Published in: Clinical cancer research 2021-03, Vol.27 (6), p.1807
• Main Authors: Garcia-Moure, Marc, Gonzalez-Huarriz, Marisol, Labiano, Sara, Guruceaga, Elizabeth, Bandres, Eva, Zalacain, Marta, Marrodan, Lucia, de Andrea, Carlos, Villalba, Maria, Martinez-Velez, Naiara, Laspidea, Virginia, Puigdelloses, Montse, Gallego Perez-Larraya, Jaime, Iñigo-Marco, Ignacio, Stripecke, Renata, Chan, Jennifer A, Raabe, Eric H, Kool, Marcel, Gomez-Manzano, Candelaria, Fueyo, Juan, Patiño-García, Ana, Alonso, Marta M
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Cell Proliferation; Central Nervous System Neoplasms - immunology; Central Nervous System Neoplasms - mortality; Central Nervous System Neoplasms - pathology; Central Nervous System Neoplasms - therapy; Female; Humans; Immunity, Cellular; Mice; Mice, Inbred C57BL; Mice, Nude; Neuroectodermal Tumors, Primitive - immunology; Neuroectodermal Tumors, Primitive - mortality; Neuroectodermal Tumors, Primitive - pathology; Neuroectodermal Tumors, Primitive - therapy; Oligopeptides - genetics; Oncolytic Virotherapy - methods; Oncolytic Viruses - genetics; Rhabdoid Tumor - immunology; Rhabdoid Tumor - mortality; Rhabdoid Tumor - pathology; Rhabdoid Tumor - therapy; Teratoma - immunology; Teratoma - mortality; Teratoma - pathology; Teratoma - therapy; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-20-3313

Atypical teratoid/rhabdoid tumors (AT/RT) and central nervous system primitive neuroectodermal tumors (CNS-PNET) are pediatric brain tumors with poor survival and life-long negative side effects. Here, the aim was to characterize the efficacy and safety of the oncolytic adenovirus, Delta-24-RGD, which selectively replicates in and kills tumor cells. Delta-24-RGD determinants for infection and replication were evaluated in patient expression datasets. Viral replication and cytotoxicity were assessed in a battery of CNS-PNET and AT/RT cell lines. , efficacy was determined in different orthotopic mouse models, including early and established tumor models, a disseminated AT/RT lesion model, and immunocompetent humanized mouse models (hCD34 -NSG-SGM3). Delta-24-RGD infected and replicated efficiently in all the cell lines tested. In addition, the virus induced dose-dependent cytotoxicity [IC value below 1 plaque-forming unit (PFU)/cell] and the release of immunogenic markers. , a single intratumoral Delta-24-RGD injection (10 or 10 PFU) significantly increased survival and led to long-term survival in AT/RT and PNET models. Delta-24-RGD hindered the dissemination of AT/RTs and increased survival, leading to 70% of long-term survivors. Of relevance, viral administration to established tumor masses (30 days after engraftment) showed therapeutic benefit. In humanized immunocompetent models, Delta-24-RGD significantly extended the survival of mice bearing AT/RTs or PNETs (ranging from 11 to 27 days) and did not display any toxicity associated with inflammation. Immunophenotyping of Delta-24-RGD-treated tumors revealed increased CD8 T-cell infiltration. Delta-24-RGD is a feasible therapeutic option for AT/RTs and CNS-PNETs. This work constitutes the basis for potential translation to the clinical setting.